Effect of Rifampin, an Inducer of CYP3A and P‐glycoprotein, on the Pharmacokinetics of Risperidone

Kim, Kyoung Ah; Park, Pil Whan; Liu, Kwang-Hyeon; Kim, Kwon Bok; Lee, Heon Jeong; Shin, Jae Gook; Park, Ji Young

doi:10.1177/0091270007309888

Cited by 39 publications

(23 citation statements)

References 35 publications

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“…Rifampin is also known for inducing P-glycoprotein efflux transporter (Kim et al, 2008). The effects mediated by rifampin in the present clinical trial are unlikely to involve transporters.…”

Section: Discussionmentioning

confidence: 60%

Effect of Rifampin on the Disposition of Brivaracetam in Human Subjects: Further Insights into Brivaracetam Hydrolysis

Stockis

Watanabe

Scheen

et al. 2016

Drug Metabolism and Disposition

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Brivaracetam (BRV) is a high-affinity synaptic vesicle protein 2A ligand developed for the treatment of uncontrolled partial-onset seizures. The present phase I, open-label, two-way crossover study was designed to assess the effect of rifampin on the pharmacokinetics of BRV and its hydroxy (BRV-OH), acid (BRV-AC), and hydroxy acid (BRV-OHAC) metabolites. Twenty-six healthy subjects received BRV (150-mg single oral dose) either alone or following 5 days of rifampin 600 mg/day. BRV and its metabolites were examined for their plasma profiles and urinary excretion. Pharmacokinetic modeling was developed to estimate the rate constants of the various metabolic routes. Parallel in vitro assays were conducted to characterize the hydrolysis of BRV to BRV-AC as well as to identify any potential effect of rifampin on the hydrolysis reaction. Rifampin did not significantly affect the maximum plasma concentration (C max ) of BRV, but decreased its area under the curve (AUC) by 45%. In addition, rifampin significantly increased the AUC of BRV-OH (+109%), decreased the AUC of BRV-AC (253%), but had little effect on BRV-OHAC (210%). In vitro assays showed that the major urinary metabolite BRV-AC (33% of the dose) was likely to be formed by amidase EC 3.5.1.4. In vitro data indicated that the enzyme was not significantly inhibited nor induced by rifampin. Modeling confirmed that all of the observed changes in vivo were secondary to the induction of the CYP2C19-mediated hydroxylation of BRV to BRV-OH (3.7-fold increase in the rate constant).

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Section: Discussionmentioning

confidence: 60%

Effect of Rifampin on the Disposition of Brivaracetam in Human Subjects: Further Insights into Brivaracetam Hydrolysis

Stockis

Watanabe

Scheen

et al. 2016

Drug Metabolism and Disposition

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“…In addition, either a strong CYP2D6 inhibitors, bupropion, or a moderate CYP2D6 inhibitor, sertraline, will affect the serum concentration of risperidone, but no influence on 9-hydroxyrisperidone serum concentration 99. The comedication of CYP2D6 inducer, rifampin, significantly decreased 51% of risperidone, 43% of 9-hydroxyrisperidone, and 45% of the active moieties of the mean area under curve 100. In addition, the antiepileptic, carbamazepine decreases 50% of plasma concentration of both risperidone and its active metabolite 101.…”

Section: Challenges Opportunities and Future Directions In The Clinmentioning

confidence: 99%

CYP2D6 polymorphisms and their influence on risperidone treatment

Puangpetch

Vanwong

Nuntamool

et al. 2016

PGPM

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Cytochrome P450 enzyme especially CYP2D6 plays a major role in biotransformation. The interindividual variations of treatment response and toxicity are influenced by the polymorphisms of this enzyme. This review emphasizes the effect of CYP2D6 polymorphisms in risperidone treatment in terms of basic knowledge, pharmacogenetics, effectiveness, adverse events, and clinical practice. Although the previous studies showed different results, the effective responses in risperidone treatment depend on the CYP2D6 polymorphisms. Several studies suggested that CYP2D6 polymorphisms were associated with plasma concentration of risperidone, 9-hydroxyrisperidone, and active moiety but did not impact on clinical outcomes. In addition, CYP2D6 poor metabolizer showed more serious adverse events such as weight gain and prolactin than other predicted phenotype groups. The knowledge of pharmacogenomics of CYP2D6 in risperidone treatment is increasing, and it can be used for the development of personalized medication in term of genetic-based dose recommendation. Moreover, the effects of many factors in risperidone treatment are still being investigated. Both the CYP2D6 genotyping and therapeutic drug monitoring are the important steps to complement the genetic-based risperidone treatment.

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“…Crizotinib has not been identified as a substrate of any uptake transporters; however, crizotinib is a substrate of P-glycoprotein (CDER, 2011), which is also induced by rifampin (Paine et al, 2002;Kim et al, 2008). Therefore, P-glycoprotein may, in part, play a role in the crizotinib-rifampin interaction (e.g., increase in entero-hepatic circulation).…”

Section: Prediction Of Crizotinib Drug-drug Interactions 1427mentioning

confidence: 99%

Prediction of Drug-Drug Interactions with Crizotinib as the CYP3A Substrate Using a Physiologically Based Pharmacokinetic Model

2015

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An orally available multiple tyrosine kinase inhibitor, crizotinib (Xalkori), is a CYP3A substrate, moderate time-dependent inhibitor, and weak inducer. The main objectives of the present study were to: 1) develop and refine a physiologically based pharmacokinetic (PBPK) model of crizotinib on the basis of clinical single-and multiple-dose results, 2) verify the crizotinib PBPK model from crizotinib single-dose drug-drug interaction (DDI) results with multiple-dose coadministration of ketoconazole or rifampin, and 3) apply the crizotinib PBPK model to predict crizotinib multiple-dose DDI outcomes. We also focused on gaining insights into the underlying mechanisms mediating crizotinib DDIs using a dynamic PBPK model, the Simcyp population-based simulator. First, PBPK model-predicted crizotinib exposures adequately matched clinically observed results in the single-and multiple-dose studies. Second, the model-predicted crizotinib exposures sufficiently matched clinically observed results in the crizotinib single-dose DDI studies with ketoconazole or rifampin, resulting in the reasonably predicted fold-increases in crizotinib exposures. Finally, the predicted fold-increases in crizotinib exposures in the multipledose DDI studies were roughly comparable to those in the singledose DDI studies, suggesting that the effects of crizotinib CYP3A time-dependent inhibition (net inhibition) on the multiple-dose DDI outcomes would be negligible. Therefore, crizotinib doseadjustment in the multiple-dose DDI studies could be made on the basis of currently available single-dose results. Overall, we believe that the crizotinib PBPK model developed, refined, and verified in the present study would adequately predict crizotinib oral exposures in other clinical studies, such as DDIs with weak/ moderate CYP3A inhibitors/inducers and drug-disease interactions in patients with hepatic or renal impairment.

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Effect of Rifampin, an Inducer of CYP3A and P‐glycoprotein, on the Pharmacokinetics of Risperidone

Cited by 39 publications

References 35 publications

Effect of Rifampin on the Disposition of Brivaracetam in Human Subjects: Further Insights into Brivaracetam Hydrolysis

Effect of Rifampin on the Disposition of Brivaracetam in Human Subjects: Further Insights into Brivaracetam Hydrolysis

CYP2D6 polymorphisms and their influence on risperidone treatment

Prediction of Drug-Drug Interactions with Crizotinib as the CYP3A Substrate Using a Physiologically Based Pharmacokinetic Model

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