Coadministration of ketoconazole (a potent inhibitor of CYP3A4 and P-gp) and doravirine increased the PK parameters of doravirine primarily by reducing the rate of CYP3A4-mediated clearance of doravirine. Investigators stated that the minimal increase in Cmax indicated that P-gp inhibition did not impact absorption of doravirine. Although investigators concluded that these PK changes were not clinically meaningful, close monitoring for doravirine-associated adverse events is warranted when this combination is utilized.
Doravirine vs ketoconazole
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Study Design
In an open-label, fixed-sequence study, healthy subjects (n=10) received a single dose of doravirine (formerly known as MK-1439) 100 mg (Period 1). Following a 7-day washout, subjects received ketoconazole 400 mg once daily for 10 days (Period 2), with coadministration of a single dose of doravirine 100 mg on Day 2 of Period 2.
Study Results
Geometric mean ratios (GMRs; doravirine + ketoconazole / doravirine) [90% CI] of AUC, Cmax, and C24h for doravirine were 3.06 [2.85, 3.29], 1.25 [1.05, 1.49], and 2.75 [2.54, 2.98], respectively. The effect of doravirine on ketoconazole PK was not reported.
References
M S Anderson, C Chung, E Tetteh, et al. Effect of ketoconazole on the pharmacokinetics of doravirine (mk-1439), a novel non-nucleoside reverse transcriptase inhibitor for the treatment of hiv-1 infection. 16th International Workshop On Clinical Pharmacology Of Hiv ; Hepatitis Therapy. Washington, DC. ; 2015.
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