Population pharmacokinetics of atazanavir in patients with human immunodeficiency virus infection

Détails

ID Serval
serval:BIB_B3F88281E351
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Population pharmacokinetics of atazanavir in patients with human immunodeficiency virus infection
Périodique
Antimicrobial Agents and Chemotherapy
Auteur(s)
Colombo  S., Buclin  T., Cavassini  M., Decosterd  L. A., Telenti  A., Biollaz  J., Csajka  C.
ISSN
0066-4804 (Print)
Statut éditorial
Publié
Date de publication
11/2006
Volume
50
Numéro
11
Pages
3801-8
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Nov
Résumé
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.
Mots-clé
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
Oui
Création de la notice
24/01/2008 20:44
Dernière modification de la notice
20/08/2019 15:22
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