Doravirine

Doravirine is a pyridinone non-nucleoside reverse transcriptase inhibitor of HIV-1 and inhibits HIV-1 replication by non-competitive inhibition of HIV-1 reverse transcriptase (RT). Doravirine does not inhibit the human cellular DNA polymerases α, β, and mitochondrial DNA polymerase γ.

Antiviral activity in cell culture

Doravirine exhibited an EC₅₀ value of 12.0±4.4 nM against wild-type laboratory strains of HIV-1 when tested in the presence of 100% normal human serum using MT4-GFP reporter cells. Doravirine demonstrated antiviral activity against a broad panel of primary HIV-1 isolates (A, A1, AE, AG, B, BF, C, D, G, H) with EC₅₀ values ranging from 1.2 nM to 10.0 nM.

Antiviral activity in combination with other HIV antiviral medicinal products The antiviral activity of doravirine was not antagonistic when combined with the NNRTIs delavirdine, efavirenz, etravirine, nevirapine, or rilpivirine; the NRTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir disoproxil, or zidovudine; the PIs darunavir or indinavir; the fusion inhibitor enfuvirtide; the CCR5 co-receptor antagonist maraviroc; or the integrase strand transfer inhibitor raltegravir.

Resistance in cell culture

Doravirine-resistant strains were selected in cell culture starting from wild-type HIV-1 of different origins and subtypes, as well as NNRTI-resistant HIV-1. Observed emergent amino acid substitutions in RT included: V106A, V106M, V106I, V108I, F227L, F227C, F227I, F227V, H221Y, M230I, L234I, P236L, and Y318F. The V106A, V106M, V108I, H221Y, F227C, M230I, P236L, and Y318F substitutions conferred 3.4-fold to 70-fold reductions in susceptibility to doravirine. Y318F in combination with V106A, V106M, V108I, and F227C conferred greater decreases in susceptibility to doravirine than Y318F alone, which conferred a 10-fold reduction in susceptibility to doravirine. Common NNRTI-resistant mutations (K103N, Y181C) were not selected in the in vitro study. V106A (yielding a fold change of around 19) appeared as an initial substitution in subtype B virus, and V106A or M in subtype A and C virus. Subsequently F227(L/C/V) or L234I emerged in addition to V106 substitution (double mutants yielding a fold change of >100).

Absorption

The pharmacokinetics of doravirine were studied in healthy subjects and HIV-1 infected subjects. Doravirine pharmacokinetics are similar in healthy subjects and HIV-1-infected subjects. Steady state was generally achieved by Day 2 of once daily dosing, with accumulation ratios of 1.2 to 1.4 for AUC_0-24, C_max, and C₂₄. Doravirine steady state pharmacokinetics following administration of 100 mg once daily to HIV-1 infected subjects, based on a population pharmacokinetics analysis, are provided below.

GM: Geometric mean, % CV: Geometric coefficient of variation

Following oral dosing, peak plasma concentrations are achieved 2 hours after dosing. Doravirine has an estimated absolute bioavailability of approximately 64% for the 100 mg tablet.

Effect of food on oral absorption

The administration of a single doravirine tablet with a high-fat meal to healthy subjects resulted in a 16% and 36% increase in doravirine AUC and C₂₄, respectively, while C_max was not significantly affected.

Distribution

Based on administration of an IV microdose, the volume of distribution of doravirine is 60.5 L. Doravirine is approximately 76% bound to plasma proteins.

Biotransformation

Based on in vitro</em data, doravirine is primarily metabolized by CYP3A.

Elimination

Doravirine has a terminal half-life (t_½) of approximately 15 hours. Doravirine is primarily eliminated via oxidative metabolism mediated by CYP3A4. Biliary excretion of unchanged medicinal product may contribute to the elimination of doravirine, but this elimination route is not expected to be significant. Excretion of unchanged medicinal product via urinary excretion is minor.

Renal impairment

Renal excretion of doravirine is minor. In a study comparing 8 subjects with severe renal impairment to 8 subjects without renal impairment, the single dose exposure of doravirine was 31% higher in subjects with severe renal impairment. In a population pharmacokinetic analysis, which included subjects with CrCl between 17 and 317 mL/min, renal function did not have a clinically relevant effect on doravirine pharmacokinetics. No dose adjustment is required in patients with mild, moderate or severe renal impairment. Doravirine has not been studied in patients with end-stage renal disease or in patients undergoing dialysis.

Hepatic impairment

Doravirine is primarily metabolized and eliminated by the liver. There was no clinically relevant difference in the pharmacokinetics of doravirine in a study comparing 8 subjects with moderate hepatic impairment (classified as Child-Pugh score B primarily due to increased encephalopathy and ascites scores) to 8 subjects without hepatic impairment. No dose adjustment is required in patients with mild or moderate hepatic impairment. Doravirine has not been studied in subjects with severe hepatic impairment (Child-Pugh score C).

Paediatric population

Mean doravirine exposures were similar in 54 paediatric patients aged 12 to less than 18 years and weighing at least 35 kg who received doravirine or doravirine/lamivudine/tenofovir disoproxil in IMPAACT 2014 (Protocol 027) relative to adults following administration of doravirine or doravirine/lamivudine/tenofovir disoproxil.

Steady state pharmacokinetics for doravirine following administration of doravirine or doravirine/lamivudine/tenofovir disoproxil in HIV infected paediatric patients aged 12 to less than 18 years and weighing at least 35 kg:

^* Presented as geometric mean (%CV: geometric coefficient of variation)
^† From population PK analysis (n=54)
Abbreviations: AUC = area under the time concentration curve; C_max = maximum concentration; C₂₄ = concentration at 24 hours

Elderly

Although a limited number of subjects aged 65 years and over has been included (n=36), no clinically relevant differences in the pharmacokinetics of doravirine have been identified in subjects at least 65 years of age compared to subjects less than 65 years of age in a Phase 1 trial or in a population pharmacokinetic analysis. No dose adjustment is required.

Gender

No clinically relevant pharmacokinetic differences have been identified between men and women for doravirine.

Race

No clinically relevant racial differences in the pharmacokinetics of doravirine have been identified based on a population pharmacokinetic analysis of doravirine in healthy and HIV-1 infected subjects.