FDA Approves PIFELTRO (Doravirine) to be Used in Combination with Other Antiretroviral Agents for the Treatment of HIV-1 Infection in Adult Patients with no Prior Antiretroviral Treatment History


On August 30, 2018, the U.S. Food and Drug Administration (FDA) approved PIFELTRO (doravirine) to be used in combination with other antiretroviral agents for the treatment of HIV-1 infection in adult patients with no prior antiretroviral treatment history. The approved recommended dosage of PIFELTRO is one 100 mg tablet taken orally once daily with or without food. Monitor patients for immune reconstitution syndrome. Additional information regarding immune reconstitution syndrome can be found in the full prescribing information linked below.

Mechanism of Action (MOA) and Pharmacokinetics (PK)

  • MOA: Doravirine is an HIV-1 non-nucleoside reverse transcriptase inhibitor.
  • General PK: At the approved recommended dosage, doravirine steady state geometric mean AUC0-24 is 16.1 mcg•h/mL (CV: 29%), Cmax is 0.962 mcg/mL (CV: 19%), and C24 is 0.396 mcg/mL (CV: 63%). Accumulation ratio is 1.2 to 1.4 and the time to steady state is 2 days.
  • Absorption: The absolute bioavailability of doravirine is 64% and the time to maximum concentration is 2 hours.
  • Food Effect: A high-fat meal did not affect doravirine AUC, Cmax, or C24 to any clinically relevant extent.
  • Distribution: The steady state volume of distribution of doravirine is 60.5 L following IV dose. Plasma protein binding is 76%.
  • Elimination: The elimination half-life of doravirine is 15 hours. The geometric mean apparent clearance is 106 mL/min (CV: 35.2%) and apparent renal clearance is 9.3 mL/min (CV: 18.6%).
  • Metabolism: Doravirine is primarily metabolized by CYP3A.
  • Excretion: The major route of elimination for doravirine is metabolism with 6% of the administered doravirine dose excreted unchanged in urine and a minor amount excreted via biliary/fecal route.


Drug Interactions

Effect of Other Drugs on PIFELTRO

  • Strong CYP3A Inducers: Co-administration of PIFELTRO with a CYP3A inducer decreases doravirine plasma concentrations, which may reduce PIFELTRO efficacy. Co-administration of PIFELTRO with strong CYP3A inducers is contraindicated and at least a 4-week cessation period is recommended prior to initiation of PIFELTRO. Strong CYP3A inducers include, but are not limited to, the following: the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin; the androgen receptor inhibitor enzalutamide; the antimycobacterials rifampin, rifapentine; the cytotoxic agent mitotane; and St. John’s wort (Hypericum perforatum).
  • CYP3A Inhibitors: Co-administration of PIFELTRO with drugs that are inhibitors of CYP3A may result in increased plasma concentrations of doravirine.
  • Rifabutin: Co-administration of PIFELTRO with rifabutin decreases the concentration of doravirine. If PIFELTRO is co-administered with rifabutin, increase PIFELTRO dosage to one tablet twice daily (approximately 12 hours apart) and at least a 4-week cessation period is recommended prior to initiation of PIFELTRO.
  • HIV Antiviral Agents: Co-administration of PIFELTRO with certain HIV antiviral agents decreases the concentration of doravirine. Use is not recommended with the following HIV antiviral agents: efavirenz, etravirine, or nevirapine.


Use in Specific Populations

No clinically significant difference in the pharmacokinetics of doravirine were observed based on age (18 to 78 years of age), sex, and race/ethnicity, mild to severe renal impairment (creatinine clearance (CLcr) > 15 mL/min, estimated by Cockcroft-Gault), or moderate hepatic impairment (Child-Pugh B). The pharmacokinetics of doravirine in patients with end-stage renal disease or undergoing dialysis, severe hepatic impairment (Child-Pugh C), or < 18 years of age is unknown.

Efficacy and Safety

The efficacy and safety of PIFELTRO to be used in combination with other antiretroviral agents for the treatment of HIV-1 infection in adult patients with no prior antiretroviral treatment history was demonstrated in two randomized, multicenter, double-blind, active controlled Phase 3 trials in HIV-1 infected subjects with no antiretroviral treatment history. The primary outcomes from these trials were change in HIV-1 RNA and CD4+ T-cell counts at week 48. Additional information regarding efficacy trials can be found in the full prescribing information linked below.

The most common adverse reactions (incidence ≥ 5%, all grades) are nausea, dizziness, headache, fatigue, diarrhea, abdominal pain, and abnormal dreams.

Full prescribing information is available at https://go.usa.gov/xP3uK.

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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.