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.
Lamivudine is a nucleoside analogue. Intracellularly, lamivudine is phosphorylated to its active 5'-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue.
Tenofovir disoproxil is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir disoproxil requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 RT by competing with the natural substrate deoxyadenosine 5'-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ.
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. The antiviral activity of doravirine was not antagonistic when combined with lamivudine and tenofovir disoproxil.
The antiviral activity of lamivudine against HIV-1 was assessed in a number of cell lines including monocytes and peripheral blood mononuclear cells (PBMCs) using standard susceptibility assays. EC50 values were in the range of 0.003 to 15 microM (1 microM = 0.23 micrograms per mL). The median EC50 values of lamivudine were 60 nM (range: 20 to 70 nM), 35 nM (range: 30 to 40 nM), 30 nM (range: 20 to 90 nM), 20 nM (range: 3 to 40 nM), 30 nM (range: 1 to 60 nM), 30 nM (range: 20 to 70 nM), 30 nM (range: 3 to 70 nM), and 30 nM (range: 20 to 90 nM) against HIV-1 clades A-G and group O viruses (n=3 except n=2 for clade B) respectively. Ribavirin (50 microM) used in the treatment of chronic HCV infection decreased the anti-HIV-1 activity of lamivudine by 3.5-fold in MT-4 cells.
The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in T lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The EC50 values for tenofovir were in the range of 0.04-8.5 microM. Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC50 values ranged from 0.5-2.2 microM).
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 substitutions (double mutants yielding a fold change of >100).
Lamivudine-resistant variants of HIV-1 have been selected in cell culture and in subjects treated with lamivudine. Genotypic analysis showed that the resistance was due to a specific amino acid substitution in the HIV-1 RT at codon 184 changing the methionine to either isoleucine or valine (M184V/I).
HIV-1 isolates selected by tenofovir expressed a K65R substitution in HIV-1 RT and showed a 2-4 fold reduction in susceptibility to tenofovir. In addition, a K70E substitution in HIV-1 RT has been selected by tenofovir and results in low-level reduced susceptibility to abacavir, emtricitabine, lamivudine, and tenofovir.
Single-dose administration of one doravirine/lamivudine/tenofovir disoproxil tablet to healthy subjects (N = 24) under fasted conditions provided comparable exposures of doravirine, lamivudine, and tenofovir to administration of doravirine tablets (100 mg) plus lamivudine tablets (300 mg) plus tenofovir disoproxil tablets (245 mg). The administration of a single doravirine/lamivudine/tenofovir disoproxil tablet with a high-fat meal to healthy subjects resulted in a 26% increase in doravirine C24, while AUC and Cmax were not significantly affected. Lamivudine Cmax decreased by 19% with a high fat meal, while AUC was not significantly affected. Tenofovir Cmax decreased by 12% and AUC increased by 27% with a high fat meal. These differences in pharmacokinetics are not clinically relevant.
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 AUC0-24, Cmax, 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.
| Parameter GM (%CV) | AUC0-24 µg•h/mL | Cmax µg/mL | C24 µg/mL |
|---|---|---|---|
| Doravirine 100 mg once daily | 16.1 (29) | 0.962 (19) | 0.396 (63) |
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.
Based on administration of an intravenous microdose, the volume of distribution of doravirine is 60.5 L. Doravirine is approximately 76% bound to plasma proteins.
Based on in vitro data, doravirine is primarily metabolised by CYP3A.
Doravirine has a terminal half-life (t½) 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.
Following oral administration, lamivudine is rapidly absorbed and extensively distributed. After multiple-dose oral administration of lamivudine 300 mg once daily for 7 days to 60 healthy subjects, steady-state Cmax (Cmax,ss) was 2.04 ± 0.54 microgram per mL (mean ± SD) and the 24-hour steadystate AUC (AUC24,ss) was 8.87 ± 1.83 mcg•hour per mL. Binding to plasma protein is low. Approximately 71% of an intravenous dose of lamivudine is recovered as unchanged medicinal product in the urine. Metabolism of lamivudine is a minor route of elimination. In humans, the only known metabolite is the trans-sulphoxide metabolite (approximately 5% of an oral dose after 12 hours). In most single-dose trials in HIV-1 infected subjects, or healthy subjects with serum sampling for 24 hours after dosing, the observed mean elimination half-life (t½) ranged from 5 to 7 hours. In HIV-1–infected subjects, total clearance was 398.5 ± 69.1 mL/min (mean ± SD).
Following oral administration of a single 245 mg dose of tenofovir disoproxil to HIV-1-infected subjects in the fasted state, Cmax was achieved in one hour. Cmax and AUC values were 0.30 ± 0.09 micrograms per mL and 2.29 ± 0.69 µg•hr per mL, respectively. The oral bioavailability of tenofovir from tenofovir disoproxil in fasted subjects is approximately 25%. Less than 0.7% of tenofovir binds to human plasma proteins in vitro over the range of 0.01 to 25 micrograms per mL. Approximately 70-80% of the intravenous dose of tenofovir is recovered as unchanged medicinal product in the urine within 72 hours of dosing. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion with a renal clearance in adults with CrCl greater than 80 mL per minute of 243.5 ± 33.3 mL per minute (mean ± SD). Following oral administration, the terminal halflife of tenofovir is approximately 12 to 18 hours. In vitro studies have determined that neither tenofovir disoproxil nor tenofovir are substrates for the CYP450 enzymes.
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.
Studies with lamivudine show that plasma concentrations (AUC) are increased in patients with renal dysfunction due to decreased clearance. Based on the lamivudine data, doravirine/lamivudine/tenofovir disoproxil combination is not recommended for patients with CrCl of <50 mL/min.
Pharmacokinetic parameters of tenofovir were determined following administration of a single dose of tenofovir disoproxil 245 mg to 40 non-HIV infected adult subjects with varying degrees of renal impairment defined according to baseline CrCl (normal renal function when CrCl >80 mL/min; mild with CrCl = 50-79 mL/min; moderate with CrCl = 30-49 mL/min and severe with CrCl = 10-29 mL/min). Compared with subjects with normal renal function, the mean (% CV) tenofovir exposure increased from 2,185 (12%) ng·h/mL in subjects with CrCl >80 mL/min to respectively 3,064 (30%) ng·h/mL, 6,009 (42%) ng·h/mL and 15,985 (45%) ng·h/mL in subjects with mild, moderate, and severe renal impairment.
The pharmacokinetics of tenofovir in non-haemodialysis adult subjects with CrCl <10 mL/min and in subjects with end-stage renal disease managed by peritoneal or other forms of dialysis have not been studied.
Doravirine is primarily metabolised 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).
The pharmacokinetic properties of lamivudine have been determined in subjects with moderate to severe hepatic impairment. Pharmacokinetic parameters were not altered by diminishing hepatic function. Safety and efficacy of lamivudine have not been established in the presence of decompensated liver disease.
The pharmacokinetics of tenofovir following a 245 mg dose of tenofovir disoproxil have been studied in healthy subjects with moderate to severe hepatic impairment. No clinically relevant differences in tenofovir pharmacokinetics were observed between subjects with hepatic impairment and healthy subjects.
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 IMPAACT 2014 (Protocol 027) relative to adults following administration of doravirine or doravirine/lamivudine/tenofovir disoproxil. Exposures of lamivudine and tenofovir in paediatric subjects following the administration of doravirine/lamivudine/tenofovir disoproxil were similar to those in adults following administration of lamivudine and tenofovir disoproxil.
Steady state pharmacokinetics for doravirine, lamivudine, and tenofovir 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:
| Parameter* | Doravirine† | Lamivudine‡ | Tenofovir‡ |
|---|---|---|---|
| AUC0-24 (µg•h/mL) | 16.4 (24) | 11.3 (28) | 2.55 (14) |
| Cmax (µg/mL) | 1.03 (16) | 2.1 (24) | 0.293 (37) |
| C24 (µg/mL) | 0.379 (42) | 0.0663 (55) | 0.0502 (9) |
* Presented as geometric mean (%CV: geometric coefficient of variation)
† From population PK analysis (n=54)
‡ From intensive PK analysis (n=10)
Abbreviations: AUC = area under the time concentration curve; Cmax = maximum concentration; C24 = concentration at 24 hours
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. The pharmacokinetics of lamivudine and tenofovir have not been studied in subjects older than 65 years. No dose adjustment is required.
No clinically relevant pharmacokinetic differences have been identified between men and women for doravirine, lamivudine, and tenofovir.
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.
There are no significant or clinically relevant racial differences in pharmacokinetics of lamivudine.
There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations following the administration of tenofovir disoproxil.
Reproduction studies with orally administered doravirine have been performed in rats and rabbits at exposures approximately 9 times (rats) and 8 times (rabbits) the exposure in humans at the recommended human dose (RHD) with no effects on embryo-foetal (rats and rabbits) or pre/postnatal (rats) development. Studies in pregnant rats and rabbits showed that doravirine is transferred to the foetus through the placenta, with foetal plasma concentrations of up to 40% (rabbits) and 52% (rats) that of maternal concentrations observed on gestation Day 20.
Doravirine was excreted into the milk of lactating rats following oral administration, with milk concentrations approximately 1.5 times that of maternal plasma concentrations.
Lamivudine was not teratogenic in animal studies but there were indications of an increase in early embryonic deaths in rabbits at relatively low systemic exposures, comparable to those achieved in humans. A similar effect was not seen in rats even at very high systemic exposure.
Reproductive toxicity studies in rats and rabbits showed no effects on mating, fertility, pregnancy or foetal parameters. However, tenofovir disoproxil reduced the viability index and weight of pups in a peri-postnatal toxicity study at maternally toxic doses.
Long-term oral carcinogenicity studies of doravirine in mice and rats showed no evidence of carcinogenic potential at estimated exposures up to 6 times (mice) and 7 times (rats) the human exposures at the RHD.
Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 12 times (mice) and 57 times (rats) the human exposures at the RHD.
Oral carcinogenicity studies in rats and mice only revealed a low incidence of duodenal tumours at an extremely high-dose in mice. These tumours are unlikely to be of relevance to humans.
Doravirine was not genotoxic in a battery of in vitro or in vivo assays.
Lamivudine was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in a cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in a microbial mutagenicity assay, in an in vitro cell transformation assay, in a rat micronucleus test, in a rat bone marrow cytogenetic assay, and in an assay for unscheduled DNA synthesis in rat liver.
Tenofovir disoproxil was mutagenic in the in vitro mouse lymphoma assay and negative in an in vitro bacterial mutagenicity test (Ames test). In an in vivo mouse micronucleus assay, tenofovir disoproxil was negative when administered to male mice.
There were no effects on fertility, mating performance or early embryonic development when doravirine was administered to rats at up to 7 times the exposure in humans at the RHD.
Lamivudine did not affect male or female fertility in rats.
Reproductive toxicity studies in rats and rabbits showed no effects on mating, fertility, pregnancy or foetal parameters.
Administration of doravirine in animal toxicity studies was not associated with toxicity.
Administration of lamivudine in animal toxicity studies at high doses was not associated with any major organ toxicity. At the highest dosage levels, minor effects on indicators of liver and kidney function were seen together with occasional reductions in liver weight. The clinically relevant effects noted were a reduction in red blood cell count and neutropenia.
Findings in repeat-dose toxicity studies in rats, dogs and monkeys at exposure levels greater than or equal to clinical exposure levels and with possible relevance to clinical use included kidney and bone changes and a decrease in serum phosphate concentration. Bone toxicity was diagnosed as osteomalacia (monkeys) and reduced bone mineral density (BMD) (rats and dogs). The bone toxicity in young adult rats and dogs occurred at exposures ≥5-fold the exposure in paediatric or adult patients; bone toxicity occurred in juvenile infected monkeys at very high exposures following subcutaneous dosing (≥40-fold the exposure in patients). Findings in the rat and monkey studies indicated that there was a substance related decrease in intestinal absorption of phosphate with potential secondary reduction in BMD.
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