Drug interaction between oral atorvastatin and verapamil in healthy subjects: effects of atorvastatin on the pharmacokinetics of verapamil and norverapamil

Choi, Dong‐Hyun; Shin, W. G.

doi:10.1007/s00228-007-0447-5

Cited by 36 publications

(37 citation statements)

References 24 publications

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“…Though this is a potential limitation, atorvastatin is not expected to meaningfully alter CYP3A4-mediated doravirine PK. This is due to atorvastatin demonstrating only a weak to moderate inhibitory effect on CYP3A4 activity (16)(17)(18). Furthermore, exposure to doravirine at 200 mg was previously well tolerated in a phase 2 trial (2).…”

Section: Discussionmentioning

confidence: 99%

“…The lack of modulation induced by atorvastatin was demonstrated using the 4␤-hydroxycholesterol/cholesterol ratio, a marker of CYP3A4 activity (16). The ratio was shown to decrease by only 13% following chronic treatment with atorvastatin at 20 mg, and these results, in addition to others obtained with drugs that are CYP3A4 substrates, indicate weak/moderate inhibition of CYP3A4 by atorvastatin (16)(17)(18). On the basis of their individual profiles, coadministration of doravirine and atorvastatin is not projected to result in clinically meaningful alterations to the PK of either drug.…”

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confidence: 80%

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Results of a Doravirine-Atorvastatin Drug-Drug Interaction Study

Khalilieh

Yee

Sánchez

et al. 2017

Antimicrob Agents Chemother

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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.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 80%

Results of a Doravirine-Atorvastatin Drug-Drug Interaction Study

Khalilieh

Yee

Sánchez

et al. 2017

Antimicrob Agents Chemother

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“…Calcium-channel blockers increase the plasma concentrations of some statins, possibly through the inhibition of CYP 3A4 and P-gp [27,28]. However, few studies have reported about the effects of HMG-CoA reductase inhibitors on the bioavailability or pharmacokinetics of antihypertensive agents [29][30][31][32]. Although a combination of nifedipine and statins have been clinically prescribed for treatment of hypertension, the pharmacokinetic interaction between a HMG-CoA reductase inhibitor and nifedipine in vivo has not been reported thus far.…”

Section: Introductionmentioning

confidence: 96%

Effects of HMG-CoA reductase inhibitors on the pharmacokinetics of nifedipine in rats: Possible role of P-gp and CYP3A4 inhibition by HMG-CoA reductase inhibitors

Lee

Choi

2015

Pharmacological Reports

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“…Après administration par voie orale, le vérapamil est absorbé à plus de 90 % et subit un fort effet de premier passage hépatique avec une biodisponibilité de 10 à 20 %. Les 2 principales voies métaboliques sont la N-déméthylation (40 %) et la N-déalkylation (33 %) [3,18]. Les pourcentages de vérapamil et norvérapamil retrouvés dans les urines sont très faibles : respectivement 2 % et 1 % [19].…”

Section: Discussionunclassified

Découverte fortuite d’une intoxication aiguë par vérapamil forme à libération prolongée : intérêt du criblage toxicologique

et al. 2012

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Résumé -Objectifs : Un patient de 29 ans a été admis en soins intensifs pour hypotension résistante et anomalies du rythme cardiaque. Le service clinique suspectant une intoxication par bisoprolol, un criblage toxicologique par chromatographie liquide couplée à la spectrométrie de masse en tandem (LC-MS/MS) a été réalisé. Ce criblage n'a pas retrouvé de bisoprolol mais a mis en évidence une intoxication par vérapamil. Afin de confirmer l'intoxication, des dosages sanguins du vérapamil et de ses principaux métabolites ont été effectués quotidiennement. Méthodes : La recherche et les dosages ont été réalisés par LC-MS/MS. Les métabolites ont été préalablement identifiés après incubation du vérapamil avec des microsomes hépatiques de souris. Résultats : Sept métabolites ont été identifiés après incubation avec les microsomes hépatiques de souris. Cinq d'entre eux ont été retrouvés dans le sérum du patient. L'évolution des taux sanguins en véra-pamil a montré une croissance le 1 er jour (1,0 mg/L à J1, 1,7 mg/L à J2 ; valeurs thérapeutiques : 0,02 à 0,25 mg/L), un plateau pendant 3 jours puis une décroissance. Les cinétiques des principaux métabolites du vérapamil (norvérapamil et N-desalkylvérapamil) étaient comparables à celle de la molécule mère. Conclusion : Le criblage toxicologique a permis de diagnostiquer l'intoxication par vérapamil dans un contexte clinique complexe. La stagnation des taux sanguins pendant 3 jours était vraisemblablement due à une intoxication avec une forme à libération prolongée du vérapamil. Mots clés : Vérapamil, intoxication aiguë, criblage toxicologique, LC-MS/MSAbstract -Objectives: A 29-year old man was admitted in intensive care unit for resistant hypotension and cardiac rhythm disturbances. Since a bisoprolol overdose was suspected, a toxicological screening was carried out on serum. This screening didn't show bisoprolol but revealed verapamil intoxication. To confirm the diagnosis, verapamil and its main metabolites were assayed on 6 serum samples taken over the period of hospitalization. Methods: Verapamil and metabolites were identified by LC-MS/MS. Metabolites have been previously recognized after mouse liver microsomal incubation and added to the data library. Results: Seven verapamil metabolites were identified after mouse liver microsomal incubation. Five of them were found in serum samples. Kinetics of verapamil and its main metabolites (norverapamil and N-desalkylverapamil) in serum samples revealed 3 stages: increase during the 1st day, stability during 3 days and decrease on 5th and 6th days. Conclusion: The present case demonstrates the importance of toxicological screening in the diagnosis of drugs overdose. The stagnation of serum levels during 3 days could be explained by intoxication with a sustained-release formulation of verapamil.

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Drug interaction between oral atorvastatin and verapamil in healthy subjects: effects of atorvastatin on the pharmacokinetics of verapamil and norverapamil

Abstract: The above data suggest that atorvastatin could inhibit the absorption of verapamil via inhibition of P-gp and/or the metabolism of verapamil by CYP3A4 in humans.

Cited by 36 publications

References 24 publications

Results of a Doravirine-Atorvastatin Drug-Drug Interaction Study

Results of a Doravirine-Atorvastatin Drug-Drug Interaction Study

Effects of HMG-CoA reductase inhibitors on the pharmacokinetics of nifedipine in rats: Possible role of P-gp and CYP3A4 inhibition by HMG-CoA reductase inhibitors

Découverte fortuite d’une intoxication aiguë par vérapamil forme à libération prolongée : intérêt du criblage toxicologique

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