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  ICAAC 2014 54th Interscience Conference
on Antimicrobial Agents and Chemotherapy
September 5-9, 2014, Washington, DC
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PK Data and Dose Selection for Experimental NNRTI, Doravirine
  ICAAC 2014. September 5-9, 2014. Washington, DC
ICAAC: Pharmacokinetics (PK) of Doravirine and Exposure-Response Analysis: Efficacy and Safety Implications - (09/08/14)
Mark Mascolini
A dose-ranging study of doravirine (MK-1439), an experimental nonnucleoside (NNRTI), indicated that a once-daily dose of 100 mg will achieve target concentrations for both wild-type (nonmutant) HIV and virus bearing some common NNRTI mutations [1]. Doses did not correlate with 24-week viral suppression or side effects.
In vitro evidence indicates that doravirine has activity against wild-type HIV-1 at a 95% effective concentration (EC95) of 20 nM as well as against the hallmark NNRTI mutations K103N (43 nM), Y181C (27 nM), and K103N plus Y181C (55 nM) [2]. When combined with tenofovir/emtricitabine (TDF/FTC) in previously untreated people, doravirine at various doses achieved a week-24 sub-40-copy noncompleter-equals-failure response rate of 76% versus 64% with efavirenz plus TDF/FTC [3].
Doravirine metabolism depends primarily on CYP3A4, but the NNRTI does not induce or inhibit that enzyme. Interactions are not expected between the experimental agent and proton pump inhibitors, and it can be dosed without regard to food.
The dose-ranging analysis [1] involved 167 of 208 patients with sparse pharmacokinetic (PK) data in the phase 2 study evaluating 25, 50, 100, and 200 mg of doravirine once daily plus TDF/FTC [3]. Merck investigators pooled that doravirine PK data with densely sampled phase 1 PK data in a population PK model to yield individual steady-state PK estimates. The researchers grouped individual area-under-the-concentration-time-curve (AUC) estimates into equal-sized clusters and plotted them against the frequency of central nervous system (CNS) adverse events, abnormal dreams, nausea, and diarrhea.
Gender, age, renal function, and HIV infection status were not identified as significant covariates in the PK model, so no dose adjustments based on these variables appear to be necessary. Post hoc estimated median steady-state AUC, maximum concentration (Cmax), and 24-hour concentration (C24h) were as follows:
Median AUC0-24h (uM/h):
25 mg: 12.71
50 mg: 20.21
100 mg: 34.58
200 mg: 55.78
Median Cmax (nM):
25 mg: 762
50 mg: 1256
100 mg: 2182
200 mg: 3544
Median C24h (nM):
25 mg: 313
50 mg: 495
100 mg: 801
200 mg: 1283
When the researchers matched individual PK estimates and week-24 viral load, they saw no apparent trend between AUC or Ctrough and proportion of participants with an undetectable viral load. There was no exposure-response relationship for viral load data stratified by pretreatment viral load above or below 100,000 copies.
Grouping doravirine AUC estimates into equal-sized bins disclosed no apparent trend between AUC and proportion of participants with CNS events, abnormal dreams, nausea, or diarrhea. In addition, a logistic regression model identified no significant relation between AUC and nausea.
PK findings indicated that with the 100-mg doravirine once-daily dose, steady-state trough concentrations should exceed trough targets for both wild-type virus and several common NNRTI mutants in more than 98% of patients.
Simulated percent of participants above target steady-state C24h with 100 mg doravirine:
Wild type (78 nM): 100%
K103N (117 nM): 100%
Y181C (195 nM): 99.5%
G190A (211 nM): 99.4%
K103N/Y181C (335 nM): 98.3%
The researchers concluded that the 100-mg dose is suitable for phase 3 trials because "this dose demonstrates efficacy, is on the exposure-response plateau, and is expected to exceed the in vitro trough concentration targets for wild-type and mutant HIV-1 strains without increasing adverse even occurrence rates over lower doses."
1. Yee KL, Chatterjee M, Dockendorf M, et al. Pharmacokinetics of doravirine and exposure-response analysis: efficacy and safety implications. ICAAC 2014. September 5-9, 2014. Washington, DC. Abstract H-647b.
2. Lai MT, Feng M, Falgueyret JP, et al. In vitro characterization of MK-1439, a novel HIV-1 nonnucleoside reverse transcriptase inhibitor. Antimicrob Agents Chemother. 2014;58:1652-1663. http://www.ncbi.nlm.nih.gov/pubmed/24379202
3. Morales-Ramirez JO, Gatell JM, Hagins DP, et al. Safety and antiviral effect of MK-1439, a novel NNRTI (+FTC/TDF) in ART-naive HIV-infected patients. 21st Conference on Retroviruses and Opportunistic Infections. Boston, March 3-6. 2014. Abstract 92LB. http://www.natap.org/2014/CROI/croi_28.htm