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FDA Approves DELSTRIGO (Doravirine, Lamivudine, and Tenofovir Disoproxil Fumarate) for the Treatment of HIV-1 Infection in Adult Patients with no Antiretroviral Treatment History

  • FLASCO
  • September 6, 2018
FDA Approves DELSTRIGO (Doravirine, Lamivudine, and Tenofovir Disoproxil Fumarate) for the Treatment of HIV-1 Infection in Adult Patients with no Antiretroviral Treatment History

On August 30, 2018, the U.S. Food and Drug Administration (FDA) approved DELSTRIGO, a three-drug combination of doravirine, lamivudine, and tenofovir disoproxil fumarate (TDF), to be used as a complete regimen for the treatment of HIV-1 infection in adult patients with no antiretroviral treatment history. The approved recommended dosage of DELSTRIGO is one tablet taken orally once daily with or without food. Prior to or when initiating DELSTRIGO, test patients for HBV infection.

 

Full prescribing information is available at https://go.usa.gov/xP3u5.

Severe acute exacerbations of hepatitis B (HBV) have been reported in patients coinfected with HIV-1 and HBV who have discontinued lamivudine or TDF, two of the components of DELSTRIGO. Closely monitor hepatic function in these patients. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

Prior to or when initiating DELSTRIGO, and during treatment with DELSTRIGO, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. Additional information regarding dosage and administration can be found in the full prescribing information linked below.

Mechanism of Action (MOA) and Pharmacokinetics (PK)

  • MOA: DELSTRIGO is a fixed-dose combination of the antiretroviral drugs doravirine, lamivudine, and TDF. Doravirine is an HIV-1 non-nucleoside reverse transcriptase inhibitor. Lamivudine and TDF are both nucleoside analogue reverse transcriptase inhibitors.
  • General PK: At the approved recommended dosage, the geometric mean steady state exposure of DELSTRIGO components are as follows: Doravirine 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%); lamivudine AUC0-24 is 8.87 (SD: ± 1.83) mcg•h/mL and Cmax is 2.04 (SD: ± 0.54) mcg/mL; and tenofovir AUC0-24 is 2.29  mcg•h/mL (SD: ± 0.69 mcg•h/mL) and Cmax is 0.30  mcg/mL (SD: ± 0.09 mcg•h/mL).
  • Absorption: The absolute bioavailability of doravirine is 64%, lamivudine is 86%, and tenofovir is 25%. The time to maximum concentration for doravirine is 2 hours and for tenofovir is 1 hour.
  • Food Effect: A high-fat meal did not affect the exposure of doravirine (AUC, Cmax, or C24), lamivudine (AUC or Cmax) or tenofovir (AUC or Cmax) to any clinically relevant extent.
  • Distribution: The steady state volume of distribution of doravirine is 60.5 L, lamivudine is 1.3 L/kg, and tenofovir is 1.3 L/kg following IV dose. Plasma protein binding of doravirine is 76%, lamivudine is < 36%, and tenofovir is < 0.7%.
  • Elimination: The elimination half-life of doravirine is 15 hours, lamivudine is 5 to 7 hours, and tenofovir is 17 hours. The geometric mean apparent clearance of doravirine is 106 mL/min (CV: 35.2%), lamivudine is 398.5 mL/min (SD: ± 69.1 mL/min), and tenofovir is 1,043.7 mL/min (SD: ± 115.4 mL/min). The apparent renal clearance of doravirine is 9.3 mL/min (CV: 18.6%), lamivudine is 199.7 mL/min (SD: ± 56.9 mL/min), and tenofovir is 243.5 mL/min (SD: ± 33.3 mL/min).
  • Metabolism: Primary metabolism pathway for doravirine is cytochrome P450 CYP3A, metabolism for lamivudine is minor, and there is no CYP metabolism for tenofovir.
  • 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. The major route of elimination of lamivudine is glomerular filtration and active tubular secretion with 71% of the administered dose excreted unchanged in urine. The major route of elimination of tenofovir is glomerular filtration and active tubular secretion with 70% to 80% of the administered dose excreted unchanged in urine.

Drug Interactions

Concomitant Use with Other Antiretroviral Medications

  • Because DELSTRIGO is a complete regimen for the treatment of HIV-1 infection, co-administration with other antiretroviral medications for treatment of HIV-1 infection is not recommended.

Effect of Other Drugs on DELSTRIGO

  • Strong CYP3A Inducers: Co-administration of DELSTRIGO with a CYP3A inducer decreases doravirine plasma concentrations, which may reduce DELSTRIGO efficacy. Co-administration of DELSTRIGO with strong CYP3A inducers is contraindicated and at least a 4-week cessation period is recommended prior to initiation of DELSTRIGO. 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; or St. John’s wort (Hypericum perforatum).
  • CYP3A Inhibitors: Co-administration of DELSTRIGO with drugs that are inhibitors of CYP3A may result in increased plasma concentrations of doravirine.
  • Rifabutin: Co-administration of DELSTRIGO with rifabutin decreases the concentration of doravirine. If DELSTRIGO is co-administered with rifabutin, one tablet of doravirine (PIFELTRO) should be taken approximately 12 hours after the dose of DELSTRIGO. At least a 4-week cessation period is recommended prior to initiation of DELSTRIGO.
  • Hepatitis C Antiviral Agents: Co-administration of DELSTRIGO with certain hepatitis C antiviral agents increases the concentration of tenofovir. Monitor for adverse reactions associated with tenofovir. Hepatitis C antiviral agents include, but are not limited to ledipasvir/sofosbuvir and sofosbuvir/velpatasvir.
  • Sorbitol: Co-administration of single doses of lamivudine and sorbitol resulted in a sorbitol dose-dependent reduction in lamivudine exposures. When possible, avoid use of drugs containing sorbitol with drugs containing lamivudine.
  • Drugs that Reduce Renal Function or Compete for Active Tubular Secretion: Co-administration of DELSTRIGO with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of lamivudine, tenofovir, and/or other renally eliminated drugs. Examples of drugs that are eliminated by active tubular secretion include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs.

Use in Specific Populations

No clinically significant differences in the pharmacokinetics of certain DELSTRIGO components were observed based on age ≥ 65 years (for doravirine), sex (for doravirine, lamivudine, TDF), and race/ethnicity (for doravirine, lamivudine). The effects of age (≥ 65 years) on the pharmacokinetics of lamivudine or TDF is unknown. The effect of race on the pharmacokinetics of TDF is unknown. The pharmacokinetics of doravirine in patients < 18 years of age is unknown.

Renal Impairment

DELSTRIGO is not recommended in patients with estimated creatinine clearance < 50 mL/min.

  • Doravirine: No clinically significant difference in the pharmacokinetics of doravirine were observed in subjects with mild to severe renal impairment (creatinine clearance (CLcr) > 15 mL/min, estimated by Cockcroft-Gault). Doravirine has not been studied in patients with end-stage renal disease or in patients undergoing dialysis.
  • Lamivudine: Lamivudine AUCinf, Cmax, and half-life increased and the apparent clearance decreased to a clinically significant extent with diminishing renal function (CLcr 111 to < 10 mL/min).
  • Tenofovir: A clinically significant increase tenofovir Cmax and AUC was observed in subjects with CLcr < 50 mL/min or with end stage renal disease requiring dialysis.

Hepatic Impairment
No dosage adjustment of DELSTRIGO is required in patients with mild or moderate (Child-Pugh Class A or B) hepatic impairment. DELSTRIGO has not been studied in patients with severe hepatic impairment (Child-Pugh Class C).

Efficacy and Safety

The efficacy of DELSTRIGO to be used as a complete regimen for the treatment of HIV-1 infection in adult patients with no antiretroviral treatment history was demonstrated in a randomized, multicenter, double-blind, active controlled Phase 3 trial in HIV-1 infected subjects with no antiretroviral treatment history. The primary outcomes were change in HIV-1 RNA and CD4+ T-cell counts at week 48. Additional information regarding efficacy trial can be found in the full prescribing information linked below.

The safety of DELSTRIGO is based on assessments from two randomized, international, multicenter, double-blind, active-controlled Phase 3 trials. The most common adverse reactions (incidence ≥ 5%, all grades) are dizziness, nausea, and abnormal dreams.

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Full prescribing information is available at https://go.usa.gov/xP3u5.

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

 

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