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Severe Renal Impairment Has Minimal Impact on Doravirine Pharmacokinetics.

ABSTRACT: Doravirine is a novel nonnucleoside reverse transcriptase inhibitor in development for use with other antiretroviral therapies to treat human immunodeficiency virus type 1 (HIV-1) infection. Doravirine metabolism predominantly occurs via cytochrome P450 3A with <10% of elimination occurring via the renal pathway. As severe renal impairment can alter the pharmacokinetics (PK) of metabolically eliminated drugs, the effect of severe renal impairment on doravirine PK was assessed. A single dose of doravirine 100 mg was administered to subjects aged 18 to 75 years with an estimated glomerular filtration rate (eGFR) of <30 ml/min/1.73 m2 (severe renal impairment group) and healthy controls with an eGFR of ?80 ml/min/1.73 m2, matched to the mean of the renal impairment group by age (±10 years) and weight (±10 kg). Doravirine plasma concentrations were determined at regular intervals, and safety was monitored throughout. The geometric mean ratios (90% confidence interval) for severe renal impairment/healthy subjects were 1.43 (1.00, 2.04), 1.38 (0.99, 1.92), and 0.83 (0.61, 1.15) for the plasma doravirine area under the curve from zero to infinity (AUC0-?), plasma concentration at 24 h postdose (C24), and maximum plasma concentration (Cmax), respectively. Doravirine was generally well tolerated in both groups. Based on the overall efficacy, safety, and PK profile of doravirine, the minor effect of severe renal impairment on doravirine PK observed in this study is not considered clinically meaningful. (This study has been registered at ClinicalTrials.gov under identifier NCT02641067.).

SUBMITTER: Ankrom W

PROVIDER: S-EPMC6105803 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Severe Renal Impairment Has Minimal Impact on Doravirine Pharmacokinetics.

Ankrom Wendy W Yee Ka Lai KL Sanchez Rosa I RI Adedoyin Adedayo A Fan Li L Marbury Thomas T Preston Richard A RA Iwamoto Marian M Khalilieh Sauzanne G SG

Antimicrobial agents and chemotherapy 20180727 8

Doravirine is a novel nonnucleoside reverse transcriptase inhibitor in development for use with other antiretroviral therapies to treat human immunodeficiency virus type 1 (HIV-1) infection. Doravirine metabolism predominantly occurs via cytochrome P450 3A with <10% of elimination occurring via the renal pathway. As severe renal impairment can alter the pharmacokinetics (PK) of metabolically eliminated drugs, the effect of severe renal impairment on doravirine PK was assessed. A single dose of d ...[more]

PMID: 29891610

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Project description:Doravirine is a novel, potent nonnucleoside reverse transcriptase inhibitor (NNRTI) for the treatment of patients with human immunodeficiency virus type 1 (HIV-1) infection that demonstrates a high genetic barrier to resistance and that has been well tolerated in studies to date. Doravirine is a candidate for patients switching from less-well-tolerated NNRTIs, such as efavirenz. While doravirine is a cytochrome P450 3A4 (CYP3A4) substrate, efavirenz induces CYP3A4; therefore, the pharmacokinetics of both drugs following a switch from efavirenz to doravirine were assessed. This was a 3-period, fixed-sequence, open-label study. Healthy adults were dosed with doravirine at 100 mg for 5 days once daily (QD) (period 1). Following a 7-day washout, efavirenz was administered at 600 mg QD for 14 days (period 2). Subsequently, doravirine was administered at 100 mg QD for 14 days (period 3). Blood samples were collected for pharmacokinetic analyses. Twenty healthy subjects were enrolled, and 17 completed the study. One day after efavirenz cessation, the doravirine area under the concentration-time curve from predosing to 24 h postdosing (AUC0-24), maximum observed plasma concentration (Cmax), and observed plasma concentration at 24 h postdosing (C24) were reduced by 62%, 35%, and 85%, respectively, compared with the values with no efavirenz pretreatment. These decreases recovered to 32%, 14%, and 50% for AUC0-24, Cmax, and C24, respectively, by day 14 after efavirenz cessation. The doravirine C24 reached projected therapeutic trough concentrations, based on in vitro efficacy, on day 2 following efavirenz cessation. Geometric mean efavirenz concentrations were 3,180 ng/ml on day 1 and 95.7 ng/ml on day 15, and efavirenz was present at therapeutic concentrations (>1,000 ng/ml) until day 4. Though doravirine exposure was transiently decreased following efavirenz treatment cessation, dose adjustment may not be necessary to maintain therapeutic concentrations of at least one drug during switching in a virologically suppressed population.

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Severe Renal Impairment Has Minimal Impact on Doravirine Pharmacokinetics.

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Severe Renal Impairment Has Minimal Impact on Doravirine Pharmacokinetics.

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