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

被引：9

作者：

Courlet, Perrine ^{[1
,2
]}

Decosterd, Laurent A. ^{[1
,2
]}

Saldanha, Susana Alves ^{[1
,2
]}

Cavassini, Matthias ^{[2
,3
]}

Stader, Felix ^{[4
,5
,6
]}

Stoeckle, Marcel ^{[4
,5
]}

Buclin, Thierry ^{[1
,2
]}

Marzolini, Catia ^{[4
,5
,6
]}

Csajka, Chantal ^{[2
,7
,8
,9
]}

Guidi, Monia ^{[1
,2
,7
,8
]}

机构：

[1] Lausanne Univ Hosp, Serv Clin Pharmacol, Lausanne, Switzerland

[2] Univ Lausanne, Lausanne, Switzerland

[3] Lausanne Univ Hosp, Serv Infect Dis, Lausanne, Switzerland

[4] Univ Hosp Basel, Div Infect Dis, Basel, Switzerland

[5] Univ Hosp Basel, Hosp Epidemiol, Basel, Switzerland

[6] Univ Basel, Basel, Switzerland

[7] Univ Hosp, Ctr Res & Innovat Clin Pharmaceut Sci, Lausanne, Switzerland

[8] Univ Geneva, Univ Lausanne, Inst Pharmaceut Sci Western Switzerland, Geneva, Switzerland

[9] Univ Geneva, Sch Pharmaceut Sci, Geneva, Switzerland

来源：

CLINICAL PHARMACOKINETICS | 2020年 / 59卷 / 08期

基金：

瑞士国家科学基金会;

关键词：

COA REDUCTASE INHIBITORS; POPULATION PHARMACOKINETICS; MODEL; ACID; LACTONE; RHABDOMYOLYSIS; PATIENT; QUANTIFICATION; POLYMORPHISM; DISPOSITION;

D O I：

10.1007/s40262-020-00876-0

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Background 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. Objective This study aimed to describe the pharmacokinetic profile of atorvastatin and its major metabolite, and to evaluate drug-drug interactions (DDIs) with antiretrovirals (ARVs). Methods 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(R). Model-based simulations were performed to evaluate the magnitude of DDIs with ARVs. Results 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. Conclusion 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.

引用

页码：1037 / 1048

页数：12

共 53 条

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