title: Pharmacokinetic and Pharmacodynamic Comparison of Once-Daily Efavirenz (400 mg vs. 600 mg) in Treatment-Naïve HIV-Infected Patients: Results of the ENCORE1 Study.
abstract: Daily efavirenz 400 mg (EFV400) was virologically noninferior to 600 mg (EFV600) at 48 weeks in treatment-naïve patients. We evaluated EFV400 and EFV600 pharmacokinetics (NONMEM v. 7.2), assessing patient demographics and genetic polymorphisms (CYP2B6, CYP2A6, CYP3A4, NR1I3) as covariates and explored relationships with efficacy (plasma HIV-RNA (pVL) <200 copies/mL) and safety outcomes at 48 weeks in 606 randomized ENCORE1 patients (female = 32%, African = 37%, Asian = 33%; EFV400 = 311, EFV600 = 295). CYP2B6 516G>T/983T>C/CYP2A6*9B/*17 and weight were associated with efavirenz CL/F. Exposure was significantly lower for EFV400 (geometric mean ratio, GMR; 90% confidence interval, CI: 0.73 (0.68-0.78)) but 97% (EFV400) and 98% (EFV600) of evaluable pVL was <200 copies/mL at 48 weeks (P = 0.802). Four of 20 patients with mid-dose concentrations <1.0 mg/L had pVL ≥200 copies/mL (EFV400 = 1; EFV600 = 3). Efavirenz exposure was similar between those with and without efavirenz-related side effects (GMR; 90% CI: 0.95 (0.88-1.02)). HIV suppression was comparable between doses despite significantly lower EFV400 exposure. Comprehensive evaluation of efavirenz pharmacokinetics/pharmacodynamics revealed important limitations in the accepted threshold concentration.
authors.affiliation: Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: L
authors.initials: L
authors.lastname: Dickinson
authors.affiliation: Kirby Institute, UNSW Australia, Sydney, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Amin
authors.affiliation: Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: L
authors.initials: L
authors.lastname: Else
authors.affiliation: Chelsea & Westminster Foundation Trust, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Boffito
authors.affiliation: Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: D
authors.initials: D
authors.lastname: Egan
authors.affiliation: Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: A
authors.initials: A
authors.lastname: Owen
authors.affiliation: Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: S
authors.initials: S
authors.lastname: Khoo
authors.affiliation: Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: D
authors.initials: D
authors.lastname: Back
authors.affiliation: Desmond Tutu HIV Foundation, Cape Town, South Africa.
authors.forename: C
authors.initials: C
authors.lastname: Orrell
authors.affiliation: HIV-NAT Thai Red Cross AIDS Research Center, Bangkok, Thailand.
authors.forename: A
authors.initials: A
authors.lastname: Clarke
authors.affiliation: Hospital Ramos Mejía, Buenos Aires, Argentina.
authors.forename: M
authors.initials: M
authors.lastname: Losso
authors.affiliation: HIV-NAT Thai Red Cross AIDS Research Center, Bangkok, Thailand.
authors.forename: P
authors.initials: P
authors.lastname: Phanuphak
authors.affiliation: Kirby Institute, UNSW Australia, Sydney, Australia.
authors.forename: D
authors.initials: D
authors.lastname: Carey
authors.affiliation: Kirby Institute, UNSW Australia, Sydney, Australia.
authors.forename: D A
authors.initials: DA
authors.lastname: Cooper
authors.affiliation: Kirby Institute, UNSW Australia, Sydney, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Emery
authors.forename: R
authors.initials: R
authors.lastname: Puls
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000480:Alkynes; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D048588:Benzoxazines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D015415:Biomarkers / Q000097:blood; D000090702:Constitutive Androstane Receptor; D003521:Cyclopropanes; D065637:Cytochrome P-450 CYP2A6 / Q000235:genetics / Q000378:metabolism; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics / Q000378:metabolism; D004334:Drug Administration Schedule; D005260:Female; D005838:Genotype; D006678:HIV / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity; D015658:HIV Infections / Q000175:diagnosis / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D017711:Nonlinear Dynamics; D010597:Pharmacogenetics; D010641:Phenotype; D011110:Polymorphism, Genetic; D012367:RNA, Viral / Q000097:blood; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D016896:Treatment Outcome; D019562:Viral Load; D055815:Young Adult
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D015415:Biomarkers; D000090702:Constitutive Androstane Receptor; D003521:Cyclopropanes; C000716327:NR1I3 protein, human; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; C585599:CYP2B6 protein, human; C422408:CYP3A43 protein, human; D065637:Cytochrome P-450 CYP2A6; D065702:Cytochrome P-450 CYP2B6; C098320:efavirenz