Clinically significant interactions have not been observed between nelfinavir and nucleoside analogues.
Viracept Summary of Product Characteristics, Roche Products Ltd, September 2011.

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

(See Summary)

At doses of adefovir dipivoxil 6- to 12-fold higher than the 10 mg dose recommended for the treatment of chronic hepatitis B, there was no interaction with nelfinavir.
Hepsera Summary of Product Characteristic, Gilead Sciences Ltd, October 2007.

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The effect on alcohol on nelfinavir exposure was investigated in HIV+ subjects who were light drinkers (<30 drinks/month) or heavy drinkers (>70 drinks/month). Nelfinavir pharmacokinetics were determined in both groups following the administration of nelfinavir without alcohol; in addition, nelfinavir was administered to the heavy drinkers in the presence of alcohol. Nelfinavir exposure was comparable when given to heavy drinkers alone or with alcohol and was 17% higher in the heavy drinkers (41912 ng.h/L, n=12) than in the light drinkers (35846 ng/h/ml, n=15).
The effect of ethanol on protease inhibitor exposure in chronic heavy ethanol users. Aweeka F, Lizak P, Karan L, et al. 10th Conference on Retroviruses and Opportunistic Infections, Boston, February 2003, abstract 545.

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Co-administration with medicinal products with narrow therapeutic windows and which are substrates of CYP3A4 [e.g., alfuzosin).
Viracept Summary of Product Characteristics, Roche Products Ltd, September 2011.

Coadministration with alfuzosin is contraindicated as potentially increased alfuzosin concentrations can result in hypotension.
Viracept Prescribing Information, Agouron Pharmaceuticals Inc, April 2012.

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Coadministration of nelfinavir and amiodarone is contraindicated due to potential for serious and/or life threatening reactions such as cardiac arrhythmias.
Viracept Prescribing Information, Agouron Pharmaceuticals Inc, April 2012.

LHPG Comment: Coadministration may inhibit the conversion of nelfinavir to its active metabolite M8; however, overall antiviral activity is unlikely to be altered.

Co-administration of nelfinavir with inhibitors of CYP2C19 (e.g., amitriptyline) may be expected to reduce the conversion of nelfinavir to its major active metabolite M8 (tert-butyl hydroxy nelfinavir) with a concomitant increase in plasma nelfinavir levels. Limited clinical trial data from patients receiving one or more of these medicinal products with nelfinavir indicated that a clinically significant effect on safety and efficacy is not expected. However, such an effect cannot be ruled out.
Viracept Summary of Product Characteristics, Roche Products Ltd, September 2011.

Coadministration of nelfinavir and drugs primarily metabolized by CYP3A (e.g., dihydropyridine calcium channel blockers) may result in increased plasma concentrations of the other drug that could increase or prolong both its therapeutic and adverse effects.
Viracept Prescribing Information, Agouron Pharmaceuticals Inc, April 2012.

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.

Co-administration is contraindicated with medicinal products with narrow therapeutic windows and which are substrates of CYP3A4 (e.g., astemizole). Nelfinavir increases terfenadine plasma concentrations. Similar interactions are likely with astemizole and cisapride. Nelfinavir must not be administered concurrently with terfenadine, astemizole or cisapride because of the potential for serious and/or life-threatening cardiac arrhythmias.
Viracept Summary of Product Characteristics, Roche Products Ltd, September 2011.

When used with nelfinavir, the lowest possible dose of atorvastatin should be administered. Coadministration of atorvastatin (10 mg once daily) and nelfinavir (1250 mg twice daily) increased atorvastatin AUC by 74%. If treatment with a HMG-CoA reductase inhibitor is indicated, pravastatin or fluvastatin is recommended.
Viracept Summary of Product Characteristics, Roche Products Ltd, September 2011.

The pharmacokinetics of atorvastatin (10 mg daily) and nelfinavir (1250 mg twice daily) were evaluated in healthy volunteers. Nelfinavir increased the AUC of atorvastatin by 74% and the Cmax by 122%. Atorvastatin did not appear to alter the pharmacokinetics of nelfinavir or M8. Caution should be exercised in coadministering these two drugs.
Pharmacokinetic interactions between nelfinavir and 3-hydroxy-3-methylglutaryl coenzyme A inhibitors atorvastatin and simvastatin. Hsyu PH, Schultz-Smith MD, Lillibridge JH, et al. Antimicrob Agents Chemother, 2001, 45: 3445-3450.

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

Coadministration of nelfinavir (750 mg three times a day for 9 days) with a single dose of azithromycin (1200 mg) caused decreases of 15%, 10% and 29% in nelfinavir AUC, Cmax and Cmin, respectively. Azithromycin AUC and Cmax increased by 112% and 136%, respectively. Dose adjustment of azithromycin is not recommended, but close monitoring for known side effects such as liver enzyme abnormalities and hearing impairment is warranted.
Viracept Prescribing Information, Agouron Pharmaceuticals Inc, April 2012.

The interaction between nelfinavir (750 mg 8 hourly) and a single dose of azithromycin (1200 mg) was evaluated in 12 healthy volunteers. Azithromycin caused a statistically, but not clinically, significant increase in the total clearance of nelfinavir from (33.1 L/h to 43.4 L/h) and M8 from (100 L/h to 130 L/h)and a decrease in AUC of nelfinavir (28%) and M8 (24%). Azithromycin Cmax and AUC were increased by greater than 100% in the presence of nelfinavir. The decrease in nelfinavir AUC is not thought to be of clinical significance, however, the increase in azithromycin exposure may be of clinical benefit. Further study of the mechanism and implications of this interaction are needed.
A study of the pharmacokinetics of azithromycin and nelfinavir when coadministered in healthy volunteers. Amsden GW, Nafziger AN, Foulds G, et al. J Clin Pharmacol, 2000, 40: 1522-1527.

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Not studied. Concomitant use of bosentan and nelfinavir may increase plasma levels of bosentan. When administered concomitantly with nelfinavir, the patient's tolerability of bosentan should be monitored.
Viracept Summary of Product Characteristics, Roche Products Ltd, September 2011.

Concentrations of bosentan may be increased when coadministered with nelfinavir. Coadministration of bosentan in patients on nelfinavir or coadministration of nelfinavir in patients on bosentan: start at or adjust bosentan to 62.5 mg once daily or every other day based upon individual tolerability.
Viracept Prescribing Information, Agouron Pharmaceuticals Inc, April 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

Bupropion metabolism is mediated primarily by CYP2B6 and in vitro data has pointed to nelfinavir, ritonavir and efavirenz being inhibitors of this enzyme. There is therefore potential for a drug interaction. This report is a case series aimed at documenting the clinical consequence of the co-administration of bupropion with nelfinavir, ritonavir, and efavirenz. The median duration of concomitant use was 8 months and ranged from 3 weeks to 2 years. There were no episodes of seizures documented in any of the medical records for patients who took bupropion with the CYP2B6 inhibitors. However, these data should be regarded as highly preliminary since: there is a low rate of seizure incidence in the literature, There were no PK measurements which are vital if we are to understand this interaction and no patients were receiving ritonavir at a dose above 100 mg bd. Further data are therefore required.
Concurrent use of bupropion with CYP2B6 inhibitors, nelfinavir, ritonavir and efavirenz: a case series. Park-Wyllie LY & Antoniou T. AIDS, 2003, 17: 638-640.

The hydroxylation of bupropion was studied in vitro using human liver microsomes. It was concluded that ritonavir, efavirenz and nelfinavir inhibited CYP2B6 and therefore bupropion hydroxylation. The IC50 for nelfinavir was 2.5 µM. This suggests that there is the potential for clinical drug interactions.
Ritonavir, efavirenz, nelfinavir inhibit CYP2B6 activity in vitro: Potential drug interactions with bupropion. Hesse LM, von Moltke LL, Snader RI, et al. Drug Met Dis, 2001, 29:100–102.

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.

In a study 11 patients received nelfinavir (750 mg three times daily) and cannabis cigarette (SMK), some patients received dronabinol (2.5 mg capsules) and some received placebo all three times a day. It was found that the AUC0-8h, Cmax and Cmin were reduced by 17.4, 12.2 and 10.2%, respectively for patients in the SMK arm. Although the decreases with SMK were statistically significant there was a large interindividual variability. It is unknown if these pharmacokinetic changes will confer long-term clinical significance.
The cannabinoids on the pharmacokinetics of indinavir and nelfinavir. Kosel BN, Aweeka FT, Benowitz NL, et al. AIDS, 2002, 16: 543-550.
Short-term safety of cannabinoids in HIV patients. Abrams D, Leiser R, Shade S, et al. 8th Conference on Retroviruses and Opportunistic Infections, 2001, abstract 744.

Coadministration is contraindicated with carbamazepine. Potent inducers of CYP3A (e.g., carbamazepine) may reduce nelfinavir plasma concentrations. Physicians should consider using alternatives when a patient is taking nelfinavir.
Viracept Summary of Product Characteristics, Roche Products Ltd, September 2011.

Carbamazepine may decrease nelfinavir plasma concentrations. Nelfinavir may not be effective due to decreased nelfinavir plasma concentrations in patients taking these agents concomitantly.
Viracept Prescribing Information, Agouron Pharmaceuticals Inc, April 2012.

A case was reported of a 50 year HIV+ man who developed excessive drowsiness following the introduction of lopinavir/ritonavir and it was found that his serum carbamazepine concentration had increased by 46%. The protease inhibitor was changed to nelfinavir, but within 3 days excessive drowsiness had developed, this time with an increase of 53% in serum carbamazepine concentrations. Decreasing the carbamazepine dose by 33% resulted in the resolution of symptoms on both instances.
Carbamezepine toxicity induced by lopinavir/ritonavir and nelfinavir. Bates DE, Herman RJ. Ann Pharmacother, 2006, 40: 1190-1195.

Carboplatin is excreted primarily by glomerular filtration in urine, with recovery of 65% of a dose within 24 hours. Most of the drug is excreted within the first 6 hours. Approximately 32% of a given dose of carboplatin is excreted unchanged.
Carboplatin 10 mg/ml Intravenous Infusion, UK Summary of Product Characteristics, Hospira UK Ltd, updated June 2009
Carboplatin Injection, US Prescribing Information, Hospira Inc, updated August 2007

Interaction of nine human hepatic cytochromes P450 (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) with six platinum complexes was studied using pooled human microsomes. The compounds used were cisplatin, oxaliplatin, carboplatin, transplatin, and trans-[PtCl2(NH3) (Am)], where Am=2-methylbutylamine or sec-butylamine. No significant inhibition of all CYP activities by carboplatin was observed.
Interaction of antitumor platinum complexes with human liver microsomal cytochromes P450. Masek V, Anzenbacherová E, Machová M et al.  Anticancer Drugs. 2009 Jun;20(5):305-11

An in vitro study determined CYP3A4 activities in human liver microsomes from 2 donors 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.  No inhibitory effect on CYP3A4 was observed with carboplatin.
Screening for inhibitory effects of antineoplastic agents on CYP3A4 in human liver microsomes. Baumhäkel M, Kasel D, Rao-Schymanski RA et al. Int J Clin Pharmacol Ther. 2001 Dec;39(12):517-28

Clinical studies in healthy volunteers show that the pharmacokinetics of caspofungin are not altered to a clinically relevant extent by nelfinavir. Although safety data are limited it appears that no special precautions are needed when nelfinavir are coadministered with caspofungin.
Cancidas Summary of Product Characteristics, Merck Sharp & Dohme Ltd, October 2004.

Clinical studies in healthy volunteers show that the pharmacokinetics of caspofungin are not altered by nelfinavir.
Cancidas Prescribing Information, Merck & Co, February 2005.

Coadministration of caspofungin (50 mg iv once daily for 14 days) and nelfinavir (1250 mg orally twice daily) was studied in 9 healthy volunteers. Although a slight elevation in caspofungin concentrations was noted on day 1, caspofungin pharmacokinetics on day 14 were unaltered by coadministration of nelfinavir. Caspofungin AUC and Ctrough increased on day 1 of coadministration (16% and 58% respectively), but by day 14 the increases in AUC (8%) and Ctrough (13%) were no longer statistically significant. This interaction is unlikely to be clinically meaningful and no dose adjustment is necessary when these two drugs are coadministered.
Potential for interactions between caspofungin and nelfinavir or rifampin. Stone JA, Migoya EM, Hickey L, et al. Antimicrob Agents Chemother, 2004, 48:4306-4314.

(See Summary)

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

The electrocardiographic effect of cetirizine was studied in 10 HIV+ subjects who were receiving PIs (details not given). No patient had significant electrocardiographic changes during cetirizine administration. The authors concluded that cetirizine is a safe antihistamine drug in patients treated with PIs.
Cetirizine is a safe antihistamine drug in HIV-infected patients under protease inhibitor treatment. Estrada JAL, Flores AD, Hernandez GC & Urdez HE. 13th International AIDS Conference, Durban, July 2000, abstract WePeB4229.

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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.

Concentrations of  ciclosporin and nelfinavir may be increased by coadministration.
Viracept Prescribing Information, Agouron Pharmaceuticals Inc, April 2012.

LHPG Comment: Citalopram is a weak inhibitor of CYP1A2 and CYP2D6, and has minimal or no inhibitory effect on CYP2C9, CYP2C19, CYP2E1 and CYP3A4. Therefore the potential for citalopram affecting the concentrations of other drugs is low. However, citalopram is extensively metabolised by CYP450; since there are no interaction data, caution is required as citalopram concentrations may be altered by other drugs.

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Based on early studies with 14C-labeled clomiphene citrate, the drug was shown to be readily absorbed orally in humans and excreted principally in the feces. Cumulative urinary and fecal excretion of the 14C averaged about 50% of the oral dose and 37% of an intravenous dose after 5 days. Mean urinary excretion was approximately 8% with fecal excretion of about 42%.
Clomid® (clomiphene citrate tablets USP) US Prescribing Information, Sanofi-aventis U.S. revised June 2006

A study aimed to define the role of CYP2D6 and CYP3A4 in the in vitro metabolism of enclomiphene, the more active isomer of clomiphene. Enclomiphene (25 microM) was incubated with human liver microsomes (from 4 extensive (EM) and 1 poor metaboliser with respect to CYP2D6) and with microsomes from lymphoblastoid cells expressing CYP2D6. Microsomes from all the EM livers and recombinant CYP2D6 metabolised enclomiphene (the disappearance of drug ranged from 40-60%). No metabolism was detected in microsomes from the PM liver. Quinidine (1 microM) completely inhibited the metabolism of enclomiphene by all the EM livers and by recombinant CYP2D6 (p<0.001, one way ANOVA). Ketoconazole (2 microM) had no significant effect on enclomiphene metabolism in 3 out of the 4 EM livers. The extent of enclomiphene metabolism was correlated with the amount of CYP2D6 present (p<0.001, Pearson correlation test). The findings indicate that CYP2D6 is primarily responsible for the metabolism of enclomiphene.
CYP2D6 is primarily responsible for the metabolism of clomiphene. Ghobadi C, Gregory A, Crewe HK, Rostami-Hodjegan A, Lennard MS. Drug Metab Pharmacokinet. 2008;23(2):101-5.

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The effect of CHOP chemotherapy (adriamycin, cyclophosphamide, vincristine and prednisolone) for non-Hodgkin’s lymphoma (NHL) on the pharmacokinetics of protease inhibitors was investigated in HIV-infected subjects receiving indinavir (800 mg three times daily, n=7) or nelfinavir (750 mg three times daily, n=3). Indinavir AUC when administered without CHOP was lower than expected (14.9 ± 9.5mg.h/L); however it increased by 38% (to 20.5 ± 9.0 vs mg.h/L, P=0.03) when given with CHOP and was then comparable to historical controls. When given without CHOP, indinavir trough concentrations at 0 and 8 h were below target (0.1 mg/L) in 3/7 patients; when given with CHOP no 0 h concentrations were below target and 2/7 8h concentrations were below target. Nelfinavir AUC and Cmax values were higher when given with CHOP, though this was not statistically significant (AUC 12.2 ± 3.6 vs 15.6 ± 7.0, Cmax 2.3 ± 0.3 vs 2.8 ± 1.5, alone vs with CHOP). The study suggests that patients with NHL may have lower PI concentrations and that CHOP increases PI concentrations. However, no dose modification of indinavir appears to be required, though TDM of PIs is recommended for HIV-infected patients receiving chemotherapy for NHL.
Pharmacokinetic interaction between chemotherapy for non-Hodgkin's lymphoma and protease inhibitors in HIV-1-infected patients. Cruciani M, Gatti G, Vaccher E, et al. J Antimicrob Chemother, 2005, 55(4):546-549.

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Protease Inhibitors and Non Nucleoside Reverse Transcriptase Inhibitors are known inhibitors of Cytochrome P450 IIIA (CYP-3A) and may also have a role in the inhibition of the drug transporting protein, P-glycoprotein (P-gp). Daunorubicin and other anthracyclines may undergo some metabolism by CYP-3A and are known substrates of P-gp. There is therefore a theoretical possibility of interaction between DaunoXome and these two groups of antiviral therapy. To date however, a single study has indicated that there is no effect of PI’s or NNRTI’s on DaunoXome’s pharmacokinetic properties. Limited data from one small study where patients were treated with and without protease inhibitors indicate that there were no major changes in DaunoXome associated toxicity.
DaunoXome® Injection (liposomal daunorubicin) UK Summary of Product Characteristics, Galen Ltd, updated October 2011

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LHPG Comment: Coadministration may inhibit the conversion of nelfinavir to its active metabolite M8; however, overall antiviral activity is unlikely to be altered.

Co-administration of nelfinavir with inhibitors of CYP2C19 (e.g., diazepam) may be expected to reduce the conversion of nelfinavir to its major active metabolite M8 (tert-butyl hydroxy nelfinavir) with a concomitant increase in plasma nelfinavir levels. Limited clinical trial data from patients receiving one or more of these medicinal products with nelfinavir indicated that a clinically significant effect on safety and efficacy is not expected. However, such an effect cannot be ruled out.
Viracept Summary of Product Characteristics, Roche Products Ltd, September 2011.

Co-administration with medicinal products with narrow therapeutic windows and which are substrates of CYP3A4 (e.g., ergot derivatives) is contraindicated.
Viracept Summary of Product Characteristics, Roche Products Ltd, September 2011.

The coadministration of ergot derivatives with nelfinavir is contraindicated due to potential for serious and/or life threatening reactions such as ergot toxicity characterised by peripheral vasospasm and ischemia of the extremities and other tissues.
Viracept Prescribing Information, Agouron Pharmaceuticals Inc, April 2012.

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LHPG Comment: Doxepin is metabolised by CYP2D6. Ritonavir is a known inhibitor of this enzyme and there is the potential for interaction in “boosted“ regimens where ritonavir is used as a pharmacoenhancer.

The pharmacokinetics of doxorubicin (when given as part of CHOP chemotherapy for non-Hodgkin’s lymphoma) were determined in 19 HIV+ subjects when given alone or with indinavir (800 mg/day, n=9), saquinavir (600 mg/day, n=6) or nelfinavir (800 mg/day, n=4). No significant effects on the pharmacokinetics (Cmax, AUC, clearance, half-life, volume of distribution) of doxorubicin were observed when doxorubicin was given with protease inhibitors (n=19). The effect of a single protease inhibitor was investigated separately and there was no significant difference due to a single PI.
Effect of highly active antiretroviral therapy (HAART) on pharmacokinetics and pharmacodynamics of doxorubicin in patients with HIV-associated non-Hodgkin's lymphoma. Toffoli G, Corona G, Cattarossi G, et al. Ann Oncol, 2004, 15(12):1805-1809.

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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(See Summary)

The effect of echinacea on CYP activity was assessed by use of a number of CYP probe drugs (caffeine for CYP1A2; tolbutamide for CYP2C9; dextromethorphan for CYP2D6 and midazolam for both hepatic and intestinal CYP3A) in a study in 12 healthy volunteers. The data demonstrated that echinacea caused inhibition of CYP1A2 and intestinal CYP3A activity and induction of hepatic CYP3A activity. The authors indicate that for CYP3A substrates (such as protease inhibitors), the type of drug interaction observed with echinacea will be dependent on the relative extraction of the drugs at hepatic and intestinal sites and will not be readily predicted. Certainly echinacea could contribute to inter-patient variability in protease inhibitor levels.
The effect of echinacea (Echinacea purpurea) root on cytochrome P450 activity in vivo. Gorski JC, Huang SM, Pinto A, et al. Clin Pharmacol Ther, 2004, 75: 89-100.

(See Summary)

Coadministration of efavirenz (600 mg once daily) and nelfinavir (750 mg three times daily) had a minimal effect (<10%) on efavirenz AUC and decreased nelfinavir AUC by 20%. No dosage adjustment for needed for either product.
Viracept Summary of Product Characteristics, Roche Products Ltd, September 2011.

Coadministration of nelfinavir (750 mg every 8 hours for 7 days) with efavirenz (600 mg once daily for 7 days), in 10 subjects caused a 12%, 12% and 22% decrease in efavirenz AUC, Cmax and Cmin, respectively. Nelfinavir AUC and Cmax increased by 20% and 21%, respectively, and there was no alteration in Cmin.
Viracept Prescribing Information, Agouron Pharmaceuticals Inc, April 2012.

Coadministration of nelfinavir (750 mg every 8 hours) and efavirenz (600 mg once daily) increased nefinavir AUC and Cmax by 20% and 21%, respectively. The combination was generally well tolerated. No dose adjustment is necessary for either medicinal product.
Sustiva Summary of Product Characteristics, Bristol-Myers Squibb Pharmaceuticals Ltd, April 2015.

Coadministration of nelfinavir (750 mg every 8 hours) and efavirenz (600 mg) was investigated in 10 subjects. A 21% and 20% increase in nelfinavir Cmax and AUC, respectively, was observed with no change in Cmin. The Cmax, AUC and Cmin of the metabolite AG-1402 (M8) was decreased by 40%, 37% and 43%, respectively. Efavirenz Cmax and AUC both decreased by 12% and Cmin decreased by 21%. No dose adjustment is recommended when efavirenz is given with nelfinavir.
Sustiva Prescribing Information, Bristol-Myers Squibb Company, March 2015.

Pharmacokinetic profiles were obtained from HIV+ patients receiving nelfinavir (1250 mg twice daily) and efavirenz (600 mg once daily) alone and in combination, 4 and 32 weeks of therapy. Data from 36 profiles of nelfinavir alone and 37 profiles of nelfinavir + efavirenz showed that efavirenz reduced nelfinavir AUC by 25% (from 30.5 to 22.8 µh.h/ml) and reduced Cmin by 45% (from 1.1 to 0.6 µg/ml); there was no significant effect on Cmax (4.3 vs 3.7 µg/ml). No significant differences in efavirenz pharmacokinetics when given alone or with nelfinavir were found (AUC 52.6 vs 43.8 µg.h/ml, alone vs combination).
Pharmacokinetics of nelfinavir and efavirenz in antiretroviral-naive, human immunodeficiency virus-infected subjects when administered alone or in combination with nucleoside analog reverse transcriptase inhibitors. Smith PF, Robbins GK, Shafer RW, et al. Antimicrob Agents Chemother, 2005, 49(8): 3558-3561.

The effect of efavirenz on the pharmacokinetics of nelfinavir and M8 was investigated in HIV+ subjects using full PK profiles (n=49) or single samples (n=552). Mean oral clearance (CL/F) estimates obtained with profiles were 59.9 L/h for NFV and 303 L/h for M8; estimates obtained with single samples were 45.4 L/h and 207 L/h respectively. Nelfinavir CL/F was significantly higher with coadministration of efavirenz (19% and 9%, higher, profiles and single samples respectively); M8 CL/F was higher by 43% and 77% (profiles and single samples respectively). These results indicating increased nelfinavir and M8 clearance in the presence of efavirenz contradict prior data reported in healthy subjects.
Effect of co-administration of efavirenz on the pharmacokinetics of nelfinavir and its active metabolite, M8, in ACTG 384. Labbé, L et al. 6th International Workshop on Clinical Pharmacology of HIV Therapy, Quebec, April 2005, abstract 22.

A pharmacokinetic study in 18 HIV+ individuals who were receiving efavirenz (600 mg once daily), nelfinavir (750 mg every 8 h) and stavudine showed that nelfinavir concentrations were consistent with those achieved without efavirenz. The authors conclude that no a priorii dose adjustment is required when nelfinavir is coadministered with efavirenz, however in 4/18 patients nelfinavir concentrations were below the MEC (400 ng/ml) and a strategy of adjusting nelfinavir dosage based on measurements of total body systemic exposure should be further evaluated.
Clinical pharmacokinetics of nelfinavir combined with efavirenz and stavudine during rescue treatment of heavily pretreated HIV-infected patients. Regazzi MB, Villani P, Maserati R, et al. J Antimicrob Chemother, 2000, 45:343–7.

Coadministration of efavirenz (600 mg once daily) and nelfinavir (750 mg every 8 h) resulted in a 20% increase in the AUC of nelfinavir and a 37% decrease in the AUC of the nelfinavir metabolite. There was a 21% increase in the Cmax of nelfinavir and a 40% decrease in the Cmax of the nelfinavir metabolite. Nelfinavir did not significantly alter the AUC or Cmax of efavirenz.
Pharmacokinetic interaction between efavirenz and nelfinavir mesylate in healthy volunteers. Fiske WD, Benedek IH, White SJ, et al. 5th Conference on Retroviruses and Opportunistic Infections, 1998, abstract 349.

Efavirenz/Amprenavir and 2nd PI

Efavirenz (600 mg once daily) was administered for 10 days to 5 groups of 11 volunteers. On day 11 amprenavir (600 mg once daily) was added; on days 15-21 one group remained on efavirenz/amprenavir whereas a second PI (nelfinavir, indinavir, ritonavir or saquinavir) was added to each of the four remaining. Efavirenz concentrations were measured on days 14 and 21. Addition of a second PI was not associated with significant changes in efavirenz clearance or exposure.
Pharmacokinetic interaction studies of efavirenz and protease inhibitors in HIV-seronegative volunteers. Ma Q, Forrest A, Okusanya OO, et al. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, October/November 2004, abstract A-459.

Efavirenz + Nelfinavir/Ritonavir (once daily)

The effect of efavirenz (600 mg once daily) on nelfinavir/ritonavir (1875/200 mg once daily) was studied in 24 healthy subjects. Following the addition of efavirenz, nelfinavir geometric mean AUC, Cmax and Cmin increased by 30%, 29% and 48% respectively. Nelfinavir Cmin increased in 21/24 subjects and decreased in 3/24 subjects. Ritonavir geometric mean AUC, Cmax and Cmin decreased by 20%, 24% and 12% respectively. Efavirenz exposure was similar to historical data.
Effect of efavirenz treatment on the pharmacokinetics of nelfinavir boosted by ritonavir in healthy volunteers. la Porte C, de Graaff-Teulen MJA, Colbers EPH, et al. Br J Clin Pharmacol, 2004, 58: 632-640.

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.

(See Summary)

Clinically significant interactions have not been observed between nelfinavir and nucleoside analogues.
Viracept Summary of Product Characteristics, Roche Products Ltd, September 2011.

In vitro, emtricitabine did not inhibit metabolism mediated by any of the following human CYP450 isoforms: 1A2, 2A6, 2B6, 2C9, 2C19, 2D6 and 3A4. Emtricitabine did not inhibit the enzyme responsible for glucuronidation. Based on the results of these in vitro experiments and the known elimination pathways of emtricitabine, the potential for CYP450 mediated interactions involving emtricitabine with other medicinal products is low.
Emtriva Summary of Product Characteristics, Gilead Sciences International Ltd, November 2016.

At concentrations up to 14-fold higher than those observed in vivo, emtricitabine did not inhibit in vitro drug metabolism mediated by any of the following human CYP450 isoforms: CYP1A2, CYP2A6, CYP2B6, CYP 2C9, CYP2C19, CYP2D6 and CYP3A4. Emtricitabine did not inhibit the enzyme responsible for glucuronidation (uridine-5’-disphosphoglucuronyl transferase). Based on the results of these in vitro experiments and the known elimination pathways of emtricitabine, the potential for CYP450 mediated interactions involving emtricitabine with other medicinal products is low.
Emtriva Prescribing Information, Gilead Sciences Inc, November 2012.

The co-administration of Descovy is not recommended with HIV protease inhibitors (PIs) other than atazanavir, lopinavir and darunavir. There are no data available to make dosing recommendations for co-administration.
Descovy Summary of Product Characteristics, Gilead Sciences Ltd, April 2016.

(See Summary)

Co-administration with medicinal products with narrow therapeutic windows and which are substrates of CYP3A4 (e.g., ergot derivatives) is contraindicated.
Viracept Summary of Product Characteristics, Roche Products Ltd, September 2011.

The coadministration of ergot derivatives with nelfinavir is contraindicated due to potential for serious and/or life threatening reactions such as ergot toxicity characterised by peripheral vasospasm and ischemia of the extremities and other tissues.
Viracept Prescribing Information, Agouron Pharmaceuticals Inc, April 2012.

Co-administration with medicinal products with narrow therapeutic windows and which are substrates of CYP3A4 (e.g., ergot derivatives) is contraindicated.
Viracept Summary of Product Characteristics, Roche Products Ltd, September 2011.

The coadministration of ergot derivatives with nelfinavir is contraindicated due to potential for serious and/or life threatening reactions such as ergot toxicity characterised by peripheral vasospasm and ischemia of the extremities and other tissues.
Viracept Prescribing Information, Agouron Pharmaceuticals Inc, April 2012.

A case report described an interaction between nelfinavir and ergotamine. An HIV + patient was receiving nelfinavir as part of HAART therapy and self-administered antimigraine medication containing ergotamine (2 mg ergotamine tartrate and 200 mg caffeine). The patient experienced pain and cyanosis in all her toes, these symptoms subsided within 15 days. Eight months later she took the same antimigraine treatment and symptoms of cyanosis and oedema in her feet and hands developed, with severe pain. No specific treatment was given and the symptoms eventually subsided.
Ergotism related to interaction between nelfinavir and ergotamine. Mortier E, Pouchot J & Vinceneux P. Am J Med, 2001, 110: 594.

Coadministration of ethinylestradiol/norethindrone (0.035/0.40 mg once daily for 15 days) and nelfinavir (750 mg three times daily for 7 days) decreased ethinylestradiol AUC by 47% and norethindrone AUC by 18%. Contraceptives with ethinyl estradiol and norethindrone should not be coadministered with nelfinavir. Alternative contraceptive measures should be considered.
Viracept Summary of Product Characteristics, Roche Products Ltd, September 2011.

Concentrations of ethinyl estradiol were decreased when coadministered with nelfinavir.Coadministration of nelfinavir (750 mg every 8 hours for 7 days) with ethinylestradiol (35 µg once daily for 15 days) caused a 47%, 28% and 62% decrease in ethinylestradiol AUC, Cmax and Cmin, respectively. Alternative or additional contraceptive measures should be used when oral contraceptives containing ethinyl estradiol and nelfinavir are coadministered.
Viracept Prescribing Information, Agouron Pharmaceuticals Inc, April 2012.

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

(See Summary)

(See Summary)

It is not recommended to coadminister etravirine with nelfinavir. Coadministration has not been studied. Etravirine is expected to increase nelfinavir plasma concentrations.
Intelence Summary of Product Characteristics, Janssen-Cilag Ltd, March 2012.

Etravirine should not be co-administered with PIs without low-dose ritonavir. Concomitant use of etravirine with PIs without coadministration of low-dose ritonavir may cause a significant alteration in the plasma concentrations of the PI. Nelfinavir concentrations may be increased.
Intelence Prescribing Information, Tibotec Pharmaceuticals Ltd, March 2012.

(See Summary)

Coadministration of nelfinavir and drugs primarily metabolized by CYP3A (e.g., dihydropyridine calcium channel blockers) may result in increased plasma concentrations of the other drug that could increase or prolong both its therapeutic and adverse effects.
Viracept Prescribing Information, Agouron Pharmaceuticals Inc, April 2012.

(See Summary)

Co-administration of nelfinavir with inhibitors of CYP2C19 (e.g., fluconazole) may be expected to reduce the conversion of nelfinavir to its major active metabolite M8 (tert-butyl hydroxy nelfinavir) with a concomitant increase in plasma nelfinavir levels. Limited clinical trial data from patients receiving one or more of these medicinal products with nelfinavir indicated that a clinically significant effect on safety and efficacy is not expected. However, such an effect cannot be ruled out.
Viracept Summary of Product Characteristics, Roche Products Ltd, September 2011.

Co-administration of nelfinavir with inhibitors of CYP2C19 (e.g., fluoxetine) may be expected to reduce the conversion of nelfinavir to its major active metabolite M8 (tert-butyl hydroxy nelfinavir) with a concomitant increase in plasma nelfinavir levels. Limited clinical trial data from patients receiving one or more of these medicinal products with nelfinavir indicated that a clinically significant effect on safety and efficacy is not expected. However, such an effect cannot be ruled out.
Viracept Summary of Product Characteristics, Roche Products Ltd, September 2011.

The metabolism of fluvastatin is not dependent on CYP3A4, and interactions are not expected with nelfinavir. If treatment with HMG-CoA reductase inhibitors is indicated in combination with nelfinavir, pravastatin or fluvastatin is recommended.
Viracept Summary of Product Characteristics, Roche Products Ltd, September 2011.

(See Summary)

(See Summary)

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

(See Summary)

(See Summary)

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.

(See Summary)

(See Summary)

(See Summary)

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.

(See Summary)

(See Summary)

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.

(See Summary)

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

(See Summary)

(See Summary)

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.

Isosorbide dinitrate is readiliy absorbed from the oral mucosa and also following oral administration. It undergoes extensive first pass metabolism, mainly in the liver.
Isosorbide Dinitrate Tablets BP 20mg UK Summary of Product Characteristics, Actavis UK Ltd, updated October 2011

Isosorbide dinitrate (ISDN) is eliminated from plasma with a short half-life (about 0.7h). The metabolic degradation of ISDN occurs via denitration and glucuronidation, like all organic nitrates. The rate of formation of the metabolites has been calculated for isosorbide-5-mononitrate (IS-5-MN) with 0.27 h -1, and isosorbide (IS) with 0.16 h-1. IS-5-MN and IS-2-MN are the primary metabolites which are also pharmacologically active. IS-5-MN is metabolised to isosorbide 5-mononitrate-2-glucuronide (IS-5-MN-2-GLU). The half-life of this metabolite (about 2.5h) is shorter than that of IS-5-MN (about 5.1h). The half-life of ISDN is the shortest of all and that of IS-2-MN (about 3.2h) lies in between.
Isoket® (Isosorbide dinitrate) 1mg/ml injection/infusion UK Summary of Product Characteristics, UCB Pharma Limited, updated July 2010

A study was designed to elucidate the role of human cytochrome P450 isoforms on nitric oxide formation from organic nitrates using lymphoblast microsomes transfected with human CYP isoforms cDNA. CYP3A4-transfected microsomes had the most effective potential of nitric oxide formation from isosorbide dinitrate. Anti-CYP3A2 antibody (which cross-reacts with CYP3A4) or ketoconazole (an inhibitor of the CYP3A superfamily) inhibited nitric oxide formation from isosorbide dinitrate in rat heart microsomes. Immunohistochemistry of human heart also showed intense bindings of CYP3A4 antibody in the endothelium of the endocardium and coronary vessels. These results suggest that the CYP3A4-NADPH-cytochrome P450 reductase system specifically participates in nitric oxide formation from isosorbide dinitrate.
Minamiyama Y, Takemura S, Akiyama T et al. Isoforms of cytochrome P450 on organic nitrate-derived nitric oxide release in human heart vessels. FEBS Lett. 1999 Jun 11;452(3):165-9.

Coadministration of nelfinavir and a strong inhibitor of CYP3A, ketoconazole, resulted in a 35% increase in nelfinavir plasma AUC. The changes in nelfinavir concentrations are not considered clinically significant and no dose adjustment is needed when ketoconazole and nelfinavir are co-administered.
Viracept Summary of Product Characteristics, Roche Products Ltd, September 2011.

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Clinically significant interactions have not been observed between nelfinavir and nucleoside analogues.
Viracept Summary of Product Characteristics, Roche Products Ltd, September 2011.

Coadministration of nelfinavir (750 mg every 8 hours for 7-10 days) with single doses of lamivudine (150 mg) and zidovudine (200 mg), in 11 subjects, caused a 10% and 31% increase in lamivudine AUC and Cmax, respectively, and a 35% and 31% decrease in zidovudine AUC and Cmax, respectively. Cmin determination was not relevant for single-dose. Nelfinavir AUC, Cmax and Cmin were unaltered.
Viracept Prescribing Information, Agouron Pharmaceuticals Inc, April 2012.

Lamivudine metabolism does not involve CYP3A, making interactions with medicinal products metabolised by this system (e.g. PIs) unlikely.
Epivir Summary of Product Characteristics, ViiV Healthcare UK Ltd, July 2016.

The absorption of nelfinavir may be reduced in situations where the gastric pH is increased irrespective of cause. Co-administration of nelfinavir with omeprazole is contra-indicated. Caution is recommended when nelfinavir is co-administered with other proton pump inhibitors. Co-administration of nelfinavir with inhibitors of CYP2C19 (e.g., lansoprazole) may be expected to reduce the conversion of nelfinavir to its major active metabolite M8 (tert-butyl hydroxy nelfinavir) with a concomitant increase in plasma nelfinavir levels. Limited clinical trial data from patients receiving one or more of these medicinal products with nelfinavir indicated that a clinically significant effect on safety and efficacy is not expected. However, such an effect cannot be ruled out.
Viracept Summary of Product Characteristics, Roche Products Ltd, September 2011.

Coadministration is contraindicated with strong inhibitors of CYP3A4. An interaction study with a strong CYP3A4 inhibitor, ketoconazole, has shown a considerable increase in plasma levels of lercanidipine (a 15-fold increase of the AUC and an 8-fold increase of the Cmax for the eutomer S-lercanidipine). Coadministration of lercanidipine with inhibitors of CYP3A4 (e.g. ketoconazole, itraconazole, ritonavir, erythromycin, troleandomycin) should be avoided.
Lercanidipine Summary of Product Characteristics, Winthrop Pharmaceuticals UK Limited, August 2010.

(See Summary)