The Effect of Single and Multiple Doses of Rifampin on the Pharmacokinetics of Doravirine in Healthy Subjects.

BACKGROUND AND OBJECTIVE: Doravirine is a novel, next-generation, non-nucleoside reverse transcriptase inhibitor in development for the treatment of human immunodeficiency virus-1 infection in combination with other antiretrovirals. Doravirine is a substrate for cytochrome P450 (CYP) 3A and P-glycoprotein. Rifampin (rifampicin) is used for treating tuberculosis in patients who are co-infected with human immunodeficiency virus. Rifampin demonstrates organic anion-transporting polypeptide 1B1 and P-glycoprotein inhibition after single-dose administration and CYP3A and P-glycoprotein induction after multiple-dose administration. The objective of this study was to evaluate the effects of co-administration of single and multiple doses of rifampin on doravirine pharmacokinetics. METHODS: In period 1 of this open-label, two-period, fixed-sequence study in healthy adults, subjects received single-dose doravirine 100 mg; blood samples for measuring plasma concentration were collected pre-dose and up to 72 h post-dose. In period 2, following a 7-day washout, subjects received doravirine 100 mg and rifampin 600 mg on day 1, rifampin 600 mg daily on days 4-18, with doravirine 100 mg co-administered on day 17; blood samples were collected pre-dose and up to 72 h post-dose on day 1 and up to 48 h post-dose on day 17. Safety assessments included adverse events, physical examinations, vital signs, and clinical laboratory measurements. RESULTS: Ten subjects completed the study. Doravirine area under the concentration-time curve from time zero extrapolated to infinity and plasma concentration at 24 h post-dose were comparable in the presence and absence of single-dose rifampin [geometric mean ratios (90% confidence intervals)] of 0.91 (0.78-1.06) and 0.90 (0.80-1.01), respectively. Doravirine maximum plasma concentration increased when co-administered with single-dose rifampin vs. doravirine alone, geometric mean ratio (90% confidence interval): 1.40 (1.21-1.63). Reductions in doravirine geometric mean ratios (90% confidence interval), area under the concentration-time curve from time zero extrapolated to infinity: 0.12 (0.10-0.15), plasma concentration at 24 h post-dose: 0.03 (0.02-0.04), maximum plasma concentration: 0.43 (0.35-0.52), and apparent terminal half-life were observed when co-administered with multiple-dose rifampin vs. doravirine administered alone. Doravirine was well tolerated. Adverse events were mild and resolved by study completion. CONCLUSIONS: Doravirine co-administration with single-dose rifampin indicated that inhibition of organic anion-transporting polypeptide uptake transporters and P-glycoprotein has little impact on doravirine pharmacokinetics. Long-term co-administration of rifampin or other strong CYP3A inducers with doravirine will likely reduce its efficacy.

Efavirenz does not meaningfully affect the single dose pharmacokinetics of 1200 mg raltegravir.

Raltegravir is a human immunodeficiency virus (HIV)-1 integrase strand transfer inhibitor currently marketed at a dose of 400 mg twice daily (BID). Raltegravir for once daily regimen (QD) at a dose of 1200 mg (2 x 600 mg) is under development and offers a new treatment option for HIV-1 infected treatment-naive subjects. Since raltegravir is eliminated mainly by metabolism via an UDP-glucuronosyltransferase (UGT) 1 A1-mediated glucuronidation pathway, co-administration of UGT1A1 inducers may alter plasma levels of raltegravir. Efavirenz, an UGT1A1 inducer, was used to assess the impact of altered UGT activity on a 1200 mg QD dose of raltegravir. An open label, randomized, 2-period fixed-sequence Phase 1 study was performed in adult healthy male and female subjects (non-childbearing potential) ≥ 19 and ≤55 years of age, with a body mass index (BMI) ≥ 18.5 and ≤32.0 kg/m2 . Subjects (n = 21) received a single oral dose of 1200 mg raltegravir at bedtime on an empty stomach on Day 1 in Period 1. After a washout period of at least 7 days, subjects received oral doses of 600 mg efavirenz QD at bedtime for 14 consecutive days in Period 2. Subjects received a single oral dose of 1200 mg raltegravir co-administered with 600 mg efavirenz on Day 12 of Period 2. Pharmacokinetic (PK) samples were collected for 72 hours following raltegravir dosing and analyzed using a validated bioanalytical method to quantify raltegravir plasma concentrations. PK parameters were estimated using non-compartmental analysis. Administration of single 1200 mg oral doses of raltegravir alone and co-administered with multiple oral doses of efavirenz were generally well tolerated in healthy subjects. Co-administration with efavirenz yielded geometric mean ratios (GMRs) and their associated 90% confidence intervals (90% CIs) for raltegravir AUC0-∞, Cmax , and C24 of 0.86 (0.73, 1.01), 0.91 (0.70, 1.17), and 0.94 (0.76, 1.17), respectively. The results show that efavirenz modestly reduced the exposure of raltegravir. The reduction in raltegravir exposure is not considered clinically meaningful. Copyright © 2016 John Wiley & Sons, Ltd.

Atazanavir increases the plasma concentrations of 1200 mg raltegravir dose.

Raltegravir is a human immunodeficiency virus (HIV)-1 integrase strand transfer inhibitor currently marketed at a dose of 400 mg twice-daily (b.i.d.). Raltegravir 1200 mg once-daily (q.d.) (investigational q.d. formulation of 2 × 600 mg tablets; q.d. RAL) was found to be generally well tolerated and non-inferior to the marketed 400 mg b.i.d. dose at 48 weeks in a phase 3 trial. Since raltegravir is eliminated mainly by metabolism via a uridine diphosphate glucuronosyltransferase (UGT) 1A1-mediated glucuronidation pathway, co-administration of UGT1A1 inhibitors may increase the plasma levels of q.d. RAL. To assess this potential, the drug interaction of 1200 mg raltegravir using atazanavir, a known UGT1A1 inhibitor, was studied. An open-label, randomized, 2-period, fixed-sequence phase 1 study was performed in adult healthy male and female (non-childbearing potential) subjects ≥ 19 and ≤ 55 years of age, with a body mass index (BMI) ≥ 18.5 and ≤ 32.0 kg/m2 . Subjects (n = 14) received a single oral dose of 1200 mg raltegravir in period 1. After a washout period of at least 7 days, the subjects received oral doses of 400 mg atazanavir q.d. for 9 consecutive days, with a single oral dose of 1200 mg raltegravir co-administered on day 7 of period 2. Serial blood samples were collected for 72 h following raltegravir dosing and analysed using a validated bioanalytical method to quantify raltegravir plasma concentrations. Co-administration with atazanavir yielded GMRs (90% CIs) for raltegravir AUC0-∞ , Cmax and C24 of 1.67 (1.34, 2.10), 1.16 (1.01, 1.33) and 1.26 (1.08, 1.46), respectively. There was no effect of raltegravir on serum total bilirubin. In contrast, atazanavir increased the mean bilirubin by up to 200%, an effect that was preserved in the atazanavir/raltegravir treatment group. Administration of single q.d. RAL alone and co-administered with multiple oral doses of atazanavir were generally well tolerated in healthy subjects. The results show that atazanavir increased the PK exposure of raltegravir; therefore, co-administration of atazanavir with raltegravir q.d. is not recommended. Copyright © 2016 John Wiley & Sons, Ltd.