Influence of Drug-Drug Interactions on the Pharmacokinetics of Atorvastatin and Its Major Active Metabolite ortho-OH-Atorvastatin in Aging People Living with HIV.

Details

Serval ID
serval:BIB_B56252981556
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Influence of Drug-Drug Interactions on the Pharmacokinetics of Atorvastatin and Its Major Active Metabolite ortho-OH-Atorvastatin in Aging People Living with HIV.
Journal
Clinical pharmacokinetics
Author(s)
Courlet P., Decosterd L.A., Alves Saldanha S., Cavassini M., Stader F., Stoeckle M., Buclin T., Marzolini C., Csajka C., Guidi M.
Working group(s)
Swiss HIV Cohort Study
ISSN
1179-1926 (Electronic)
ISSN-L
0312-5963
Publication state
Published
Issued date
08/2020
Peer-reviewed
Oui
Volume
59
Number
8
Pages
1037-1048
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
People living with HIV (PLWH) are aging and experience age-related physiological changes and comorbidities. Atorvastatin is a widely prescribed lipid-lowering agent metabolized by cytochrome P450 (CYP) 3A4, whose hepatocyte uptake is facilitated by organic anion transporting polypeptide (OATP) 1B1/1B3. Inhibition or induction of this enzyme and hepatic transporter can increase or decrease atorvastatin exposure, respectively.
This study aimed to describe the pharmacokinetic profile of atorvastatin and its major metabolite, and to evaluate drug-drug interactions (DDIs) with antiretrovirals (ARVs).
The atorvastatin pharmacokinetic profile was best described by a two-compartment model with first-order absorption and elimination. Metabolite concentrations were described by considering both linear metabolism from atorvastatin and presystemic metabolism. The influence of demographic and clinical covariates on drug and metabolite pharmacokinetics was assessed using NONMEM <sup>®</sup> . Model-based simulations were performed to evaluate the magnitude of DDIs with ARVs.
Full pharmacokinetic profiles (98 atorvastatin + 62 o-OH-atorvastatin concentrations) and sparse concentrations (78 and 53 for atorvastatin and o-OH-atorvastatin, respectively) were collected in 59 PLWH. Interindividual variability was high. The coadministration of boosted ARVs decreased atorvastatin clearance by 58% and slowed down o-OH-atorvastatin formation by 88%. Atorvastatin clearance increased by 78% when coadministered with CYP3A4 inducers. Simulations revealed a 180% increase and 44% decrease in atorvastatin exposure (area under the curve) in the presence of ARVs with inhibiting and inducing properties, respectively.
This study showed an important interindividual variability in atorvastatin pharmacokinetics that remains largely unexplained after the inclusion of covariates. Since boosted ARVs double atorvastatin exposure, the initial dosage might be reduced by half, and titrated based on individual clinical targets.
Pubmed
Web of science
Open Access
Yes
Create date
25/04/2020 20:10
Last modification date
23/10/2020 5:23
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