This interaction has not been studied. Based on the different elimination pathways of the other NRTIs zidovudine, emtricitabine, stavudine, lamivudine, that are primarily renally excreted, and abacavir for which metabolism is not mediated by CYP450, no interactions are expected for these medicinal compounds and darunavir coadministered with low dose ritonavir.
Prezista Summary of Product Characteristics, Janssen-Cilag Ltd, June 2012.

Based on the different elimination pathways of the NRTIs (zidovudine, zalcitabine, emtricitabine, stavudine, lamivudine and abacavir) that are primarily renally excreted, no drug interactions are expected for these drugs and darunavir/ritonavir.
Prezista Prescribing Information, Tibotec Inc, June 2012.

The steady-state plasma pharmacokinetics of abacavir (600 mg once daily) were investigated when co-administered with darunavir/ritonavir (900/100 mg once daily) to 19 HIV+ subjects. Abacavir AUC, Cmax and Cmin decreased by 27%, 22% and 38%, respectively in the presence of darunavir/ritonavir. It is important to relate the change in plasma abacavir exposure to the active intracellular carbovir triphosphate and a study is in progress.
Pharmacokinetics (PK) of plasma abacavir (ABC) in the absence and in the presence of darunavir/ritonavir (DRV/r) or raltegravir (RAL) in HIV-infected subjects. Jackson A, Gedela K, Dickinson L, et al. 12th European AIDS Conference (EACS), Cologne, November 2009, abstract PE4.3/2.

Acetazolamide is fairly rapidly absorbed from the gastro-intestinal tract with peak plasma concentrations occurring about 2 hours after administration by mouth. It has been estimated to have a plasma half-life of about 4 hours. It is tightly bound to carbonic anhydrase and accumulates in tissues containing this enzyme, particularly red blood cells and the renal cortex. It is also bound to plasma proteins. It is excreted unchanged in the urine; renal clearance being enhanced in alkaline urine.
Diamox® (Acetazolamide) Tablets 250mg UK Summary of Product Characteristics, Mercury Pharma Group, updated November 2011

Acetazolamide is excreted unchanged by the kidneys via tubular secretion and passive reabsorption. After administration of the oral tablets or after IV injection, 70–100% (average 90%) of the dose is excreted in urine within 24 hours; 47% of the dose is excreted within 24 hours following administration of the extended-release capsules.
AHFS Drug Information, published by the American Society of Health-System Pharmacists Inc, January 2009

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In a sequential pharmacokinetic study, healthy male volunteers (n=8) were administered a single oral dose of 400 mg albendazole, in absence and after short-term (2 doses) and long-term (8 days) treatment with ritonavir 200 mg twice daily. Pharmacokinetic parameters of albendazole and  its metabolite albendazole sulfoxide, were not changed by short-term administration of ritonavir. However long-term administration resulted in significant changes in albendazole disposition, with a significant decrease in albendazole and albendazole sulfoxide AUC0-24 (73% and 59% respectively) and Cmax (74% and 48% respectively). Tmax and the terminal half-life were not significantly changed. The observation is most likely due to a ritonavir-mediated induction of metabolising enzymes (CYP2C9, CYP1A2, UGTs) or transporters, although changes in absorption are also possible. These findings need to be replicated with a key boosted PI such as lopinavir/ritonavir. 
Effect of ritonavir on the pharmacokinetics of the benzimidazoles albendazole and mebendazole: an interaction study in healthy volunteers. Corti N, Heck A, Rentsch K, et al.Eur J Clin Pharmacol. 2009;65:999-1006.

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LHPG Comment: Note the difference in recommendations between the European SPC (contraindicated) and the US Prescribing Information (caution). The charts reflect the more cautious option.

Coadministration of darunavir with low dose ritonavir with active substances that are highly dependent on CYP3A for clearance and for which increased systemic exposure is associated with serious and/or life-threatening events (narrow therapeutic index) is contraindicated. These medicinal products include amiodarone.
Prezista Summary of Product Characteristics, Janssen-Cilag Ltd, June 2012.

Concentrations of amiodarone may be increased when co-administered with darunavir/ritonavir. Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when co-administered with darunavir/ritonavir.
Prezista Prescribing Information, Tibotec Inc, June 2012.

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Ampicillin is excreted mainly in the bile and urine with a plasma half life of 1-2 hours.
Penbritin® (ampicillin) UK Summary of Product Characteristics, Chemidex Pharma Ltd. Updated February 2009

Ampicillin is metabolised to some extent to penicilloic acid which is excreted in the urine. Renal clearance of ampicillin occurs partly by glomerular filtration and partly by tubular secretion; it is reduced by probenecid. About 20 to 40% of an oral dose may be excreted unchanged in the urine in 6 hours; urinary concentrations have ranged from 0.25 to 1 mg/mL after a dose of 500 mg. After parenteral use about 60 to 80% is excreted in the urine within 6 hours.
Martindale Complete Drug Reference. Pharmaceutical Press (via Medicines Complete), latest modification: 20-August-2010

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LHPG Comment: Artemisinin, and its derivatives such as artesunate and artemether, are rapidly metabolized via CYP3A4 to a biologically active metabolite, dihydroartemisinin (the metabolism of artesunate is so rapid that it may be considered a pro-drug for dihydroartemisinin). Although the parent drugs and dihydroartemisinin all have antimalarial activity, dihydroartemisinin has greater potency than the parent drugs. Inhibition of CYP3A4 would reduce dihydroartemisinin, but increase concentrations of the parent drug and potentially increase the half life of the parent drug. The effects of protease inhibitors and non-nucleoside reverse transcriptase inhibitors are unclear.

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Coadministration of darunavir with low dose ritonavir with active substances that are highly dependent on CYP3A for clearance and for which increased systemic exposure is associated with serious and/or life-threatening events (narrow therapeutic index) is contraindicated. These medicinal products include astemizole.
Prezista Summary of Product Characteristics, Janssen-Cilag Ltd, June 2012.

Coadministration of atorvastatin (10 mg once daily) and darunavir/ritonavir (at a dose lower than recommended or with a different dosing regimen) increased atorvastatin AUC by 3-4-fold, increase Cmin by ~5.5-10-fold and increased Cmax by ~2-fold. When administration of atorvastatin and darunavir coadministered with low dose ritonavir is desired, it is recommended to start with an atorvastatin dose of 10 mg once daily. A gradual dose increase of atorvastatin may be tailored to the clinical response.
Prezista Summary of Product Characteristics, Janssen-Cilag Ltd, June 2012.

Coadministration of atorvastatin (10 mg once daily) and darunavir/ritonavir (300/100 mg twice daily) was studied in 15 subjects. When compared to values obtained with atorvastatin alone (40 mg once daily), atorvastatin Cmax and AUC increased by 44% and 15%, respectively and Cmin increased by 81%. Titrate atorvastatin dose carefully and use the lowest necessary dose while monitoring for safety. Do not exceed atorvastatin 20 mg/day.
Prezista Prescribing Information, Tibotec Inc, June 2012.

Systemic use: Atropine is metabolised in the liver by oxidation and conjugation to give inactive metabolites. About 50% of the dose is excreted within 4 hours and 90% in 24 hours in the urine, about 30 to 50% as unchanged drug.
Atropine Injection BP Minijet UK Summary of Product Characteristics, International Medication Systems (UK) Ltd, updated October 2005

Ocular use: Atropine is also absorbed by mucous membranes but less readily from the eye and skin, although significant toxicity can sometimes occur through absorption of excessive eye drops. Atropine is metabolised by hepatic oxidation and conjugation to inactive metabolites, with about 2% undergoing hydrolysis to tropine and tropic acid. About 30% of the dose is excreted unchanged in the urine. Only trace amounts of the dose are eliminated in the faeces.
Minims Atropine Sulphate 1%, Eye drops solution UK Summary of Product Characteristics, Bausch & Lomb U.K Limited, updated July 2012

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LHPG Comment: Note the difference in recommendations between the European SPC (contraindicated) and the US Prescribing Information (caution). The charts reflect the more cautious option.

Coadministration of darunavir with low dose ritonavir with active substances that are highly dependent on CYP3A for clearance and for which increased systemic exposure is associated with serious and/or life-threatening events (narrow therapeutic index) is contraindicated. These medicinal products include bepridil.
Prezista Summary of Product Characteristics, Janssen-Cilag Ltd, June 2012.

Concentrations of bepridil may be increased when co-administered with darunavir/ritonavir. Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when co-administered with darunavir/ritonavir.
Prezista Prescribing Information, Tibotec Inc, June 2012.

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A drug-drug interaction study assessing the effect of ketoconazole, a potent CYP3A4 inhibitor, on bortezomib showed a mean bortezomib AUC increase of 35% (CI 90% 1.032 to 1.772) based on data from 12 patients. Therefore, patients should be closely monitored when given bortezomib in combination with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir).
Velcade Summary of Product Characteristics, Janssen-Cilag Ltd, September 2012.

Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Monitor patients for signs of bortezomib toxicity and consider a bortezomib dose reduction if bortezomib must be given in combination with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir).
Velcade Prescribing Information, Millennium Pharmaceuticals Inc, October 2012.

Coadministration has not been studied. Concomitant use of bosentan and darunavir co-administered with low dose ritonavir may increase plasma concentrations of bosentan. When administered concomitantly with darunavir and low dose ritonavir, the patient's tolerability of bosentan should be monitored.
Prezista Summary of Product Characteristics, Janssen-Cilag Ltd, June 2012.

Coadminsitration may increase bosentan concentrations. In patients who have been receiving darunavir/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. In patients on bosentan, discontinue use of bosentan at least 36 hours prior to initiation of darunavir/ritonavir. After at least 10 days following the initiation of darunavir/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Prezista Prescribing Information, Tibotec Inc, June 2012.

In a clinical study where ritonavir 100 mg capsules twice daily were coadministered with 50 µg intranasal fluticasone propionate (4 times daily) for 7 days in healthy subjects, fluticasone propionate plasma concentrations increased significantly, whereas the intrinsic cortisol levels decreased by approximately 86% (90% CI 82 to 89%). Greater effects may be expected when fluticasone propionate is inhaled. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate; this could also occur with other corticosteroids metabolised via the P450 3A pathway e.g. budesonide. Consequently, concomitant administration of darunavir, coadministered with low dose ritonavir and these glucocorticoids, is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. A dose reduction of the glucocorticoid should be considered with close monitoring of local and systemic effects or a switch to a glucocorticoid, which is not a substrate for CYP3A4 (e.g. beclomethasone). Moreover, in case of withdrawal of glucocorticoids progressive dose reduction may have to be performed over a longer period. The effects of high fluticasone systemic exposure on ritonavir plasma levels are as yet unknown.
Prezista Summary of Product Characteristics, Janssen-Cilag Ltd, June 2012.

Bupivacaine is extensively metabolised in the liver, predominately by aromatic hydroxylation to 4-hydroxy-bupivacaine and N-dealkylation to PPX, both mediated by cytochrome P4503A4. About 1% of bupivacaine is excreted in the urine as unchanged drug in 24 h and approximately 5% as PPX. The plasma concentrations of PPX and 4-hydroxy-bupivacaine during and after continuous administration of bupivacaine are low as compared to the parent drug.
Marcain® Polyamp Steripack 0.25% and 0.5% UK Summary of Product Characteristics, AstraZeneca UK Limited, updated May 2012

Coadministration of buprenorphine/naloxone (8/2 mg to 16/4 mg once daily) and darunavir/ritonavir decreased buprenorphine AUC and Cmax by 11% and 8%, respectively, with no change in Cmin. AUC, Cmax and Cmin of norbuprenorphine increased by 46%, 36% and 71%, respectively. There was no change in naloxone AUC or Cmax. The clinical relevance of the increase in norbuprenorphine pharmacokinetic parameters has not been established. Dose adjustment for buprenorphine may not be necessary when coadministered with darunavir/ritonavir but a careful clinical monitoring for signs of opiate toxicity is recommended.
Prezista Summary of Product Characteristics, Janssen-Cilag Ltd, June 2012.

Coadministration of buprenorphine/naloxone (8/2 to 16/4 mg once daily) and darunavir/ritonavir (600/100 mg twice daily) decreased buprenorphine AUC, Cmax and Cmin by 11%, 8% and 2% respectively. AUC, Cmax and Cmin of norbuprenorphine increased by 46%, 36% and 71%, respectively. Naloxone AUC and Cmax were comparable when buprenorphine/naloxone was administered with or without darunavir/ritonavir. No dose adjustment for buprenorphine or buprenorphine/naloxone is required with concurrent administration of darunavir/ritonavir. Clinical monitoring is recommended if darunavir/ritonavir and buprenorphine or buprenorphine/naloxone are coadministered.
Prezista Prescribing Information, Tibotec Inc, June 2012.

When administered with a potent inhibitor of CYP3A4, a low dose of buspirone, used cautiously, is recommended. When used in combination with a potent inducer of CYP3A4, e.g. phenobarbital, phenytoin, carbamazepine, St. John's wort, an adjustment of the dosage of buspirone may be necessary to maintain buspirone’s anxiolytic effect.
Buspirone Summary of Product Characteristics, Actavis UK Ltd, August 2012.

Substances that inhibit CYP3A4, such as ketoconazole or ritonavir, may inhibit buspirone metabolism and increase plasma concentrations of buspirone while substances that induce CYP3A4, such as dexamethasone or certain anticonvulsants (phenytoin, phenobarbital, carbamazepine), may increase the rate of buspirone metabolism. If a patient has been titrated to a stable dosage on buspirone, a dose adjustment of buspirone may be necessary to avoid adverse events attributable to buspirone or diminished anxiolytic activity. Consequently, when administered with a potent inhibitor of CYP3A4, a low dose of buspirone used cautiously is recommended. When used in combination with a potent inducer of CYP3A4 the dosage of buspirone may need adjusting to maintain anxiolytic effect.
Buspar Prescribing Information, Bristol Myers Squibb, November 2010.

Coadministration of carbamazepine (200 mg twice daily) and darunavir/ritonavir increased carbamazepine AUC, Cmax and Cmin by 45%, 43% and 54%, respectively. There was no change in darunavir AUC or Cmax, but Cmin decreased by 15%. No dose adjustment for darunavir/ritonavir is recommended. If there is a need to combine darunavir/ritonavir and carbamazepine, patients should be monitored for potential carbamazepine related adverse events. Carbamazepine concentrations should be monitored and its dose should be titrated for adequate response. Based upon the findings, patients should be monitored for potential carbamazepine related adverse events. Based upon the findings, the carbamazepine dose may need to be reduced by 25% to 50% in the presence of darunavir/ritonavir.
Prezista Summary of Product Characteristics, Janssen-Cilag Ltd, June 2012.

Coadministration of carbamazepine (200 mg twice daily) and darunavir/ritonavir (600/100 mg twice daily) was studied in 16 subjects. There was no change in darunavir AUC; Cmax increased by 4% and Cmin decreased by 15%. The AUC, Cmax and Cmin of carbamazepine increased by 45%, 43% and 54%, respectively; carbamazepine epoxide AUC and Cmax decreased by 54% and Cmin decreased by 52%. The dose of either darunavir/ritonavir or carbamazepine does not need to be adjusted when initiating coadministration with darunavir/ritonavir and carbamazepine. Clinical monitoring of carbamazepine concentrations and its dose titration is recommended to achieve the desired clinical response.
Prezista Prescribing Information, Tibotec Inc, June 2012.

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Cefixime is predominantly eliminated as unchanged drug in the urine. Glomerular filtration is considered the predominant mechanism. Metabolites of cefixime have not been isolated from human serum or urine.
Suprax® tablets (Cefixime) Summary of Product Characteristics, Sanofi-Aventis, updated November 2010

Approximately 50% of the absorbed dose is excreted unchanged in the urine in 24 hours. In animal studies, it was noted that cefixime is also excreted in the bile in excess of 10% of the administered dose. There is no evidence of metabolism of cefixime in vivo.
Suprax® (cefixime) US Prescribing Information, Lupin Pharmaceuticals INC, updated November 2011

In vitro studies using human liver microsomes have suggested that cefixime neither inhibited nor induced the metabolism of probe substrates via activity of cytochrome P450 metabolic enzymes CYP1A1/2, CYP2A6, CYP2B6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4. Cefixime would not be expected to cause clinically significant interactions with other drugs, which are metabolized by CYP450 enzymes.
Effect of cefixime and cefdinir, oral cephalosporins, on cytochrome P450 activities in human hepatic microsomes. Niwa T, Shiraga T, Hashimoto T, Kagayama A. Biol Pharm Bull. 2004; 27: 97-9.

Approximately 20-36% of an intravenously administered dose of 14C-cefotaxime is excreted by the kidney as unchanged cefotaxime and 15-25% as the desacetyl derivative, the major metabolite. The desacetyl metabolite has been shown to contribute to the bactericidal activity. Two other urinary metabolites (M2 and M3) account for about 20-25%. They lack bactericidal activity.
Cefotaxime for injection US Prescribing Information, Pfizer Labs, updated December 2009

Cefotaxime is partially metabolised prior to excretion. The principal metabolite is the microbiologically active product, desacetyl-cefotaxime. Most of a dose of cefotaxime is excreted in the urine - about 60% as unchanged drug and a further 24% as desacetyl-cefotaxime. Plasma clearance is reported to be between 260 and 390ml/minute and renal clearance 145 to 217 ml/minute.
Probenecid interferes with renal tubular transfer of cefotaxime delaying its excretion and increasing the plasma concentration.
Cefotaxime for injection Summary of Product Characteristics, Wockhardt UK Ltd, updated August 2008

Ceftazidime is not metabolised in the body and is excreted unchanged in the active form into the urine by glomerular filtration. Approximately 80 to 90% of the dose is recovered in the urine within 24 hours. Less than 1% is excreted via the bile, significantly limiting the amount entering the bowel.
Fortum® 500 injection (ceftazidime) Summary of Product Characteristics, GlaxoSmithKline UK, updated August 2009

Approximately 80% to 90% of an IM or IV dose of ceftazidime is excreted unchanged by the kidneys over a 24-hour period. After the IV administration of single 500-mg or 1-g doses, approximately 50% of the dose appeared in the urine in the first 2 hours. An additional 20% was excreted between 2 and 4 hours after dosing, and approximately another 12% of the dose appeared in the urine between 4 and 8 hours later. The calculated plasma clearance of approximately 115 mL/min indicated nearly complete elimination of ceftazidime by the renal route. Administration of probenecid before dosing had no effect on the elimination kinetics of ceftazidime, suggesting that ceftazidime is eliminated by glomerular filtration and is not actively secreted by renal tubular mechanisms.
Fortaz® (ceftazidime for injection) US Prescribing Information, GlaxoSmithKline, updated August 2010

Ceftriaxone is eliminated mainly as unchanged drug; approximately 60% of the dose being excreted in the urine (almost exclusively by glomerular filtration) and the remainder via the biliary and intestinal tracts. The elimination of ceftriaxone is not altered by probenecid
Rocephin® (ceftriaxone) 250mg, 1g and 2g vials Summary of Product Characteristics, Roche Products Limited, updated May 2011

Thirty-three percent to 67% of a ceftriaxone dose was excreted in the urine as unchanged drug and the remainder was secreted in the bile and ultimately found in the feces as microbiologically inactive compounds. The elimination of ceftriaxone is not altered by co-administration with probenecid.
Rocephin® (ceftriaxone sodium) for injection, US Prescribing Information, Genentech USA, Inc, updated November 2010

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In vitro data indicate that CYP3A4 is the major enzyme involved in the metabolism of the active metabolite of ciclesonide M1 in man. In a drug-drug interaction study at steady state with ciclesonide and ketoconazole as a potent CYP3A4 inhibitor, the exposure to the active metabolite M1 increased approximately 3.5-fold, whereas the exposure to ciclesonide was not affected. Therefore the concomitant administration of potent inhibitors of CYP 3A4 (e.g. ketoconazole, itraconazole and ritonavir or nelfinavir) should be avoided unless the benefit outweighs the increased risk of systemic side effects of corticosteroids.
Alvesco Summary of Product Characteristics, Nycomed UK Ltd, February 2009.

This interaction has not been studied. Exposure to cyclosporine, tacrolimus, or sirolimus will be increased when coadministered with darunavir coadministered with low dose ritonavir. Therapeutic drug monitoring of the immunosuppressive agent must be done when coadministration occurs.
Prezista Summary of Product Characteristics, Janssen-Cilag Ltd, June 2012.

Plasma concentrations of cyclosporine, tacrolimus or sirolimus may be increased when co-administered with darunavir/ritonavir. Therapeutic concentration monitoring of the immunosuppressive agent is recommended for immunosuppressant agents when co-administered with darunavir/ritonavir.
Prezista Prescribing Information, Tibotec Inc, June 2012.

Based on results with ranitidine (no effect on darunavir AUC, Cmax or Cmin), darunavir coadministered with low dose ritonavir can be coadministered with H2 receptor antagonists without dose adjustments.
Prezista Summary of Product Characteristics, Janssen-Cilag Ltd, June 2012.

Coadministration of darunavir with low dose ritonavir with active substances that are highly dependent on CYP3A for clearance and for which increased systemic exposure is associated with serious and/or life-threatening events (narrow therapeutic index) is contraindicated. These medicinal products include cisapride.
Prezista Summary of Product Characteristics, Janssen-Cilag Ltd, June 2012.

Co-administration of darunavir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index). Coadministration with cisapride is contraindicated due to potential for serious and/or life threatening reactions such as cardiac arrhythmias.
Prezista Prescribing Information, Tibotec Inc, June 2012.

Coadministration of clarithromycin (500 mg twice daily) and darunavir/ritonavir (at a dose lower than recommended or with a different dosing regimen) increased clarithromycin AUC, Cmax and Cmin by 57%, 26% and 174%, respectively. Darunavir AUC and Cmax decreased by 13% and 17%, respectively; Cmin increased by 1%. Concentrations of the metabolite 14OH-clarithromycin were not detectable. when combined with darunavir/ritonavir. Darunavir/ritonavir increases the plasma concentrations of clarithromycin as a result of CYP3A4 inhibition and possible P-gp inhibition. Caution should be exercised when clarithromycin is combined with darunavir coadministered with low dose ritonavir.
Prezista Summary of Product Characteristics, Janssen-Cilag Ltd, June 2012.

Coadministration of clarithromycin (500 mg twice daily) and darunavir/ritonavir (400/100 mg twice daily) was studied in 17 subjects. There was no significant change in darunavir exposure and increased clarithromycin exposure. Darunavir Cmax and AUC decreased by 17% and 13%, respectively; Cmin increased by 1%. Clarithromycin Cmax, AUC and Cmin increased by 26%, 57% and 174%, respectively. No dose adjustment of darunavir or clarithromycin is required for patients with normal renal function. For patients with renal impairment, the following dose adjustments should be considered: for subjects with CLcr of 30-60 mL/min, the dose of clarithromycin should be reduced by 50%; for subjects with CLcr of <30 mL/min, the dose of clarithromycin should be reduced by 75%.
Prezista Prescribing Information, Tibotec Inc, June 2012.

Coadministration of a non-licensed dose of darunavir/ritonavir (400/100 mg twice daily) and clarithromycin (500 mg twice daily) was studied in 18 HIV- volunteers. Darunavir Cmax and AUC decreased by 17% and 13% respectively. Ritonavir Cmax and AUC were unchanged. Clarithromycin Cmax and AUC increased by 26% and 57%, respectively; 14-OH clarithromycin concentrations were reduced to below the lower limit of quantification (50 ng/ml).
Darunavir/ritonavir pharmacokinetics following coadministration with clarithromycin in healthy volunteers. Sekar VJ, Spinosa-Guzman S, De Paepe E, et al. J Clin Pharmacol, 2008, 48: 60-65.

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The impact of boosted antiretroviral therapies on the pharmacokinetics of clopidogrel and prasugrel active metabolites (AM) and on the efficacy of prasugrel and clopidogrel were evaluated in a randomized crossover study. A significantly lower exposure of clopidogrel AM (69% decrease) and prasugrel AM (52% decrease) were demonstrated in HIV-infected patients treated sequentially with a loading dose of clopidogrel (300 mg) and prasugrel (60 mg) while on a ritonavir- or cobicistat- containing antiretroviral regimen compared to healthy volunteers receiving only the corresponding antiplatelet agent. Of interest, the coadministration with ritonavir or cobicistat had a differential impact on clopidogrel and prasugrel pharmacodynamics effect. Treatment with clopidogrel resulted in adequate platelet inhibition in all healthy volunteers (no coadministration of ritonavir- or cobicistat-boosted regimens) while 44% of HIV-infected patients were shown to have insufficient platelet inhibition (coadministration with ritonavir- or cobicistat-boosted regimens). On the contrary, treatment with prasugrel resulted in a potent platelet inhibition in both healthy and HIV-infected subjects. The authors conclude that prasugrel remains an adequate antiplatelet agent in HIV-infected patients and could be preferred to clopidogrel in this context, regardless of the metabolic interaction and inhibition of its bioactivation pathways.
Impact of boosted antiretroviral therapy on the pharmacokinetics and efficacy of clopidogrel and prasugrel active metabolites. Marsousi N, Daali Y, Fontana P, et al. Clin Pharmacokinet, 2018 [epub ahead of print].

The impact of ritonavir on the pharmacokinetics of clopidogrel active metabolite (AM) and the pharmacodynamic effect was evaluated in a randomized, placebo-controlled, crossover study in 12 healthy volunteers. Subjects ingested either placebo or clopidogrel (300 mg followed by 75 mg the two following days) alone and together with ritonavir (100 mg twice daily). Ritonavir significantly decreased the exposure of clopidogrel AM by 51% and average platelet inhibition significantly decreased from 51% without ritonavir to 31% with ritonavir (mean difference 90% CI -27% to -12%). The maximal platelet inhibition by clopidogrel was also reduced from 60% to 40% during concurrent ritonavir (mean difference 90% CI -29% to -11%). The authors conclude that patients receiving ritonavir are at risk for diminished clopidogrel response and consequently increased risk for atherothrombotic events if the two drugs are used concurrently. The authors recommend to avoid concomitant administration of clopidogrel with ritonavir.
Clopidogrel increases dasabuvir exposure with or without ritonavir, and ritonavir inhibits the bioactivation of clopidogrel. Itkonen MK, Tornio A, Lapatto-Reiniluoto O, et al. Clin Pharmacol Ther, 2018, [epub ahead of print].

A 45-year-old HIV infected patient treated with darunavir/ritonavir plus emtricitabine/tenofovir. The patient underwent coronary stenting as he presented a significant stenosis of the coronary artery. The patient was subsequently started on dual antiplatelet therapy with aspirin and clopidogrel while his actual antiretroviral treatment was maintained. Six month later, the patient presented an episode of chest pain with electrocardiographic signs of acute anterior myocardial infarction, and evidence of thrombosis of the implanted stent. He underwent thromboaspiration and implantation of a novel stent. Clopidogrel was replaced by prasugrel while the darunavir/ritonavir regimens was maintained. No novel stent thrombosis episodes occurred while on prasugrel.
Recurrent coronary disease in HIV-infected patients: role of drug-drug interactions. Bravo I, Alvarez H, Marino A, Clotet B, Molto J. Br J Clin Pharmacol 2018 [epub ahead of print].

A 64-year-old man presented with increasing shortness of breath, fatigue and chest pain radiating to his left shoulder and neck. His home medications included darunavir, ritonavir, emtricitabine-tenofovir, isoniazid, pyridoxine, clopidogrel, aspirin, carvedilol, rosuvastatin, valsartan, sertraline, tamsulosin and esomeprazole. Potential drug-drug interactions between isoniazid and clopidogrel, and ritonavir and clopidogrel were identified that could interfere with clopidogrel activation. Based on this, platelet function testing was completed and impaired clopidogrel response was seen on two platelet function tests. There was no genetic cause (i.e., CYP2C19 genotype) for the impaired clopidogrel response.
A patient with HIV and tuberculosis with diminished clopidogrel response. Metzger NL, Momary KN. Int J STD AIDS, 2013, 25(7): 532-534.

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Coadministration of dabigatran (150 mg single dose) simultaneously with or 2 h before ritonavir alone (100 mg once daily administered at steady state) was studied in 16 HIV negative subjects. Simultaneous administration did not significantly change dabigatran PK (possibly due to mixed induction and inhibition of P-gp by ritonavir). Administration 2 hours before ritonavir decreased dabigatran AUC by 29% and Cmax by 27%. These results suggests that dabigatran can be administered simultaneously with ritonavir used as a once daily pharmacokinetic enhancer.
Cobicistat, but not ritonavir, increases dabigatran exposure. Brooks KM, Gordon LA, Penzak S, et al. Conference on Retroviruses and Opportunistic Infections (CROI) Seattle, February 2017, abstract 409.

LHPG Comment: Metabolism of dapsone is mainly by N-acetylation with a component of N-hydroxylation, and is via multiple CYP P450 enzymes. Clinically significant interactions are unlikely, but can not be excluded.

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Concomitant use of desipramine and darunavir/ritonavir may increase plasma concentrations of desipramine which may lead to adverse events such as nausea, dizziness, hypotension and syncope. If desipramine is used with darunavir/ritonavir, the combination should be used with caution and a lower dose of desipramine should be considered
Prezista Prescribing Information, Tibotec Therapeutics, June 2012.

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Coadministration of darunavir/ritonavir and digoxin (0.4 mg single dose) increased digoxin AUC and Cmax by 60% and 29%, respectively. The increase in digoxin is from probably inhibition of Pgp. Given that digoxin has as a narrow therapeutic index, it is recommended that the lowest possible dose of digoxin should initially be prescribed in case digoxin is given to patients on darunavir/ritonavir therapy. The digoxin dose should be carefully titrated to obtain the desired clinical effect while assessing the overall clinical state of the subject.
Prezista Summary of Product Characteristics, Janssen-Cilag Ltd, June 2012.

Coadministration of digoxin (0.4 mg) and darunavir/ritonavir (600/100 mg twice daily) was studied in 8 subjects. Digoxin Cmax increased by 15% and AUC increased by 36%. The lowest dose of digoxin should be initially prescribed. The serum digoxin concentrations should be monitored and used for titration of digoxin dose to obtain the desired clinical effect.
Prezista Prescribing Information, Tibotec Therapeutics, June 2012.

Coadministration of darunavir with low dose ritonavir with active substances that are highly dependent on CYP3A for clearance and for which increased systemic exposure is associated with serious and/or life-threatening events (narrow therapeutic index) is contraindicated. These medicinal products include dihydroergotamine.
Prezista Summary of Product Characteristics, Janssen-Cilag Ltd, June 2012.

Co-administration of darunavir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index). Coadministration with ergot derivatives is contraindicated due to potential for serious and/or life threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
Prezista Prescribing Information, Tibotec Inc, June 2012.

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Docetaxel should be administered with caution in patients concomitantly receiving potent CYP3A4 inhibitors (e.g. protease inhibitors like ritonavir, azole antifungals). A drug interaction study performed in patients receiving ketoconazole and docetaxel showed that the clearance of docetaxel was reduced by half by ketoconazole, probably because the metabolism of docetaxel involves CYP3A4 as a major (single) metabolic pathway. Reduced tolerance of docetaxel may occur, even at lower doses.
Taxotere (docetaxel) Summary of Product Characteristics, Sanofi-Aventis, December 2009.

Three cases have been reported where administration of IV docetaxel to HIV+ patients on ritonavir-containing regimens resulted in severe haematological and cutaneous toxicity 3-7 days after the first infusion of docetaxel (70-100 mg/m2), despite patients having normal baseline liver function and blood cell counts. Each patient recovered following the withdrawal of docetaxel.
Severe toxicity related to a pharmacokinetic interaction between docetaxel and ritonavir in HIV-infected patients. Mir O, Dessard-Diana B, Louet AL, et al. Br J Clin Pharmacol, 2010, 69(1): 99-101.

A study was carried out in 12 patients with solid tumours. One cohort of patients (n=4) received 10 mg of oral docetaxel and a subsequent cohort (n=8) 100 mg of oral docetaxel, coadministered with 100 mg oral ritonavir randomized to simultaneous administration or ritonavir given 60 minutes before docetaxel on days 1 and 8. On day 15 or 22, patients received 100 mg i.v. docetaxel. Docetaxel AUC in patients who received 10 mg oral docetaxel in combination with ritonavir was low, and the dose could safely be increased to 100 mg. The AUC in patients who received 100 mg oral docetaxel combined with ritonavir simultaneously or ritonavir given 60 minutes before docetaxel was 2.4 ± 1.5 and 2.8 ± 1.4 mg/L.h, respectively, compared with 1.9 ± 0.4 mg/L.h after i.v. docetaxel. The apparent oral bioavailability of docetaxel combined with ritonavir simultaneously or ritonavir given 60 minutes before docetaxel was >100% (i.e. 131 ± 90% and 161 ± 91%, respectively), indicating marked inhibition by ritonavir of gut wall and/or hepatic metabolism. Coadministration of ritonavir significantly enhanced the apparent oral bioavailability of docetaxel and caution is essential when giving docetaxel with boosted PIs.
Coadministration of ritonavir strongly enhances the apparent oral bioavailability of docetaxel in patients with solid tumors. Oostendorp RL, Huitema A, Rosing H, et al. Clin Cancer Res, 2009, 15(12): 4228-4233.

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Doxycycline is almost completely absorbed and is not subject to presystemic metabolism, the mean bioavailability being approximately 93%. No significant metabolism occurs and Doxycycline is cleared intact by renal and biliary mechanisms. Studies to date have indicated that administration of doxycycline at the usual recommended doses does not lead to excessive accumulation of the antibiotic in patients with renal impairment.
Doxycycline Capsules BP 100mg, UK Summary of Product Characteristics, Actavis UK Ltd, updated June 2011

Doxycycline is excreted in the urine and faeces as unchanged active substance. Between 40% and 60% of an administered dose can be accounted for in the urine by 92 hours, and approximately 30% in the faeces.
Efracea® 40mg Modified Release Hard Capsules, Summary of Product Characteristics, Galderma (U.K) Ltd, updated November 2011
Oracea® US Prescribing Information, Galderma Laboratories, US Prescribing Information, updated May 2010

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Efavirenz in combination with darunavir/ritonavir 800/100 mg once daily may result in sub-optimal darunavir Cmin. If efavirenz is to be used in combination with darunavir/ritonavir, the darunavir/ritonavir 600/100 mg twice daily regimen should be used. Coadministration of efavirenz (600 mg once daily) and darunavir/ritonavir (at a dose lower than recommended or with a different dosing regimen) increased efavirenz AUC, Cmax and Cmin by 21%, 15% and 17%, respectively. Darunavir AUC, Cmax and Cmin were decreased by 13%, 15% and 31%, respectively. Efavirenz decreases the plasma concentrations of darunavir as a result of CYP3A4 induction. Darunavir/ritonavir increases the plasma concentrations of efavirenz as a result of CYP3A4 inhibition. Clinical monitoring for central nervous system toxicity associated with increased exposure to efavirenz may be indicated when darunavir coadministered with low dose ritonavir is given in combination with efavirenz.
Prezista Summary of Product Characteristics, Janssen-Cilag Ltd, June 2012.

The interaction between darunavir/ritonavir and efavirenz was evaluated in clinical studies and no dose adjustment is needed for either drug. Coadministration of efavirenz (600 mg once daily) and darunavir/ritonavir (300/100 mg twice daily) was studied in 12 subjects. Darunavir exposure decreased and efavirenz exposure increased. Darunavir Cmax, AUC and Cmin decreased by 15%, 13% and 31%, respectively. Efavirenz Cmax, AUC and Cmin increased by 15%, 21% and 17%, respectively.
Prezista Prescribing Information, Tibotec Inc, June 2012.

The effect of efavirenz (600 mg once daily) on a once daily regimen of darunavir/ritonavir (900/100 mg) was investigated in 12 HIV- subjects. Coadministration decreased darunavir trough concentration by 57% (p<0.001), AUC decreased by 14% (p=0.05) and Cmax decreased by 8% (p=0.23). Ritonavir trough concentrations and AUC were also significantly reduced by 54% and 26%, respectively. There was no significant effect on efavirenz trough concentrations (1% increase), AUC (9% decrease) or Cmax (20% decrease), but efavirenz half life was significantly increased by 66% in the combination phase. Although trough concentrations of darunavir were significantly reduced, all remained above the EC50 of wild-type virus.
Pharmacokinetics of darunavir at 900 milligrams and ritonavir at 100 milligrams once daily when coadministered with efavirenz at 600 milligrams once daily in healthy volunteers. Soon GH, Shen P, Yong EL, et al. Antimicrob Agents Chemother, 2010, 54(7): 2775-2780.

The pharmacokinetic interaction between a non-licensed dose of darunavir/ritonavir (300/100 mg twice daily) and efavirenz (600 mg twice daily) was investigated in HIV-negative subjects. In the presence of darunavir/ritonavir, efavirenz Cmin and Cmax increased by ~17% and AUC increased by 21%. Coadministration decreased darunavir Cmin by 31% and decreased AUC by 13%. Since the clinical significance of the changes in AUC and Cmin seen during coadministration has not been established, this combination should be used with caution. Similar findings are expected with the approved darunavir/ritonavir 600/100 mg twice daily dose.
Pharmacokinetic interaction between TMC114/r and efavirenz in healthy volunteers. Sekar VJ, De Pauw M, Marien K, et al. Antiviral Ther, 2007, 12(4): 509-514.

After intravenous doses about 80% is excreted unchanged in the urine in 24 hours. The terminal elimination half-life is about 3 hours. It is distributed to the CSF.
Less than 1% of a dose is absorbed after topical application.
Martindale Complete Drug Reference. Pharmaceutical Press (via Medicines Complete), latest modification: 23-Sep-2011

Eflornithine was administered to six healthy men in single intravenous doses of 5 and 10 mg/kg and oral doses of 10 and 20 mg/kg. Peak plasma concentrations were reached within 6 hr after oral doses. The decay of the plasma concentrations followed first-order kinetics with a mean half-life (t 1/2) for all four doses studied of 199 +/- 6 min (+/- SD). Mean renal clearance was determined as 0.99 +/- 0.03 ml . min-1 . kg-1, accounting for 83% of drug elimination. Mean apparent volume of distribution (aVD) was 0.337 +/- 0.031 l/kg-1, corresponding to 24 l for 70 kg of body weight. The amount of unchanged drug in 24-hr urine samples was 47 +/- 7% and 40 +/- 11% after 10 and 20 mg/kg orally, and 78% and 81 +/- 8% after 5 and 10 mg/kg intravenously. Twenty-four-hour urinary recovery of unchanged drug was 46.9% of the 10mg/kg and 40.3% of the 20 mg/kg oral doses. >86% of the oral doses were cleared from the body by renal filtration. In the case of intravenous dosing, 81% of the drug was eliminated by the kidneys.
Kinetics of alpha-difluoromethylornithine: an irreversible inhibitor of ornithine decarboxylase. Haegele KD, Alken RG, Grove J et al. Clin Pharmacol Ther. 1981 Aug;30(2):210-7.

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This interaction has not been studied. Based on the different elimination pathways of the other NRTIs zidovudine, emtricitabine, stavudine, lamivudine, that are primarily renally excreted, and abacavir for which metabolism is not mediated by CYP450, no interactions are expected for these medicinal compounds and darunavir coadministered with low dose ritonavir.
Prezista Summary of Product Characteristics, Janssen-Cilag Ltd, June 2012.

Based on the different elimination pathways of the NRTIs (zidovudine, zalcitabine, emtricitabine, stavudine, lamivudine and abacavir) that are primarily renally excreted, no drug interactions are expected for these drugs and darunavir/ritonavir.
Prezista Prescribing Information, Tibotec Inc, June 2012.

When given with darunavir with ritonavir or cobicistat, the dose of Descovy is 200/10 mg once daily. Co-administration of Descovy with medicinal products that inhibit P-gp (e.g., cobicistat or ritonavir) are expected to increase the absorption and plasma concentration of tenofovir alafenamide. Coadministration of darunavir/cobicistat (800/150 mg once daily), emtricitabine and tenofovir alafenamide (25 mg once daily) had no effect on the AUC and Cmax of tenofovir alafenamide, but increased tenofovir AUC, Cmax and Cmin by 224%, 216% and 221%, respectively. There was no change in darunavir AUC, Cmax and Cmin. Coadministration of darunavir/cobicistat (800/150 mg once daily) and tenofovir alafenamide (10 mg once daily) had no effect on the AUC and Cmax of tenofovir alafenamide, but increased tenofovir AUC andCmax by 105% and 142%. There was no change in darunavir AUC, Cmax and Cmin.
Descovy Summary of Product Characteristics, Gilead Sciences Ltd, April 2016.

Based on drug interaction studies conducted with the components of Descovy, no clinically significant drug interactions have been either observed or are expected when Descovy is combined with darunavir with ritonavir or cobicistat. Coadministration darunavir/cobicistat (800/150 mg once daily) and tenofovir alafenamide (25 mg once daily, dosed as Descovy) was studied in 11 subjects. Tenofovir alafenamide Cmax and AUC decreased by 7% and 2%; darunavir Cmax increased by 2%, but AUC and Cmin decreased by 1% and 3%. Coadministration of darunavir/ritonavir (800/100 mg once daily) and tenofovir alafenamide (10 mg once daily) was studied in 10 subjects. Tenofovir alafenamide Cmax and AUC increased by 42% and 6%; darunavir Cmax decreased by 1%, but AUC and Cmin increased by 1% and 13%.
Descovy US Prescribing Information, Gilead Sciences Inc, April 2016.

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Coadministration of darunavir with low dose ritonavir with active substances that are highly dependent on CYP3A for clearance and for which increased systemic exposure is associated with serious and/or life-threatening events (narrow therapeutic index) is contraindicated. These medicinal products include ergometrine.
Prezista Summary of Product Characteristics, Janssen-Cilag Ltd, June 2012.

Co-administration of darunavir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index). Coadministration with ergot derivatives is contraindicated due to potential for serious and/or life threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
Prezista Prescribing Information, Tibotec Inc, June 2012.

Coadministration of darunavir with low dose ritonavir with active substances that are highly dependent on CYP3A for clearance and for which increased systemic exposure is associated with serious and/or life-threatening events (narrow therapeutic index) is contraindicated. These medicinal products include ergotamine.
Prezista Summary of Product Characteristics, Janssen-Cilag Ltd, June 2012.

Co-administration of darunavir/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index). Coadministration with ergot derivatives is contraindicated due to potential for serious and/or life threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
Prezista Prescribing Information, Tibotec Inc, June 2012.

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Based on results with omeprazole (no effect on darunavir AUC, Cmax or Cmin), darunavir coadministered with low dose can be coadministered with proton pump inhibitors without dose adjustments.
Prezista Summary of Product Characteristics, Janssen-Cilag Ltd, June 2012.

Coadministration of an oral contraceptive (ethinylestradiol/norethindrone 0.035/1.0 mg once daily) and darunavir/ritonavir was studied. Ethinylestradiol AUC, Cmax and Cmin decreased by 44%, 32% and 62%, respectively. Norethindrone AUC and Cmin decreased by 14% and 30%, respectively and there was no change in Cmax. Alternative or additional contraceptive measures are recommended when oestrogen based contraceptives are coadministered with darunavir and low dose ritonavir. Patients using oestrogens as hormone replacement therapy should be clinically monitored for signs of oestrogen deficiency.
Prezista Summary of Product Characteristics, Janssen-Cilag Ltd, June 2012.

Patients receiving estrogen-based contraceptives should be instructed to use alternate contraceptive measures during therapy with darunavir/ritonavir because hormonal levels may decrease. Coadministration of ethinylestradiol/norethindrone (0.035/1.0 mg once daily) and darunavir/ritonavir (600/100 mg twice daily) was studied in 11 women. Ethinylestradiol Cmax, AUC and Cmin decreased by 32%, 44% and 62%, respectively. Norethindrone Cmax, AUC and Cmin decreased by 10%, 14% and 30%, respectively. Plasma concentrations of ethinyl estradiol are decreased due to induction of its metabolism by ritonavir. Alternative methods of nonhormonal contraception are recommended.
Prezista Prescribing Information, Tibotec Inc, June 2012.

The effect of multiple doses of darunavir/ritonavir (600/100 mg twice daily) on the steady state pharmacokinetics of a combined oral contraceptive containing ethinyl estradiol and norethindrone was studied in 19 HIV-negative women. When given with darunavir/ritonavir, ethinyl estradiol Cmin, Cmax and AUC decreased by 62%, 32% and 44%, respectively and norethindrone decreased by 30%, 10% and 14%, respectively. Five participants discontinued the study due to grade 2 cutaneous events during treatment with darunavir/ritonavir and the contraceptive. Alternative or additional contraceptive measures should be used when oestrogen-based contraceptives are co-administered with darunavir/ritonavir.
Pharmacokinetic interaction between ethinyl estradiol, norethindrone and darunavir with low-dose ritonavir in healthy women. Sekar VJ, Lefebvre E, Spinosa Guzman S, et al. Antiviral Ther, 2008, 13(4): 563-569.

Ethionamide is extensively metabolized to active and inactive metabolites. Metabolism is presumed to occur in the liver and 6 metabolites have been isolated: 2-ethylisonicotinamide, carbonyl-dihydropyridine, thiocarbonyl-dihydropyridine, S-oxocarbamoyl dihydropyridine, 2-ethylthioiso-nicotinamide, and ethionamide sulphoxide. The sulphoxide metabolite has been demonstrated to have antimicrobial activity against Mycobacterium tuberculosis. Less than 1% of the oral dose is excreted as ethionamide in urine.
Trecator® US Prescribing Information, Wyeth Pharmaceuticals Inc. (now Pfizer) revised November 2007

An in vitro study examined the inhibitory effects of pyrazinamide and ethionamide, both of which are chemically related to isoniazid, on the CYP-mediated activities in human liver microsomes and compared them to that of isoniazid. No remarkable effects on any CYP activities were observed by pyrazinamide and ethionamide.
Inhibitory effect of antituberculosis drugs on human cytochrome P450-mediated activities. Nishimura Y, Kurata N, Sakurai E, Yasuhara H. J Pharmacol Sci. 2004 Nov;96(3):293-300.

Flavin-containing monooxygenases (FMOs) are a superfamily of flavoprotein monooxygenases active towards a wide range of xenobiotics. ethionamide (ETA) is a pro-drug requiring bioactivation to exert toxicity. M. tuberculosis possesses a flavin monooxygenase (EtaA) that oxygenates ETA first to the sulfoxide and then to 2-ethyl-4-amidopyridine, presumably through a second oxygenation involving sulfinic acid. ETA is also a substrate for mammalian flavincontaining monooxygenases (FMOs). A study examined activity of expressed human and mouse FMOs toward ETA, as well as liver and lung microsomes. All FMOs converted ETA to the S-oxide (ETASO), the first step in bioactivation. Co-incubations with the general CYP and FMO inhibitors SKF-525A and thiourea, suggest that ETA S-oxygenation in mouse liver and lung microsomes is predominantly, FMO-mediated.
Metabolism of the anti-tuberculosis drug ethionamide by mouse and human FMO1, FMO2 and FMO3 and mouse and human lung microsomes. Henderson MC, Siddens LK, Morré JT, et al. Toxicol Appl Pharmacol. 2008 Dec 15;233(3):420-7

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Coadministration of a lower than recommended etravirine dose (100 mg twice daily) and darunavir/ritonavir decreased etravirine AUC, Cmax and Cmin by 37%, 32% and 49%, respectively. Darunavir AUC in creased by 15% and there was no significant effect on Cmax or Cmin. Darunavir coadministered with low dose ritonavir and etravirine 200 mg twice daily can be used without dose adjustments.
Prezista Summary of Product Characteristics, Janssen-Cilag Ltd, June 2012.

The interaction between darunavir/ritonavir and etravirine was evaluated in clinical studies and no dose adjustment is needed for either drug. Coadministration of etravirine (200 mg twice daily) and darunavir/ritonavir (600/100 mg twice daily) was studied in 15 subjects. Darunavir AUC, Cmax and Cmin increased by 15%, 11% and 2%, respectively. Etravirine AUC, Cmax and Cmin decreased by 37%, 32% and 49%, respectively.
Prezista Prescribing Information, Tibotec Inc, June 2012.

Etravirine and darunavir/ritonavir can be used without dose adjustments. Coadministration with darunavir/ritonavir (600/100 mg twice daily) increased darunavir AUC (15%) and Cmax (11%), but had no effect on Cmin. Etravirine AUC decreased by 37%, Cmax decreased by 32% and Cmin decreased by 49%.
Intelence Summary of Product Characteristics, Janssen-Cilag Ltd, March 2012.

The mean systemic exposure (AUC) of etravirine was reduced when etravirine was co-administered with darunavir/ritonavir. Because all subjects in the Phase 3 trials received darunavir/ritonavir as part of the background regimen and etravirine exposures from these trials were determined to be safe and effective, etravirine and darunavir/ritonavir can be co-administered without dose adjustments. Coadministration of darunavir/ritonavir (600/100 mg twice daily) and etravirine was studied in 15 subjects. Data from 14 subjects showed that etravirine Cmax, AUC and Cmin decreased by 32%, 37% and 49%, respectively. Darunavir Cmax, AUC and Cmin increased by 11%, 15% and 2%, respectively.
Intelence Prescribing Information, Tibotec Pharmaceuticals Ltd, March 2012.

The pharmacokinetics of etravirine and darunavir were determined in 10 HIV+ subjects receiving etravirine (200 mg twice daily, phase III formulation) and darunavir/ritonavir (600/100 mg twice daily). Darunavir exposure was similar to historical controls and etravirine concentrations were similar to those obtained when administered with a boosted PI.
Pharmacokinetics and antiretroviral response to darunavir/ritonavir and etravirine combination in patients with high-level resistance. Boffito et al. AIDS, 2007, 21: 1449-1455.

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Based on results with ranitidine (no effect on darunavir AUC, Cmax or Cmin), darunavir coadministered with low dose ritonavir can be coadministered with H2 receptor antagonists without dose adjustments.
Prezista Summary of Product Characteristics, Janssen-Cilag Ltd, June 2012.

This interaction has not been studied. Darunavir coadministered with low dose ritonavir can be expected to increase the plasma concentrations of calcium channel antagonists. Clinical monitoring of therapeutic and adverse effects is recommended when these medicines are concomitantly administered with darunavir with low dose ritonavir.
Prezista Summary of Product Characteristics, Janssen-Cilag Ltd, June 2012.

Plasma concentrations of calcium channel blockers may increase when darunavir/ritonavir are co-administered. Caution is warranted and clinical monitoring of patients is recommended.
Prezista Prescribing Information, Tibotec Inc, June 2012.

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Coadministration of darunavir and ritonavir and medicinal products which are primarily metabolised by CYP2D6 (such as flecainide, propafenone, metoprolol) may result in increased plasma concentrations of these medicinal products, which could increase or prolong their therapeutic effect and adverse reactions.
Prezista Summary of Product Characteristics, Janssen-Cilag Ltd, June 2012.

Concentrations of flecainide may be increased when co-administered with darunavir/ritonavir. Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when co-administered with darunavir/ritonavir.
Prezista Prescribing Information, Tibotec Inc, June 2012.

In a clinical study where ritonavir 100 mg capsules twice daily were coadministered with 50 µg intranasal fluticasone propionate (4 times daily) for 7 days in healthy subjects, fluticasone propionate plasma concentrations increased significantly, whereas the intrinsic cortisol levels decreased by approximately 86% (90% CI 82 to 89%). Greater effects may be expected when fluticasone propionate is inhaled. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate; this could also occur with other corticosteroids metabolised via the P450 3A pathway e.g. budesonide. Consequently, concomitant administration of darunavir, coadministered with low dose ritonavir and these glucocorticoids, is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. A dose reduction of the glucocorticoid should be considered with close monitoring of local and systemic effects or a switch to a glucocorticoid, which is not a substrate for CYP3A4 (e.g. beclomethasone). Moreover, in case of withdrawal of glucocorticoids progressive dose reduction may have to be performed over a longer period. The effects of high fluticasone systemic exposure on ritonavir plasma levels are as yet unknown.
Prezista Summary of Product Characteristics, Janssen-Cilag Ltd, June 2012.

Concomitant use of inhaled fluticasone propionate and darunavir/ritonavir may increase plasma concentrations of fluticasone propionate. Alternatives should be considered, particularly for long term use.
Prezista Prescribing Information, Tibotec Inc, June 2012.

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Gentamicin is not metabolized in the body but is excreted unchanged in microbiologically active form predominantly via the kidneys.
Gentamicin 40 mg/ml Injection Summary of Product Characteristics, Hospira UK Ltd, updated August 2011

Little, if any, metabolic transformation occurs; the drug is excreted principally by glomerular filtration.  After several days of treatment, the amount of gentamicin excreted in the urine approaches, but does not equal, the daily dose administered.  As with other aminoglycosides, a small amount of the gentamicin dose may be retained in the tissues, especially in the kidneys.  Minute quantities of aminoglycosides have been detected in the urine of some patients weeks after drug administration was discontinued.  Renal clearance of gentamicin is similar to that of endogenous creatinine. Probenecid does not affect renal tubular transport of gentamicin.
Gentamicin Injection USP, US Prescribing Information, APP Pharmaceuticals, revised August 2011

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The effect of Ginkgo biloba extract (120 mg twice daily for 4 weeks) on the steady state pharmacokinetics of lopinavir/ritonavir (400/100 mg twice daily) or single doses of midazolam (8 mg) was studied in 14 HIV- subjects. Coadministration had no effect on lopinavir or ritonavir concentrations, but decreased midazolam AUC by 34% and Cmax by 31%. The results suggest that Gingko biloba extract is unlikely to reduce exposure of ritonavir-boosted protease inhibitors, but unboosted regimens may be affected.
Effect of Ginkgo biloba extract on lopinavir, midazolam and fexofenadine pharmacokinetics in healthy subjects. Robertson SM, Davey RT, Voell J, et al. Curr Med Res Opin, 2008, 24(2): 591-599.

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A case report in a single patient describes that ciclosporin (a CYP3A4 substrate) levels decreased 2 weeks after initiation of griseofulvin, and markedly increased on discontinuation.
Cyclosporin A and griseofulvin: another drug interaction. Abu-Romeh SH, Rashed A. Nephron. 1991;58(2):237

After intravenous or subcutaneous injection heparin is extensively bound to plasma proteins. The half-life of heparin depends on its dose and route as well as the method of calculation and is subject to wide inter- and intra-individual variation; a range of 1 to 6 hours with an average of 1.5 hours has been cited. It may be slightly prolonged in renal impairment, decreased in patients with pulmonary embolism, and either increased or decreased in patients with liver disorders. Heparin is taken up by the reticuloendothelial system. It is excreted in the urine, mainly as metabolites, although after large doses up to 50% may be excreted unchanged.
Martindale Complete Drug Reference. Pharmaceutical Press (via Medicines Complete), last reviewed 2011-11-15

Heparin is not eliminated enzymatically nor by glomerular filtration or renal tubular secretion. In all likelihood, the anticoagulant is transferred to reticuloendothelial cells, which may also provide the means for its degradation.
Estes JW. Clinical pharmacokinetics of heparin. Clin Pharmacokinet 1980; 5: 204–20.

After either subcutaneous or intravenous injection heparin is distributed primarily within the intravascular space. A short distribution phase is seen which is thought to correspond to endothelial cell binding and internalisation. The disposition curve for unfractionated heparin has a unique concave-convex shape which is the result of combined saturable and nonsaturable elimination mechanisms. The nonsaturable elimination mechanism is renal and is the primary route of elimination for low molecular weight heparins.
Kandrotas RJ. Heparin pharmacokinetics and pharmacodynamics. Clin Pharmacokinet 1992; 22: 359–74.

This study showed hop extracts to induce the expression of drug metabolism and excretion proteins. mRNA levels for CYP3A4, CYP2B6 and MDR1 were increased in a concentration dependent manner by activating PXR. The efficacy with which hops activated PXR was comparable to that of St John's wort.
Structural basis of human pregnane X receptor activation by the hops constituent colupulone. Teotico DG, Bischof JJ, Peng L, et al. Mol Pharmacol, 2008, 74: 1512-1520.

Pharmacokinetic data indicate hydralazine has an extensive and complex metabolism depending on acetylator status: slow acetylators undergo primary oxidative metabolism, while rapid acetylators are acetylated.
Mulrow JP, Crawford MH. Clinical pharmacokinetics and therapeutic use of hydralazine in congestive heart failure. Clin Pharmacokinet. 1989 Feb;16(2):86-9

Previous studies showed that several drugs inhibited quinine 3-hydroxylation, a cytochrome P450 (CYP) 3A4-mediated reaction, in vitro. In this extended study, 13 drugs were selected and tested by human liver microsomes in order to further determine their respective inhibition constant (Ki) and type of inhibition. According to the apparent Ki values, the inhibitory rank order of these tested drugs was as follows: ketoconazole > doxycycline > omeprazole > tetracycline > troleandomycin (with pre-incubation) > primaquine > troleandomycin (without pre-incubation) > nifedipine > erythromycin > verapamil > oleandomycin > diltiazem > cimetidine > hydralazine. Among these drugs, doxycycline, tetracycline, ketoconazole, nifedipine and hydralazine were judged as mixed inhibitors; whereas, the remaining other drugs tested were judged as competitive inhibitors. When the plasma/serum concentrations possibly attained after their usual therapeutic doses were taken into account, tetracycline, doxycycline, omeprazole, ketoconazole, nifedipine, troleandomycin and erythromycin are likely to be inhibitors of quinine metabolism in patients when these drugs are co-administrated with quinine.
Zhao XJ, Ishizaki T. A further interaction study of quinine with clinically important drugs by human liver microsomes: determinations of inhibition constant (Ki) and type of inhibition. Eur J Drug Metab Pharmacokinet. 1999 Jul-Sep;24(3):272-8.

An in vitro study reports a method using cryopreserved human hepatocytes and the time-dependent aldehyde oxidase (AO) inhibitor hydralazine (K(I) = 83 ± 27 μM, k(inact) = 0.063 ± 0.007 min(-1)), which estimates the contribution of AO metabolism relative to total hepatic clearance. Using zaleplon as a probe substrate and simultaneously monitoring the AO-catalyzed formation of oxozaleplon and the CYP3A-catalyzed formation of desethyzaleplon in the presence of a range of hydralazine concentrations, it was determined that >90% inhibition of the AO activity with minimal effect on the CYP3A activity could be achieved with 25 to 50 μM hydralazine. Differences in estimated f(m(AO)) between two batches of pooled human hepatocytes suggest that sensitivity to hydralazine varies slightly with hepatocyte preparations. Substrates with a CYP2D6 contribution to clearance were affected by hydralazine to a minor extent, because of weak inhibition of this enzyme.
Strelevitz TJ, Orozco CC, Obach RS. Hydralazine as a selective probe inactivator of aldehyde oxidase in human hepatocytes: estimation of the contribution of aldehyde oxidase to metabolic clearance. Drug Metab Dispos. 2012 Jul;40(7):1441-8.

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The pharmacokinetics of ifosfamide exhibit considerable interindividual variation. It is a prodrug that is extensively metabolised, chiefly by cytochrome P450 isoenzymes such as CYP3A4 and CYP2B6 in the liver, to both active and inactive metabolites; there is some evidence that metabolism is saturated at very high doses. Although licensed product information states that a mean terminal elimination half-life is about 15 hours after a single high-dose intravenous bolus, most studies at lower doses recorded elimination half-lives of 4 to 8 hours. After repeated doses there is a decrease in the elimination half-life, apparently due to autoinduction of metabolism. It is excreted largely in urine, as unchanged drug and metabolites.
Martindale Complete Drug Reference. Pharmaceutical Press (via Medicines Complete), latest modification: 20-Aug-2010
Wagner T. Clin Pharmacokinet 1994; 26: 439–56; Boddy AV, Yule SM. Clin Pharmacokinet 2000; 38: 291–304; Kerbusch T, et al. Clin Pharmacokinet 2001; 40: 41–62.

In patients (n=32) with advanced solid tumours, continuous once daily sunitinib, in escalating doses per cohort, was combined with ifosfamide, 9 g/m2 for 3 days or 6 g/m2 for 5 days, administered every 3 weeks. Neutropenia-related adverse events were dose-limiting toxicities. Sunitinib did not affect ifosfamide PK. Ifosfamide significantly decreased exposure to sunitinib and increased exposure to its metabolite, SU12662. No consistent changes in PD parameters were observed. Ifosfamide produced decreased sunitinib blood levels due to CYP3A induction. As PK interactions cannot explain the relatively low sunitinib doses that can be combined with ifosfamide, synergy in toxicity is likely. Whether this is true for anti-tumour activity needs to be further explored.
Decreased exposure to sunitinib due to concomitant administration of ifosfamide: results of a phase I and pharmacokinetic study on the combination of sunitinib and ifosfamide in patients with advanced solid malignancies. Hamberg P, Steeghs N, Loos WJ et al. Br J Cancer. 2010 Jun 8;102(12):1699-706.

An in vitro study screened 18 widely used anticancer drugs for their ability to activate PXR-mediated CYP3A4 induction. A CYP3A4 reporter gene assay was employed to identify PXR agonists among the eighteen anticancer drugs. Subsequently CYP3A4 mRNA and protein expression following treatment with these PXR agonists was assessed. Finally, the effect of pre-treatment with these agents on the 1'-hydroxylation of midazolam (a specific CYP3A4 probe) was determined. Ifosfamide was able to activate PXR and may therefore have the propensity to cause clinically relevant drug-drug interactions as a result of CYP3A4 induction.
Nuclear receptor mediated induction of cytochrome P450 3A4 by anticancer drugs: a key role for the pregnane X receptor. Harmsen S, Meijerman I, Beijnen JH, Schellens JH. Cancer Chemother Pharmacol. 2009 Jun;64(1):35-43

In vitro studies have demonstrated that conversion to the active metabolite occurs via CYP3A4. Both CYP3A4 and CYP2B6 are involved in detoxification. CYP3A4 metabolism of (S)-ifosfamide may generate a neurotoxic metabolite.
Granvil CP, Madan A, Sharkawi M, et al. Drug Metab Dispos1999; 27: 533-41; Roy P, Tretyakov O, Wright J, et al. Drug Metab Dispos 1999; 27: 1309-18

CYP3A4 activities in human liver microsomes from 2 donors were determined using the oxidation of the dihydropyridine denitronifedipine, a specific CYP3A4 substrate, at a concentration of 50 microM (= KM). Formation of the pyridine metabolite was measured using HPLC. Ifosfamide showed an inhibitory effect on CYP3A4, IC50 3.6/2.5 mmol/l for 2 microsome sample. Comparing IC50 values with plasma concentrations present during antineoplastic therapy, ifosfamide could possibly cause clinical drug interactions by inhibition of CYP3A4.
Screening for inhibitory effects of antineoplastic agents on CYP3A4 in human liver microsomes. Baumhäkel M, Kasel D, Rao-Schymanski RA, Böcker R et al. Int J Clin Pharmacol Ther. 2001 Dec;39(12):517-28

Ketoconazole given orally for 4 days, starting 1 day before intravenous ifosfamide (given as a 24-hour infusion), decreased ifosfamide clearance. However, ifosfamide metabolism to active metabolites was decreased, and urinary excretion of ifosfamide was increased. Ketoconazole may decrease the therapeutic efficacy of ifosfamide.
Kerbusch T, et al. Modulation of the cytochrome P450-mediated metabolism of ifosfamide by ketoconazole and rifampin. Clin Pharmacol Ther 2001; 70: 132–41.

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Substances that inhibit the cytochrome P450 isoenzyme CYP3A4 activity (e.g. protease inhibitors such as indinavir, lopinavir/ritonavir, ritonavir, saquinavir, telaprevir, nelfinavir, boceprevir; ketoconazole, itraconazole; erythromycin, clarithromycin) could decrease metabolism and increase imatinib concentrations. There was a significant increase in exposure to imatinib (the mean Cmax and AUC of imatinib rose by 26% and 40%, respectively) in healthy subjects when it was co-administered with a single dose of ketoconazole (a CYP3A4 inhibitor). Caution should be taken when administering imatinib with inhibitors of the CYP3A4 family. Imatinib increases the mean Cmax and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5-fold, respectively, indicating an inhibition of the CYP3A4 by imatinib. Therefore, caution is recommended when administering Imatinib with CYP3A4 substrates with a narrow therapeutic window. Imatinib may increase plasma concentration of other CYP3A4 metabolised drugs.
Glivec Summary of Product Characteristics, Novartis Pharmaceuticals UK Ltd, October 2012.

There was a significant increase in exposure to imatinib (mean Cmax and AUC increased by 26% and 40% respectively) in healthy subjects when imatinib was co-administered with a single dose of ketoconazole (a CYP3A4 inhibitor). Caution is recommended when administering imatinib with strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nelfinavir, ritonavir, saquinavir). Substances that inhibit CYP3A4 activity may decrease metabolism and increase imatinib concentrations. Imatinib increases the mean Cmax and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5-fold, respectively, suggesting an inhibition of the CYP3A4 by imatinib. Particular caution is recommended when administering imatinib with CYP3A4 substrates that have a narrow therapeutic window.
Gleevec Prescribing Information, Novartis, January 2013.

Imatinib pharmacokinetics alone and in combination with ritonavir (600 mg once daily for 3 days) were evaluated in 11 cancer patients receiving imatinib for at least 2 months (400-800 mg). The dose of imatinib was decreased by 50% during coadministration with ritonavir (for safety reasons) and pharmacokinetic parameters were normalised to an imatinib dose of 400 mg. Coadministration had no significant effect on imatinib AUC or Cmax (decreases of 3% and 13%, respectively). However, plasma exposure of CGP74588 (an active metabolite) was increased by approximately 40%. A population analysis with a time-dependent covariate confirmed that ritonavir did not influence the clearance or bioavailability of imatinib. The authors suggest that at steady state imatinib is insensitive to acute CYP3A4 inhibition by ritonavir and relies on alternate elimination pathways.
Influence of CYP3A4 inhibition on the steady-state pharmacokinetics of imatinib. van Erp NP, Gelderblom H, Karlsson MO et al. Clin Cancer Res, 2007, 13(24): 7394-7400.

When administered alone, imipenem is metabolised in the kidneys by dehydropeptidase-I. Individual urinary recoveries ranged from 5 to 40%, with an average recovery of 15-20% in several studies. Cilastatin is a specific inhibitor of dehydropeptidase-I enzyme and effectively inhibits metabolism of imipenem so that concomitant administration of imipenem and cilastatin allows therapeutic antibacterial levels of imipenem to be attained in both urine and plasma.
Approximately 70% of the administered antibiotic was recovered intact in the urine within ten hours, and no further urinary excretion of imipenem was detectable. Urine concentrations of imipenem exceeded 10 μg/ml for up to eight hours after a 500 mg/500 mg dose of imipenem/cilastatin. The remainder of the administered dose was recovered in the urine as antibacterially inactive metabolites, and faecal elimination of imipenem was essentially nil.
Primaxin® IV Injection Summary of Product Characteristics, Merck Sharp & Dohme Limited, updated October 2011
Primaxin® I.V. (Imipenem and cilastatin for injection) US Prescribing Information, Merck&Co Inc, Issued February 2010

Approximately 70-80% of the dose of cilastatin was recovered unchanged in the urine as cilastatin within 10 hours of administration of imipenem/cilastatin. No further cilastatin appeared in the urine thereafter. Approximately 10% was found as the N-acetyl metabolite, which has inhibitory activity against dehydropeptidase comparable to that of cilastatin. Activity of dehydropeptidase-I in the kidney returned to normal levels shortly after the elimination of cilastatin from the blood stream.
Primaxin® IV Injection Summary of Product Characteristics, Merck Sharp & Dohme Limited, updated October 2011
Primaxin® I.V. (Imipenem and cilastatin for injection) US Prescribing Information, Merck&Co Inc, Issued February 2010

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After intravenous administration approximately 60% of the dose is metabolised, mainly by conjugation (40%), wheras after inhalation about 77% of the systemically available dose is metabolised by ester hydrolysis (41%) and conjugation (36%). After inhalation of ipratropium bromide either with HFA 134a or CFC propellant, cumulative renal excretion over 24 hours was approximately 12% and 10%, respectively.  In an excretion balance study cumulative renal excretion (6 days) of drug-related radioactivity (including parent compound and all metabolites) accounted for 72.1% after intravenous administration, 9.3% after oral administration and 3.2% after inhalation. The main urinary metabolites bind poorly to the muscarinic receptor and have to be regarded as ineffective.
Atrovent® (Ipratropium bromide) 20 micrograms/actuation Inhaler CFC-Free UK Summary of Product Characteristics, Boehringer Ingelheim Limited, updated August 2011

After inhalation, around 10 to 30% of a dose is deposited in the lungs where it exerts its therapeutic effect. Only a small amount of ipratropium reaches the systemic circulation. The majority of a dose is swallowed but is poorly absorbed from the gastrointestinal tract. Following oral administration, the apparent systemic availability was around 2%, and after inhalation it was 6.9%. Ipratropium and its metabolites are eliminated in the urine and faeces.
Ensing K, et al. Pharmacokinetics of ipratropium bromide after single dose inhalation and oral and intravenous administration. Eur J Clin Pharmacol 1989; 36: 189–94.

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This interaction has not been studied. Concomitant systemic use of itraconazole and darunavir coadministered with low dose ritonavir may increase plasma concentrations of darunavir. Simultaneously, plasma concentrations of itraconazole may be increased by darunavir coadministered with low dose ritonavir. Caution is warranted and clinical monitoring is recommended. When coadministration is required the daily dose of itraconazole should not exceed 200 mg.
Prezista Summary of Product Characteristics, Janssen-Cilag Ltd, June 2012.

Itraconazole is a potent inhibitor as well as a substrate of CYP3A. Concomitant systemic use of itraconazole and darunavir/ritonavir may increase plasma concentration of darunavir. Plasma concentrations of itraconazole may be increased in the presence of darunavir/ritonavir. When co-administration is required, the daily dose of itraconazole should not exceed 200 mg.
Prezista Prescribing Information, Tibotec Inc, June 2012.