title: Population Pharmacokinetics Modeling of Unbound Efavirenz, Atazanavir, and Ritonavir in HIV-Infected Subjects With Aging Biomarkers.
abstract: Unbound drug is the pharmacodynamically relevant concentration. This study aimed to determine if chronologic age or markers of biologic aging, such as the frailty phenotype and p16INK4agene expression, altered unbound pharmacokinetics (PKs) of efavirenz (EFV) and atazanavir/ritonavir (ATV/RTV). Sixty human immunodeficiency virus (HIV)-infected participants receiving EFV and 31 receiving ATV/RTV provided 1 to 11 samples to quantify total and unbound plasma concentrations. Population PK models with total and unbound concentrations simultaneously described are developed for each drug. The unbound fractions for EFV, ATV, and RTV are 0.65%, 5.67%, and 0.63%, respectively. Covariate analysis suggests RTV unbound PK is sensitive to body size; unbound fraction of RTV is 34% lower with body mass index (BMI) above 30 kg/m2. No alterations in drug clearance or unbound fraction with age, frailty, or p16INK4aexpression were observed. Assessing functional and physiologic aging markers to inform potential PK changes is necessary to determine if drug/dosing changes are warranted in the aging population.
authors.affiliation: UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Dumond
authors.affiliation: UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.affiliation: UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: M
authors.initials: M
authors.lastname: Cottrell
authors.affiliation: UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: C R
authors.initials: CR
authors.lastname: Trezza
authors.affiliation: School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Hma
authors.initials: H
authors.lastname: Prince
authors.affiliation: UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: C
authors.initials: C
authors.lastname: Sykes
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: C
authors.initials: C
authors.lastname: Torrice
authors.affiliation: UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: N
authors.initials: N
authors.lastname: White
authors.affiliation: UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: S
authors.initials: S
authors.lastname: Malone
authors.affiliation: UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: R
authors.initials: R
authors.lastname: Wang
authors.affiliation: School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: K B
authors.initials: KB
authors.lastname: Patterson
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: N E
authors.initials: NE
authors.lastname: Sharpless
authors.affiliation: UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: A
authors.initials: A
authors.lastname: Forrest
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000480:Alkynes; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000069446:Atazanavir Sulfate / Q000008:administration & dosage / Q000493:pharmacokinetics*; D048588:Benzoxazines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D049628:Body Size; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D003521:Cyclopropanes; D004359:Drug Therapy, Combination; D005260:Female; D016330:Frail Elderly; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D017711:Nonlinear Dynamics; D019438:Ritonavir / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D003521:Cyclopropanes; D000069446:Atazanavir Sulfate; C098320:efavirenz; D019438:Ritonavir