HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI).
Pharmacology: Mechanism of Action:
PIFELTRO is an antiviral drug [see Pharmacodynamics as follows].
Pharmacodynamics: Effects on Electrocardiogram:
At a doravirine dose of 1200 mg, which provides approximately 4 times the peak concentration observed following the maximum approved dose, doravirine does not prolong the QT interval to any clinically relevant extent.
Treatment-Naïve Adult Subjects: The efficacy of PIFELTRO is based on the analyses of 48-week data from two randomized, multicenter, double-blind, active controlled Phase 3 trials, (DRIVE-FORWARD and DRIVE-AHEAD) in antiretroviral treatment-naïve, HIV-1 infected subjects (n=1494).
In DRIVE-FORWARD, 766 subjects were randomized and received at least 1 dose of either PIFELTRO once daily or DRV+r 800/100 mg once daily each in combination with emtricitabine/tenofovir DF (FTC/TDF) or abacavir/lamivudine (ABC/3TC) selected by the investigator. At baseline, the median age of subjects was 33 years, 16% were female, 27% were non-white, 4% had hepatitis B and/or C virus co-infection, 10% had a history of AIDS, 20% had HIV-1 RNA greater than 100,000 copies/mL, 86% had CD4+ T-cell count greater than 200 cells/mm3, 13% received ABC/3TC and 87% received FTC/TDF; these characteristics were similar between treatment groups.
In DRIVE-AHEAD, 728 subjects were randomized and received at least 1 dose of either DELSTRIGO or EFV/FTC/TDF once daily. At baseline, the median age of subjects was 31 years, 15% were female, 52% were non-white, 3% had hepatitis B or C co-infection, 14% had a history of AIDS, 21% had HIV-1 RNA greater than 100,000 copies/mL, and 88% had CD4+ T-cell count greater than 200 cells/mm3
; these characteristics were similar between treatment groups.
Week 48 outcomes for DRIVE-FORWARD and DRIVE-AHEAD are provided in Table 1. Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs.
In DRIVE-FORWARD, PIFELTRO demonstrated consistent efficacy across demographic and baseline prognostic factors, including gender, race, ethnicity, NRTI background therapy, baseline HIV-1 RNA (≤100,000 or >100,000 copies/mL), CD4+ T-cell count, and viral subtypes. Mean CD4+ T-cell counts in the PIFELTRO and DRV+r groups increased from baseline by 193 and 186 cells/mm3
In DRIVE-AHEAD, DELSTRIGO demonstrated consistent efficacy across demographic and baseline prognostic factors, including gender, race, ethnicity, baseline HIV-1 RNA (≤100,000 or >100,000 copies/mL), CD4+ T-cell count, and viral subtypes. Mean CD4+ T-cell counts in the DELSTRIGO and EFV/FTC/TDF groups increased from baseline by 198 and 188 cells/mm3
, respectively. (See Table 1.)
Click on icon to see table/diagram/image
P007 was a Phase 2b trial in antiretroviral treatment-naïve HIV-1 infected adult subjects (n=340). In Part I, subjects were randomized to receive one of 4 doses of PIFELTRO or EFV, each in combination with FTC/TDF. After Week 24, all subjects randomized to receive PIFELTRO were switched to (or maintained on) PIFELTRO 100 mg. Additional subjects were randomized in Part II to receive either PIFELTRO 100 mg or EFV, each in combination with FTC/TDF. In both parts of the trial, PIFELTRO and EFV were administered as blinded-therapy and FTC/TDF was administered open-label.
At Week 48, the proportion of subjects with HIV-1 RNA less than 50 copies/mL was 79% (85/108) and 82% (89/108) for PIFELTRO 100 mg and EFV, respectively (FDA Snapshot Approach). At Week 96, the proportion of subjects with HIV-1 RNA less than 50 copies/mL was 76% (82/108) and 76% (82/108) for PIFELTRO 100 mg and EFV, respectively. At Week 48, mean CD4+ T-cell counts in the PIFELTRO 100 mg and EFV groups increased from baseline by 192 and 195 cells/mm3
, respectively. At Week 96, mean CD4+ T-cell counts in the PIFELTRO 100 mg and EFV groups increased from baseline by 259 and 264 cells/mm3
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 is generally achieved by Day 2 of once daily dosing, with accumulation ratios of 1.2 to 1.4 for AUC0-24
, and C24
. Doravirine steady state pharmacokinetics following administration of 100 mg once daily to HIV-1 infected subjects, based on a population pharmacokinetic analysis, are provided as follows. (See Table 2.)
Click on icon to see table/diagram/image
Following oral dosing, peak plasma concentrations are achieved 2 hours after dosing. Doravirine has an absolute bioavailability of approximately 64% for the 100 mg tablet.
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.
Based on in vitro
data, doravirine is primarily metabolized by CYP3A.
Doravirine has a terminal half-life (t1/2
) of approximately 15 hours. Doravirine is primarily eliminated via oxidative metabolism. Excretion of unchanged drug via urinary excretion is minor. Biliary excretion of unchanged drug is not expected to be significant.
Effect of Food on Oral Absorption:
The administration of a single PIFELTRO tablet with a high-fat meal to healthy subjects resulted in a 16% and 36% increase in doravirine AUC and C24
, respectively, while Cmax
was not significantly affected.
Renal Impairment: Renal excretion of doravirine is minor: approximately 6% of the administered dose is excreted unchanged in urine. In a study comparing 8 subjects with severe renal impairment to 8 subjects without renal impairment, the single dose exposure of doravirine was 43% higher in subjects with severe renal impairment. In a population pharmacokinetic analysis, 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 [see Renal Impairment under Precautions].
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 (Child-Pugh score B) 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) [see Hepatic Impairment under Precautions].
Pediatric: The pharmacokinetics and dosing recommendations of PIFELTRO in patients younger than 18 years of age have not been established [see Use in Children under Precautions].
Elderly: 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 [see Use in the Elderly under Precautions].
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.
Gender: No clinically relevant pharmacokinetic differences have been identified between men and women for doravirine.
Drug Interaction Studies:
Doravirine is primarily metabolized by CYP3A, and drugs that induce or inhibit CYP3A may affect the clearance of doravirine. Co-administration of doravirine and drugs that induce CYP3A may result in decreased plasma concentrations of doravirine. Co-administration of doravirine and drugs that inhibit CYP3A may result in increased plasma concentrations of doravirine.
Doravirine is not likely to have a clinically relevant effect on the exposure of medicinal products metabolized by CYP enzymes. Drug interaction studies were performed with doravirine and other drugs likely to be co-administered or commonly used as probes for pharmacokinetic interactions. The effects of co-administration of other drugs on the Cmax
, AUC, and C24
values of doravirine are summarized in Table 3. The effects of co-administration of doravirine on the Cmax
and AUC values of other drugs are summarized in Table 4. [See Interactions.] (See Tables 3 and 4.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
Toxicology: Animal Toxicology:
Acute Toxicity: No acute toxicity studies were performed with doravirine.
Chronic Toxicity: In repeat-dose oral toxicity studies, doravirine was very well tolerated in all animal species up to the highest doses tested. There were no adverse effects or target organs of toxicity identified in rats dosed for 6 months with 450 mg/kg/day, or in dogs dosed with 1000 mg/kg/day for 9 months (approximately 7-fold and 18-fold, respectively, above the exposure at the RHD).
Carcinogenesis: Long-term oral carcinogenicity studies of doravirine in mice and rats showed no evidence of carcinogenic potential at exposures up to 6 times (mice) and 7 times (rats) the human exposures at the RHD.
Mutagenesis: Doravirine was not genotoxic in a battery of in vitro
or in vivo
assays, including microbial mutagenesis, chromosomal aberration in Chinese Hamster Ovary cells, and in in vivo
rat micronucleus assays.
Reproduction: There were no effects on fertility, mating performance or early embryonic development when doravirine was administered to rats up to the highest dose tested. Systemic exposures (AUC) to doravirine were approximately 7 times the exposure in humans at the RHD.
Development: Reproduction studies with orally administered doravirine have been performed in rats and rabbits at exposures approximately 9 (rats) and 8 (rabbits) times the exposure in humans at the RHD with no effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development. Doravirine was administered orally at up to 300 mg/kg/day to pregnant rabbits on gestation days 7 to 20, and up to 450 mg/kg/day to rats on gestation days 6 to 20, and also to rats on gestation day 6 to lactation/postpartum day 20. Studies in pregnant rats and rabbits showed that doravirine is transferred to the fetus through the placenta, with fetal 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 (450 mg/kg/day) from gestation day 6 to lactation day 14, with milk concentrations approximately 1.5 times that of maternal plasma concentrations observed 2 hours post dose on lactation day 14.
Microbiology: Mechanism of Action:
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 (NHS) 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 Agents:
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 DF, or zidovudine; the PIs darunavir or indinavir; the fusion inhibitor enfuvirtide; the CCR5 co-receptor antagonist maraviroc; or the integrase strand transfer inhibitor raltegravir.
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, F227V, H221Y, M230I, L234I, P236L, and Y318F.
In Clinical Trials: The phase 3 studies, DRIVE-FORWARD and DRIVE-AHEAD, including previously untreated patients (n=747) where the following NNRTI substitutions were part of the exclusion criteria: L100I, K101E, K101P, K103N, K103S, V106A, V106I, V106M, V108I, E138A, E138G, E138K, E138Q, E138R, V179L, Y181C, Y181I, Y181V, Y188C, Y188H, Y188L, G190A, G190S, H221Y, L234I, M230I, M230L, P225H, F227C, F227L, F227V.
In the doravirine treatment arms of the treatment-naïve trials DRIVE-FORWARD and DRIVE-AHEAD (n=747), emergent doravirine-associated resistance substitutions were observed in 7 of 30 subjects in the resistance analysis subset (subjects with HIV-1 RNA greater than 400 copies per mL at virologic failure or at early study discontinuation and having resistance data). In the DRV+r treatment arm of the DRIVE-FORWARD trial (n=383), no emergent darunavir-associated resistance substitutions were observed in the 11 subjects in the resistance analysis subset. In the EFV/FTC/TDF treatment arm of the DRIVE-AHEAD trial (n=364), emergent efavirenz-associated resistance substitutions were observed in 12 out of 24 subjects in the resistance analysis subset.
Emergent doravirine associated resistance substitutions in RT included one or more of the following: A98G, V106I, V106A, V106M/T, Y188L, H221Y, P225H, F227C, F227C/R, and Y318Y/F.
Laboratory strains of HIV-1 harboring the common NNRTI-associated mutations K103N, Y181C, or K103N/Y181C substitutions in RT exhibit less than a 3-fold decrease in susceptibility to doravirine compared to wild-type virus when evaluated in the presence of 100% NHS. Doravirine was able to suppress the following NNRTI-associated substitutions: K103N, Y181C, G190A, and E138K mutants under clinically relevant concentrations.
A panel of 96 diverse clinical isolates containing NNRTI-associated mutations was evaluated for susceptibility to doravirine in the presence of 10% fetal bovine serum. Clinical isolates containing the Y188L substitution or V106 substitutions in combination with A98G, H221Y, P225H, F227C or Y318F showed a greater than 100-fold reduced susceptibility to doravirine.
Treatment emergent doravirine resistance associated substitutions may confer cross resistance to efavirenz, rilpivirine, nevirapine, and etravirine. Of the 7 virologic failures who developed doravirine phenotypic resistance, all had phenotypic resistance to nevirapine, 6 had phenotypic resistance to efavirenz, 4 had phenotypic resistance to rilpivirine, and 3 had partial resistance to etravirine based on the Monogram Phenosense assay.