Doravirine versus Elbasvir/Grazoprevir
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Study Design
This was an openlabel, multiple-dose, fixed-sequence study in twelve healthy males and females aged 19 to 64. In Period 1, 100 mg doravirine was administered once daily (QD) for 5 days, followed by a 5 day washout. In Period 2, 200 mg grazoprevir + 50 mg elbasvir was administered QD for 10 days; Period 3 began immediately following Period 2. In Period 3, 100 mg doravirine was coadministered with 200 mg grazoprevir + 50 mg elbasvir QD for 5 days. Plasma PK samples for all drugs were collected following the last dose in each period when all three drugs had reached near steady-state exposures. The dose of
grazoprevir was selected to match the PK in HCV-infected individuals at the approved 100 mg dose. The PK (AUC0-24, Cmax, C24) for each analyte was natural log-transformed and evaluated separately using a linear mixed effects model with fixed effects terms for treatment. An unstructured covariance matrix was used to allow for unequal treatment variances and to model the correlation between the treatment measurements within each subject.
Study Results
Coadministration of doravirine with elbasvir + grazoprevir did not meaningfully alter the PK of any drug. For the comparison of doravirine + elbasvir + grazoprevir/elbasvir + grazoprevir alone, the geometric mean ratios (GMRs) (90% confidence intervals (CIs)) of elbasvir AUC0-24, Cmax, and C24 for were 0.96 (0.90, 1.02), 0.96 (0.91, 1.01), and 0.96 (0.89, 1.04), respectively, and for grazoprevir they were 1.07 (0.94, 1.23), 1.22 (1.01, 1.47), and 0.90 (0.83, 0.96), respectively. The GMRs (90% CI) of doravirine AUC0-24, Cmax, and C24 for the doravirine + elbasvir + grazoprevir / doravirine alone comparison were
1.56 (1.45, 1.68), 1.41 (1.25, 1.58), and 1.61 (1.45, 1.79), respectively. Six subjects (50%) reported ≥1 adverse event (AE) during treatment. Four (33%) subjects reported a drug related AE. Coadministration of all three drugs was generally well tolerated.
Study Conclusions
The authors concluded that there was no meaningful effect on doravirine, elbasvir or grazoprevir PK when these drugs were coadministered. The results of this study suggest that doravirine and elbasvir + grazoprevir may be co-administered in patients coinfected with HIV and HCV without a dose adjustment.
References
Ankrom W, Li K, Wolford D, Mitra P, Fan L, Sanchez R. Doravirine does not have a clinically meaningful pharmacokinetic interaction with elbasvir plus grazoprevir. International Workshop On Clinical Pharmacology Of Antiviral Therapy. Chicago, IL, USA. 18; June 2017.
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