Doravirine Study Suggests 100-mg Dose Effective Against Mutant HIV Strains, Too
Matthew Rizk of Merck & Co., Inc., presented part one of a phase 2 dosage-selection study of doravirine (MK-1439), a once-daily non-nucleoside reverse transcriptase inhibitor (NNRTI) under development, at ICAAC 2014. Based on this study, the 100-mg dose of doravirine was selected for part two of the trial because it offered better NNRTI-resistance mutation coverage than did the lower dosages. The hope is that the 100-mg dose will also provide sufficient drug concentrations in the blood even if a patient misses a dose.
In part one of the study, 208 HIV-positive treatment-naive participants were randomly assigned to five different study arms: 25 mg, 50 mg, 100 mg or 200 mg of doravirine once daily, or 600 mg of efavirenz (Sustiva, Stocrin) daily, each of them combined with tenofovir/emtricitabine (Truvada). Patients' CD4 cell counts were ≥ 100 cells/mm3 and their HIV RNA levels were ≥ 1,000 copies/mL.
After 24 weeks, 71.4%-80% (average: 76.4%) of participants in the doravirine arms were virally suppressed, at HIV RNA levels of < 40 copies/mL, compared to 64.3% in the efavirenz arm. Drug-related adverse events (dizziness, abnormal dreams, diarrhea, nausea and fatigue) were reported by an average of 34.9% patients who took doravirine, compared to 57.1% of patients who were on efavirenz.
Exposure-response analyses and a population pharmacokinetics model established that the doravirine dose does not need to be adjusted based on gender, renal function, HIV infection status or age. Researchers estimated median steady-state maximum (Cmax) and 24-hour (C24h) concentrations for each of the doravirine doses studied:
- 25-mg dose: Cmax 762 nM, C24h 313 nM
- 50-mg dose: Cmax 1,256 nM, C24h 495 nM
- 100-mg dose: Cmax 2,182 nM, C24h 801 nM
- 200-mg dose: Cmax 3,544 nM, C24h 1,283 nM
The study authors then determined in a simulation that the 100-mg dose would achieve sufficient drug concentrations even at the lowest level between drug doses (Ctrough) to protect 92.3% of patients not only against the wild-type virus, but also against all common resistance mutations. The 50-mg dose would only achieve this in 69.5% of patients, while the corresponding number for the 25-mg dose is only 26.6%.
Part two of the study will assign 120 patients to one of two arms: 100 mg of doravirine once daily or 600 mg of efavirenz once daily, both combined with a daily dose of tenofovir/emtricitabine, to confirm that dosage selection.