A randomized, double-blind, placebo-controlled, short-term monotherapy study of doravirine in treatment-naive HIV-infected individuals
- 2 January 2016
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in AIDS
- Vol. 30 (1), 57-63
- https://doi.org/10.1097/qad.0000000000000876
Abstract
To assess the antiviral activity, pharmacokinetics, and safety of doravirine in nonnucleoside reverse transcriptase inhibitor-naïve, HIV-infected men. Double-blind, randomized, two-panel, dose-escalation study. In two sequential panels, 18 individuals received doravirine [25 mg (Panel A) or 200 mg (Panel B)] or matching placebo once daily for 7 days. Plasma samples were collected daily for measurement of HIV-1 RNA levels and doravirine pharmacokinetics. For the mean change from baseline in HIV RNA (log10 copies/ml) at 24 h after the day 7 dose, the mean difference (90% confidence interval) between doravirine and placebo was -1.37 (-1.60, -1.14) in the 25-mg group and -1.26 (-1.51, -1.02) in the 200-mg group. None of the participants had viral breakthrough. Increases in mean AUC0-24 h, Cmax, and C24 h were slightly less than dose-proportional, with median Tmax of 1.0-2.0 h. Steady state was achieved after 3-5 days of once-daily dosing. At steady state, accumulation ratios (day 7/day 1) for AUC0-24 h, Cmax, and C24 h were 1.2-1.6. The calculated effective t1/2 (10-16 h) was similar to that in HIV-uninfected individuals. Adverse events were limited in number, transient, and generally mild to moderate in intensity. One participant had a serious adverse event of elevated liver enzymes (judged probably not drug related) in concurrence with a newly acquired hepatitis C infection. Doravirine monotherapy demonstrated robust antiviral activity at both dose levels, without evidence of viral resistance, and was generally well tolerated. Doravirine pharmacokinetics in HIV-infected individuals were similar to those in uninfected individuals receiving similar doses in prior studies.Keywords
This publication has 12 references indexed in Scilit:
- In Vitro Resistance Selection with Doravirine (MK-1439), a Novel Nonnucleoside Reverse Transcriptase Inhibitor with Distinct Mutation Development PathwaysAntimicrobial Agents and Chemotherapy, 2015
- The Emerging Profile of Cross-Resistance among the Nonnucleoside HIV-1 Reverse Transcriptase InhibitorsViruses, 2014
- Safety, Tolerability and Pharmacokinetics of Doravirine, a Novel HIV Non-Nucleoside Reverse Transcriptase Inhibitor, after Single and Multiple doses in Healthy SubjectsAntiviral Therapy, 2014
- Has the time come to abandon efavirenz for first-line antiretroviral therapy?Journal of Antimicrobial Chemotherapy, 2014
- In VitroCharacterization of MK-1439, a Novel HIV-1 Nonnucleoside Reverse Transcriptase InhibitorAntimicrobial Agents and Chemotherapy, 2014
- Rilpivirine: drug profile of a second-generation non-nucleoside reverse transcriptase HIV-inhibitorExpert Review of Anti-infective Therapy, 2013
- Neurological and psychiatric tolerability of rilpivirine (TMC278) vs. efavirenz in treatment‐naïve, HIV‐1‐infected patients at 48 weeksHIV Medicine, 2013
- Nonnucleoside Reverse Transcriptase Inhibitor Resistance and the Role of the Second-Generation AgentsAnnals of Pharmacotherapy, 2010
- Activity, pharmacokinetics and safety of lersivirine (UK-453,061), a next-generation nonnucleoside reverse transcriptase inhibitor, during 7-day monotherapy in HIV-1-infected patientsAIDS, 2009
- Short-term antiviral activity of TMC278 – a novel NNRTI – in treatment-naive HIV-1-infected subjectsAIDS, 2006