Coadministration of rifampicin (400 mg single dose) decreased raltegravir AUC, C12 and Cmax by 40%, 61% and 38%, respectively. If co-administration with rifampicin is unavoidable, a doubling of the dose of twice daily raltegravir can be considered. Rifampicin has not been studied with raltegravir 1,200 mg once daily, but could result in decreased raltegravir trough plasma levels; based on the reduction in trough concentrations observed with raltegravir 400 mg twice daily; therefore, co-administration with raltegravir 1,200 mg once daily is not recommended. 
Isentress 600 mg Summary of Product Characteristics, Merck Sharp & Dohme Ltd, September 2021.

Coadministration with rifampin decreased raltegravir concentrations. The recommended dose of raltegravir coadministered with rifampin is 800 mg twice daily. There are no data to guide coadministration of raltegravir with rifampin in patients below 18 years of age. Coadministration is not recommended with once daily raltegravir. Coadministration of rifampin (600 mg once daily) and raltegravir (400 mg single dose) to 9 subjects decreased raltegravir AUC (40%), Cmax (38%) and Cmin (61%). Coadministration of rifampin (600 mg once daily) and raltegravir (400 mg twice daily given alone or 800 mg twice daily given with rifampin) to 14 subjects increased raltegravir AUC (27%) and Cmax (62%), but decreased Cmin (53%).
Isentress Prescribing Information, Merck & Co Inc, August 2021.

The pharmacokinetics of raltegravir were determine following the administration of chewable raltegravir given at 12 mg/kg (twice the usual paediatric dose) to HIV/TB coinfected children receiving rifampicin. Children were recruited into two age-defined groups: cohort 1 (2 to <6 years old; n=12) and cohort 2 (6 to <12 years old; n=12). Pharmacological targets (AUC12 h of 14-45 μmol/L.h and C12 h ≥75 nmol/L) were reached in both cohort 1 (28.8 μmol/L. h and 229 nmol/L) and cohort 2 (38.8 μmol/L.h and 228 nmol/L. Raltegravir-based ART was well tolerated by most participants and at week 8, 22 of 24 participants (92%) had HIV RNA concentrations below 400 copies/ml, with 19 of 24 (79%) being below 50 copies/ml. These results suggest that in HIV and TB co-infected children aged 2 to 12 years, the chewable formulation of raltegravir at a dose of 12mg/kg twice daily safely achieved pharmacokinetic levels similar to HIV-1-infected children receiving the current recommended dose of 6 mg/kg/dose and not on treatment for TB.
Pharmacokinetics and safety of a raltegravir-containing regimen in HIV-infected children aged 2-12 years on rifampicin for tuberculosis. Meyers T, Samson P, Acosta EP, et al. AIDS. 2019;33(14):2197-2203.

The pharmacokinetic of raltegravir were determined in 13 HIV/TB coinfected infants and children (aged 4 weeks to two years) receiving rifampicin. Raltegravir chewable tablets were crushed and dispersed in liquid and administered at 12 mg/kg twice daily (twice the approved dose). Raltegravir pharmacokinetic targets were defined as 14-45 µM.h for AUC12h and ≥75 nM (33 ng/mL) for C12h. Cohort pharmacokinetic targets were achieved for AUC12h (32.7 µM.h) and C12h (106.5 nM). None of the 13 participants who received raltegravir experienced any adverse events deemed at least possibly related to raltegravir. Evaluable efficacy data at week 8 was available in 12 of the 13 participants (1/13 discontinued raltegravir prior to the week 8 visit, but after PK collection, due to disallowed medications). Protocol-defined virologic responses occurred in 11/12 participants, with a median change in HIV viral load of –3.05 log10 copies/mL. The one participant who did not meet the virological response criterion 8 had PK values that were within the range of target values but was ill at the time of virological failure. Malabsorption was suspected but not proven. Further experience with raltegravir and other integrase inhibitors during treatment with rifampicin is needed in children in this age range to better define the potency of such regimens.
Pharmacokinetics and safety of a raltegravir-containing regimen in children aged 4 weeks to 2 years living with human immunodeficiency virus and receiving rifampin for tuberculosis. Krogstad P, Samson P, Acosta EP, et al. J Pediatric Infect Dis Soc. 2020, ePub ahead of print.

Coadministration of rifampicin (10 mg/kg/day) and raltegravir (in combination with tenofovir-DF and lamivudine) was studied in two groups. Patients in arm 1 (n=21), received raltegravir (400 mg twice daily) whereas in arm 2 (n=16), patients received raltegravir at a higher dose (800 mg twice daily initially then 400 mg twice daily 4 weeks after rifampicin discontinuation). Pharmacokinetic sampling was performed over 12-hour periods, 4 weeks after initiation of raltegravir together with rifampicin (period 1), 4 weeks after rifampicin discontinuation (period 2), and after the raltegravir dose reduction in arm 2 (period 3).In arm 1, the geometric mean ratio (GMR) between period 1 and period 2 was 0.94 (90% confidence interval [CI], .64-1.37) for AUC, and 0.69 (90% CI, .42-1.13) for C12. In arm 2, the corresponding GMRs were 0.75 (90% CI, .48-1.17) and 1.10 (90% CI, .61-2.00) for period 1 vs period 2, and 1.10 (90% CI, .78-1.55) and 1.68 (90% CI, .88-3.23) for period 1 vs period 3. The double dose of raltegravir overcompensated for rifampicin induction, but the standard dose was associated with only small decreases in AUC and C12 during rifampicin coadministration, warranting further evaluation in patients with HIV/tuberculosis coinfection. 
Pharmacokinetics of raltegravir in HIV-infected patients on rifampicin-based antitubercular therapy. Taburet AM, Sauvageon H, Grinsztejn B, et al. Clin Infect Dis, 2015, 61:1328-1335.

Over a period of 38 days, healthy subjects received 5 days of standard-dose raltegravir (400 mg twice daily) followed by 28 days of standard-dose raltegravir plus rifampicin three times a week followed by 5 days of high-dose (800 mg twice daily) raltegravir plus rifampicin three times a week. Sixteen subjects (12 females) completed the study. Raltegravir trough plasma concentration (C12) was significantly lower in the presence of rifampicin when dosed at 400 mg twice daily (40%), which was not observed with 800 mg twice daily dosing. Raltegravir Cmax and AUC were both significantly higher in the presence of rifampicin when dosed at 800 mg twice daily (76% and 84%, respectively), but this dose was well tolerated. This study suggests that rifampicin induction of raltegravir is comparable between daily and intermittent rifampicin. In the absence of definitive clinical efficacy data to suggest otherwise, doses of 800 mg of raltegravir twice daily with rifampicin thrice weekly are well tolerated and yield higher AUCs and comparable C12 when compared with raltegravir alone. 
Effect of intermittent rifampicin on the pharmacokinetics and safety of raltegravir. Reynolds HE, Chrdle A, Egan D, et al. J Antimicrob Chemother, 2015, 70:550-554.

In a multicentre, randomised trial at eight sites in Brazil and France, 155 antiretroviral-naive adult patients with HIV-1 and tuberculosis (aged ≥18 years with a plasma HIV RNA concentration of >1000 copies per mL) were randomised to receive raltegravir 400 mg twice daily, raltegravir 800 mg twice daily, or efavirenz 600 mg once daily plus tenofovir and lamivudine. Patients began study treatment after the start of tuberculosis treatment. 153 (51 in each group) received at least one dose of the study drug and were included in the primary analysis. 133 patients (87%) completed follow-up at week 48. At week 24, virological suppression was achieved in 39 patients (76%, 95% CI 65-88) in the raltegravir 400 mg group, 40 patients (78%, 67-90) in the raltegravir 800 mg group, and 32 patients (63%, 49-76) in the efavirenz group. The adverse-event profile was much the same across the three groups. Three (6%) patients allocated to efavirenz and three (6%) patients allocated to raltegravir 800 mg twice daily discontinued the study drugs due to adverse events. Seven patients died during the study (one in the raltegravir 400 mg group, four in the raltegravir 800 mg group, and two in the efavirenz group): none of the deaths was deemed related to study treatment. Raltegravir 400 mg twice daily might be an alternative to efavirenz for the treatment of patients co-infected with HIV and tuberculosis. 
Raltegravir for the treatment of patients co-infected with HIV and tuberculosis (ANRS 12 180 Reflate TB): a multicenter, phase 2, non-comparative, open-label, randomized trial. Grinsztejn B, de Castro N, Arnold V, et al. Lancet Infect Dis, 2014, 14:459-467.

Two studies were conducted to examine the effect of rifampicin administration on raltegravir pharmacokinetics. Study 1 examined rifampicin (600 mg once daily) on the PK of single dose raltegravir (400 mg); study 2 examined rifampicin (600 mg once daily) on the PK of raltegravir (800 mg twice daily) compared to raltegravir alone (400 mg twice daily). The results demonstrated a substantial effect of rifampicin. In study 1 raltegravir exposure decreased by 61% (C12h), 40% (AUC) and 38% (Cmax). In study 2, raltegravir trough concentrations decreased by 53%, but AUC and Cmax increased by 27% and 62%. Doubling the dose of raltegravir to 800 mg when given with rifampicin compensated for the effect on AUC but not on C12h. On the basis of these data, the recommendation is that if coadministration is unavoidable, a doubling of the raltegravir dose should be considered. 
Effect of rifampin, a potent inducer of drug metabolising enzymes, on the pharmacokinetics of raltegravir. Wenning LA, Hanley WD, Brainard DM, et al. Antimicrob Agents Chemother, 2009, 53(7): 2852-2856.

It was investigated whether increasing raltegravir to 800 mg twice daily when given with rifampicin (600 mg once daily) could overcome the inducing effect of rifampicin. When compared to raltegravir alone (400 mg twice daily), coadministration of the higher dose with rifampicin decreased raltegravir trough concentrations by 53%, but increased AUC and Cmax by 27% and 62%, respectively. Therefore, doubling the dose of raltegravir does not overcome the effect of rifampicin on raltegravir trough concentrations. 
Doubling the dose of raltegravir does not increase trough levels in the presence of rifampin. Brainaird DM, Petry A, Hanley WD, et al. 48th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, October 2008, abstract A-964.

The effect of rifampicin (600 mg once daily for 14 days) on the pharmacokinetics of a single dose of raltegravir (400 mg) was studied in 10 HIV- subjects. Rifampicin reduced the Cmin, AUC and Cmax of raltegravir by 61%, 40% and 38%, respectively.
Rifampin modestly reduces plasma levels of MK-0518. Iwamoto M, et al. 8th International Congress on Drug Therapy in HIV Infection, Glasgow, November 2006, abstract 299.