Doravirine dose Selection and 96-Week Safety and Efficacy versus Efavirenz in Antiretroviral Therapy-Naive Adults with HIV-1 Infection in a Phase IIb Trial

Abstract

Background: The safety and efficacy of doravirine were compared with that of efavirenz as initial treatment of adults living with HIV-1 infection (NCT01632345). Methods: A Phase IIb double-blind trial with participants stratified by screening HIV-1 RNA (≤ or >100,000 copies/ml) and randomized 1:1:1:1:1 to receive oncedaily doravirine (25, 50, 100 or 200 mg) or efavirenz 600 mg (Part I) for up to 96 weeks, with open-label tenofovir disoproxil fumarate 300 mg/emtricitabine 200 mg (TDF/FTC). After dose selection at week 24, doravirine 100 mg was provided to participants receiving the other doses of doravirine and additional participants were randomized 1:1 to receive once-daily doravirine 100 mg or efavirenz 600 mg for 96 weeks with TDF/FTC (Part II). Primary outcomes were the proportion of participants with HIV-1 RNA <40 copies/ml at week 24, and central nervous system (CNS) adverse events (AEs) by weeks 8 and 24 (Parts I+II combined). Results: 210 and 132 participants were randomized in Parts I and II, respectively, and 216 (108 on doravirine 100 mg, 108 on efavirenz) were evaluable for Parts I+II combined. At week 24, the proportion of participants with HIV-1 RNA <40 copies/ml was 72.9% for doravirine 100 mg and 73.1% for efavirenz (difference -0.5 [95% CI -12.3, 11.2]). In addition, CNS AEs were reported by 26.9% and 47.2% of doravirine and efavirenz recipients, respectively (difference -20.4 [95% CI -32.6, -7.5]; P=0.002). Conclusions: Doravirine 100 mg with TDF/FTC demonstrated similar antiretroviral activity and superior CNS safety compared with efavirenz 600 mg with TDF/FTC.

Clinical Pharmacokinetics of the Novel HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitor Doravirine: An Assessment of the Effect of Patient Characteristics and Drug–Drug Interactions

“…A 40% decrease in doravirine C 24 also corresponds approximately to the C 24 values associated with the 50 mg once-daily dose and is nearly twice the C 24 associated with the 25 mg once-daily dose [ 14 ], which were studied in the phase IIb trial and had efficacy similar to 100 mg once daily [ 17 ]. Even at this decreased C 24 , doravirine plasma concentrations exceed the pharmacokinetic target of 78 nM, which is greater than 6-fold the in vitro IC 50 for inhibition of wild-type virus, and exceeds IC 50 values for common single resistance mutations (K103N, Y181C, G190A), and of the K103N/Y181C double mutant [ 16 , 18 , 19 ].…”

“…In phase I trials, there was no evidence that the incidence of overall AEs or specific AEs was temporally associated with doravirine T max [ 11 , 15 , 20 – 31 ], therefore suggesting that C max does not play a major role in safety or tolerability. In the phase IIb trial, there was no evidence of exposure- or dose-related toxicities across the range of 25–200 mg doses evaluated, and no meaningful association between doravirine steady-state exposure and the incidence of neuropsychiatric AEs or fasting lipid levels that would further limit the exposure of doravirine from a safety perspective [ 17 ].…”

Physiologically Based Pharmacokinetic Modeling of Doravirine and Its Major Metabolite to Support Dose Adjustment With Rifabutin

“…In the case of the recommended doravirine dose adjustment to 100 mg twice daily in the presence of rifabutin, where the total daily dose is doubled, the increase in M9 exposure is therefore predicted to be approximately 2.4‐fold relative to the exposure of doravirine at the recommended dose of 100 mg once daily in the absence of induction. The approximately 2‐fold increase in M9 exposure is within the range of clinical experience with M9, as doravirine doses up to 200 mg once daily have been evaluated in a phase 2 trial 26 and supports the recommended dose adjustment to 100 mg twice daily doravirine when coadministered with rifabutin 2…”

<p>Doravirine and Its Potential in the Treatment of HIV: An Evidence-Based Review of the Emerging Data</p>

“…The greatest amount of data existing on doravirine is derived from the DRIVE trials along with Phase II dose finding trials (Table 1). [9][10][11][12][13][14][15][16][17] These trials outline efficacy and safety data for doravirine and are the basis for its approval by the US Food and Drug Administration. Longterm efficacy data is available up to 96 weeks in the DRIVE-FORWARD 10,11 and DRIVE-AHEAD 14,15 trials.…”