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TheBodyPRO.com covers ICAAC 2014

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Doravirine Study Suggests 100-mg Dose Effective Against Mutant HIV Strains, Too

November 3, 2014

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.

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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.

Barbara Jungwirth is a freelance writer and translator based in New York.

Follow Barbara on Twitter: @reliabletran.


Copyright © 2014 Remedy Health Media, LLC. All rights reserved.



This article was provided by TheBodyPRO.com. It is a part of the publication The 54th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2014).
 


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Please note: Knowledge about HIV changes rapidly. Note the date of this summary's publication, and before treating patients or employing any therapies described in these materials, verify all information independently. If you are a patient, please consult a doctor or other medical professional before acting on any of the information presented in this summary. For a complete listing of our most recent conference coverage, click here.

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