Effect of cytochrome P450 3A4 inhibitor ketoconazole on risperidone pharmacokinetics in healthy volunteers

Mahatthanatrakul, Werawath; Sriwiriyajan, Somchai; Ridtitid, Wibool; Boonleang, Jutima; Wongnawa, Malinee; Rujimamahasan, N.; Pipatrattanaseree, Weerachai

doi:10.1111/j.1365-2710.2011.01271.x

Cited by 29 publications

(16 citation statements)

References 14 publications

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“…Studies in a more diverse patient population, which would include patients receiving chronic therapy and especially with PMs of CYP2D6, may allow a more meaningful examination of the influence of CYP2D6 on risperidone disposition. Besides, it was expected that the other enzymes including CYP3A4/5 might have influence on the metabolism of risperidone as seen from drug interaction studies with ketoconazole [44] and rifampin [45]. This study would provide comparative information on the metabolic index between Korean and other ethnic groups, and this information would be useful in establishing criteria for phenotype/genotype correlation in the future study.…”

Section: Discussionmentioning

confidence: 97%

Population pharmacokinetic analysis of risperidone and 9-hydroxyrisperidone with genetic polymorphisms of CYP2D6 and ABCB1

Yoo

Cho

Lee

et al. 2012

J Pharmacokinet Pharmacodyn

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This study estimated the population pharmacokinetics of risperidone and its active metabolite, 9-hydroxyrisperidone, according to genetic polymorphisms in the metabolizing enzyme (CYP2D6) and transporter (ABCB1) genes in healthy subjects. Eighty healthy subjects who received a single oral dose of 2 mg risperidone participated in this study. However, eight subjects with rare genotype variants in CYP2D6 alleles were excluded from the final model built in this study. We conducted the population pharmacokinetic analysis of risperidone and 9-hydroxyrisperidone using a nonlinear mixed effects modeling (NONMEM) method and explored the possible influence of genetic polymorphisms in CYP2D6 alleles and ABCB1 (2677G>T/A and 3435C>T) on the population pharmacokinetics of risperidone and 9-hydroxyrisperidone. A two-compartment model with a first-order absorption and lag time fitted well to serum concentration-time curve for risperidone. 9-hydroxyrisperidone was well described by a one-compartment model as an extension of the parent drug (risperidone) model with first-order elimination and absorption partially from the depot. Significant covariates for risperidone clearance were genetic polymorphisms of CYP2D6*10, including CYP2D6*1/*10 (27.5 % decrease) and CYP2D6*10/*10 (63.8 % decrease). There was significant difference in the absorption rate constant (k ( a )) of risperidone among the CYP2D6*10 genotype groups. In addition, combined ABCB1 3435C>T and CYP2D6*10 genotypes had a significant (P < 0.01) effect on the fraction of metabolite absorbed from the depot. The population pharmacokinetic model of risperidone and 9-hydroxyrisperidone including the genetic polymorphisms of CYP2D6*10 and ABCB1 3435C>T as covariates was successfully constructed. The estimated contribution of genetic polymorphisms in CYP2D6*10 and ABCB1 3435C>T to population pharmacokinetics of risperidone and 9-hydroxyrisperidone suggests the interplay of CYP2D6 and ABCB1 on the pharmacokinetics of risperidone and 9-hydroxyrisperidone according to genetic polymorphisms.

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Section: Discussionmentioning

confidence: 97%

Population pharmacokinetic analysis of risperidone and 9-hydroxyrisperidone with genetic polymorphisms of CYP2D6 and ABCB1

Yoo

Cho

Lee

et al. 2012

J Pharmacokinet Pharmacodyn

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“…CYP3A4 is abundant in human liver microsomes and plays an important role in the metabolism of many drugs, including anticancer drugs. Furthermore, CYP3A4 shows about five-to tenfold inter-patient variability [25][26][27] in the disposition of these drugs metabolic efficiency, and intra-patient variability is widely recognized for several major inducers [28,29] or inhibitors [30,31].…”

Section: Discussionmentioning

confidence: 99%

Phase I dose-finding and pharmacokinetic study of docetaxel and gefitinib in patients with advanced or metastatic non-small-cell lung cancer: evaluation of drug–drug interaction

Motonaga

Yamamoto²,

Makino

et al. 2015

Cancer Chemother Pharmacol

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“…Inhibition of CYP3A4 by ketoconazole has been shown to result in increased plasma concentrations or decreased clearance of several atypical antipsychotics, including clozapine, quetiapine, ziprasidone, and risperidone [19][20][21]. Studies in healthy volunteers have shown that rifampin decreases plasma concentrations and increases clearance of risperidone [22,23], and there is evidence implicating rifampin in a clinically significant interaction with clozapine [24].…”

Section: Discussionmentioning

confidence: 99%

Lurasidone drug-drug interaction studies: a comprehensive review

Chiu

Ereshefsky

Preskorn

et al. 2014

Drug Metabolism and Drug Interactions

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Background: To evaluate potential drug-drug interactions with the atypical antipsychotic lurasidone. Methods: Seven phase I studies were conducted to investigate the effects of repeated dosing of ketoconazole, diltiazem, rifampin, or lithium on the pharmacokinetics (PK) of single oral doses of lurasidone, or the effects of repeated dosing of lurasidone on the PK of digoxin, midazolam, or the oral contraceptive norgestimate/ethinyl estradiol. Two 6-week, phase III studies included evaluation of the potential for interaction between lurasidone and lithium or valproate. Maximum serum or plasma concentration (C max ) and area under the concentration-time curve (AUC) were calculated. Results: Concomitant ketoconazole administration resulted in a 6.8-fold increase in lurasidone C max and a 9.3-fold increase in lurasidone AUC; concomitant diltiazem administration resulted in 2.1-and 2.2-fold increases, respectively. Rifampin decreased lurasidone C max and AUC (one-seventh and onefifth of lurasidone alone, respectively). Steady-state dosing with lurasidone increased C max and AUC 0-24 (AUC from time 0 to 24 h postdose) of digoxin by 9% and 13%, respectively, and of midazolam by 21% and 44%, respectively. There were no significant interactions between lurasidone and lithium, valproate, ethinyl estradiol, or norelgestromin (the major active metabolite of norgestimate). Conclusions: Lurasidone PK is altered by strong cytochrome P450 (CYP) 3A4 inhibitors or inducers, and coadministration is contraindicated; whereas moderate CYP3A4 inhibitors have less effect, and lurasidone dosage restrictions are recommended. No dose adjustment

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Effect of cytochrome P450 3A4 inhibitor ketoconazole on risperidone pharmacokinetics in healthy volunteers

Abstract: The pharmacokinetics of risperidone was affected by the concomitant administration of ketoconazole. If a CYP3A4 inhibitor is used concomitantly with risperidone, it is necessary for the clinicians to monitor their patients for signs of adverse drug reactions.

Cited by 29 publications

References 14 publications

Population pharmacokinetic analysis of risperidone and 9-hydroxyrisperidone with genetic polymorphisms of CYP2D6 and ABCB1

Population pharmacokinetic analysis of risperidone and 9-hydroxyrisperidone with genetic polymorphisms of CYP2D6 and ABCB1

Phase I dose-finding and pharmacokinetic study of docetaxel and gefitinib in patients with advanced or metastatic non-small-cell lung cancer: evaluation of drug–drug interaction

Lurasidone drug-drug interaction studies: a comprehensive review

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