Population pharmacokinetics of atazanavir in patients with human immunodeficiency virus infection
Details
Serval ID
serval:BIB_B3F88281E351
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Population pharmacokinetics of atazanavir in patients with human immunodeficiency virus infection
Journal
Antimicrobial Agents and Chemotherapy
ISSN
0066-4804 (Print)
Publication state
Published
Issued date
11/2006
Volume
50
Number
11
Pages
3801-8
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Nov
Research Support, Non-U.S. Gov't --- Old month value: Nov
Abstract
Atazanavir (ATV) is a new azapeptide protease inhibitor recently approved and currently used at a fixed dose of either 300 mg once per day (q.d.) in combination with 100 mg ritonavir (RTV) or 400 mg q.d. without boosting. ATV is highly bound to plasma proteins and extensively metabolized by CYP3A4. Since ATV plasma levels are highly variable and seem to be correlated with both viral response and toxicity, dosage individualization based on plasma concentration monitoring might be indicated. This study aimed to assess the ATV pharmacokinetic profile in a target population of HIV patients, to characterize interpatient and intrapatient variability, and to identify covariates that might influence ATV disposition. A population analysis was performed with NONMEM with 574 plasma samples from a cohort of 214 randomly selected patients receiving ATV. A total of 346 randomly collected ATV plasma levels and 19 full concentration-time profiles at steady state were available. The pharmacokinetic parameter estimates were an oral clearance (CL) of 12.9 liters/h (coefficient of variation [CV], 26%), a volume of distribution of 88.3 liters (CV, 29%), an absorption rate constant of 0.405 h(-1) (CV, 122%), and a lag time of 0.88 h. A relative bioavailability value was introduced to account for undercompliance due to infrequent follow-ups (0.81; CV, 45%). Among the covariates tested, only RTV significantly reduced CL by 46%, thereby increasing the ATV elimination half-life from 4.6 h to 8.8 h. The pharmacokinetic parameters of ATV were adequately described by a one-compartment population model. The concomitant use of RTV improved the pharmacokinetic profile. However, the remaining high interpatient variability suggests the possibility of an impact of unmeasured covariates, such as genetic traits or environmental influences. This population pharmacokinetic model, together with therapeutic drug monitoring and Bayesian dosage adaptation, can be helpful in the selection and adaptation of ATV doses.
Keywords
Adult
Aged
Algorithms
Area Under Curve
Bayes Theorem
Dose-Response Relationship, Drug
Female
HIV Infections/drug therapy/*metabolism
HIV Protease Inhibitors/administration &
dosage/*pharmacokinetics/therapeutic use
Humans
Male
Middle Aged
Models, Statistical
Oligopeptides/administration & dosage/*pharmacokinetics/therapeutic use
Population
Pyridines/administration & dosage/*pharmacokinetics/therapeutic use
Reproducibility of Results
Ritonavir/administration & dosage/pharmacology/therapeutic use
Treatment Outcome
Pubmed
Web of science
Open Access
Yes
Create date
24/01/2008 21:44
Last modification date
20/08/2019 16:22