Journal Article

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

Brejda, John, Khalilieh, Sauzanne G., Sanchez, Rosa I., Liu, Rachael, Judge, Timothy, Anderson, Matt S., Butterton, Joan R., Yee, Ka Lai, Manthos, Helen

2017

Overview

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.

• Publisher: Springer International Publishing,Springer Nature B.V
• Subject: Acquired immune deficiency syndrome / Adult / AIDS / Antimicrobial agents / Antiretroviral drugs / Area Under Curve / ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism / Chemotherapy / Confidence intervals / Cytochrome / Cytochrome P-450 CYP3A - metabolism / Cytochrome P-450 CYP3A Inducers - pharmacology / Drug dosages / Enzymes / Food / Half-Life / Health care / HIV / Human immunodeficiency virus / Humans / Infections / Internal Medicine / Male / Medicine / Medicine & Public Health / Middle Aged / Original Research Article / Pharmacokinetics / Pharmacology/Toxicology / Pharmacotherapy / Polypeptides / Pyridones - pharmacokinetics / Reverse Transcriptase Inhibitors - pharmacokinetics / Rifampin - administration & dosage / Rifampin - pharmacology / Solute Carrier Organic Anion Transporter Family Member 1b1 - metabolism / Triazoles - pharmacokinetics / Tuberculosis / Young Adult