Effect of food on the pharmacodynamics and pharmacokinetics of atorvastatin, an inhibitor of HMG-CoA reductase

Whitfield, Lloyd R.; Stern, Robert L.; Sedman, Allen J.; Abel, Robert; Gibson, Donald M.

doi:10.1007/bf03190074

Cited by 28 publications

(20 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, this decrease is not considered clinically relevant, as similar decreases associated with food intake and nighttime dosing have been observed, while efficacy was maintained when these other factors were present (19)(20)(21). Extensive meta-analysis indicated that the efficacy of statins correlates with total daily exposure rather than with peak exposure.…”

Section: Discussionmentioning

confidence: 99%

Results of a Doravirine-Atorvastatin Drug-Drug Interaction Study

Khalilieh

Yee

Sánchez

et al. 2017

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Doravirine is a novel, highly potent, nonnucleoside reverse transcriptase inhibitor that is administered once daily and that is in development for the treatment of HIV-1 infection. In vitro and clinical data suggest that doravirine is unlikely to cause significant drug-drug interactions via major drug-metabolizing enzymes or transporters. As a common HIV-1 infection comorbidity, hypercholesterolemia is often treated with statins, including the commonly prescribed atorvastatin. Atorvastatin is subject to drug-drug interactions with cytochrome P450 3A4 (CYP3A4) inhibitors. Increased exposure due to CYP3A4 inhibition may lead to serious adverse events (AEs), including rhabdomyolysis. Furthermore, atorvastatin is a substrate for breast cancer resistance protein (BCRP), of which doravirine may be a weak inhibitor; this may increase atorvastatin exposure. The potential of doravirine to affect atorvastatin pharmacokinetics was investigated in a two-period, fixed-sequence study in healthy individuals. In period 1, a single dose of atorvastatin at 20 mg was administered followed by a 72-h washout. In period 2, doravirine at 100 mg was administered once daily for 8 days, with a single dose of atorvastatin at 20 mg concomitantly being administered on day 5. Sixteen subjects were enrolled, and 14 completed the trial; 2 discontinued due to AEs unrelated to the treatment. The atorvastatin area under the curve from time zero to infinity was similar with and without doravirine (geometric mean ratio [GMR] for doravirine-atorvastatin/atorvastatin, 0.98; 90% confidence interval [CI], 0.90 to 1.06), while the maximum concentration decreased by 33% (GMR for doravirineatorvastatin/atorvastatin, 0.67; 90% CI, 0.52 to 0.85). These changes were deemed not to be clinically meaningful. Both of the study drugs were generally well tolerated. Doravirine had no clinically relevant effect on atorvastatin pharmacokinetics in healthy subjects, providing support for the coadministration of doravirine and atorvastatin.

show abstract

Section: Discussionmentioning

confidence: 99%

Results of a Doravirine-Atorvastatin Drug-Drug Interaction Study

Khalilieh

Yee

Sánchez

et al. 2017

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…The published data on atorvastatin show that a reduction in LDL-C associated with the administration of atorvastatin is more highly correlated with the total daily atorvastatin dose rather than with the measurement of peak atorvastatin exposure ( C max ). 1,2,3,4 …”

Section: Discussionmentioning

confidence: 99%

“…1,2,3,4 Reductions in atorvastatin C max are not associated with changes in LDL-C lowering efficacy. 1,5,6 The biological processes governing the changes in LDL-C occur over a range of weeks to months, whereas plasma concentrations of atorvastatin peak within an hour after dosing.…”

mentioning

confidence: 95%

Prediction of Clinical Irrelevance of PK Differences in Atorvastatin Using PK/PD Models Derived From Literature-Based Meta-Analyses

Vargo

Adewale

Behm

et al. 2014

Clin Pharmacol Ther

View full text Add to dashboard Cite

To support the development of a fixed-dose combination (FDC) of ezetimibe and atorvastatin for the treatment of dyslipidemia, bioequivalence (BE) studies were conducted across a combined dose range (10/10, 10/20, 10/40, and 10/80 mg of ezetimibe/atorvastatin). In the BE trials, all parameters met traditional BE bounds except for atorvastatin peak plasma concentration (Cmax) at two intermediate doses. Literature-based metadata analysis predicted that the observed difference in Cmax between an ezetimibe+atorvastatin FDC and coadministration of these agents translates directly into a non–clinically significant change of <1.2% absolute difference in the percentage lowering of low-density-lipoprotein cholesterol . Both FDC doses were confirmed to be clinically equivalent to coadministration in the subsequent clinical equivalence trials. These data suggest that modeling of dose–response relationships may be useful in predicting clinical equivalence, lowering cost/timelines through effective powering of studies, and predicting the effectiveness of new dosage formulations without the need for additional clinical efficacy trials in regulatory settings.

show abstract

“…The bioavailability of pravastatin was reduced by 31% when taken with food, but its lipid-lowering efficacy was unchanged [96]. For atorvastatin and fluvastatin, the bioavailability and effects were not affected by food intake [97][98][99]. GFJ is a clinically important beverage because GFJ constituents inhibit intestinal CYP3A4 [100,101].…”

Section: Drug--food Interactions With Cypsmentioning

confidence: 99%