Prediction of inter-individual variability on the pharmacokinetics of CYP1A2 substrates in non-smoking healthy volunteers

Haraya, Kenta; Kato, Motohiro; Chiba, Koji; Sugiyama, Yuichi

doi:10.1016/j.dmpk.2016.03.003

Cited by 3 publications

(1 citation statement)

References 87 publications

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“…Nonetheless, a bioequivalence study in healthy volunteers has shown no differences in the values of exposure parameters of erlotinib between different dose strength formulations ( 24 ). Lastly, it has been reported that CYP1A2 expression is subject to high interindividual variability ( 25 ). In the presence of ritonavir, the metabolism of erlotinib is mainly taken over by CYP1A2.…”

Section: Discussionmentioning

confidence: 99%

Ritonavir-Boosted Exposure of Kinase Inhibitors: an Open Label, Cross-over Pharmacokinetic Proof-of-Concept Trial with Erlotinib

et al. 2022

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Background Although kinase inhibitors (KIs) are generally effective, their use has a large impact on the current health care budget. Dosing strategies to reduce treatment costs are warranted. Boosting pharmacokinetic exposure of KIs metabolized by cytochrome P450 (CYP)3A4 with ritonavir might result in lower doses needed and subsequently reduces treatment costs. This study is a proof-of-concept study to evaluate if the dose of erlotinib can be reduced by co-administration with ritonavir. Methods In this open-label, cross-over study, we compared the pharmacokinetics of monotherapy erlotinib 150 mg once daily (QD) (control arm) with erlotinib 75 mg QD plus ritonavir 200 mg QD (intervention arm). Complete pharmacokinetic profiles at steady-state were taken up to 24 h after erlotinib intake for both dosing strategies. Results Nine patients were evaluable in this study. For the control arm, the systemic exposure over 24 h, maximum plasma concentration and minimal plasma concentration of erlotinib were 29.3 μg*h/mL (coefficient of variation (CV):58%), 1.84 μg/mL (CV:60%) and 1.00 μg/mL (CV:62%), respectively, compared with 28.9 μg*h/mL (CV:116%, p = 0.545), 1.68 μg/mL (CV:68%, p = 0.500) and 1.06 μg/mL (CV:165%, p = 0.150) for the intervention arm. Exposure to the metabolites of erlotinib (OSI-413 and OSI-420) was statistically significant lower following erlotinib plus ritonavir dosing. Similar results regarding safety in both dosing strategies were observed, no grade 3 or higher adverse event was reported. Conclusions Pharmacokinetic exposure at a dose of 75 mg erlotinib when combined with the strong CYP3A4 inhibitor ritonavir is similar to 150 mg erlotinib. Ritonavir-boosting is a promising strategy to reduce erlotinib treatment costs and provides a rationale for other expensive therapies metabolized by CYP3A4.

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Section: Discussionmentioning

confidence: 99%

Ritonavir-Boosted Exposure of Kinase Inhibitors: an Open Label, Cross-over Pharmacokinetic Proof-of-Concept Trial with Erlotinib

et al. 2022

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Application of a PBPK Model Incorporating the Interplay Between Transporters and Drug‐Metabolizing Enzymes for the Precise Prediction of Drug Toxicity

Maeda

2021

Transporters and Drug‐Metabolizing Enzymes in Drug Toxicity

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Prediction of inter-individual variability on the pharmacokinetics of CYP2C8 substrates in human

Haraya

Kato²,

Chiba

et al. 2017

Drug Metabolism and Pharmacokinetics

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Inter-individual variability in pharmacokinetics can lead to unexpected side effects and treatment failure, and is therefore an important factor in drug development. CYP2C8 is a major drug-metabolizing enzyme known to be involved in the metabolism of over 100 drugs. In this study, we predicted the inter-individual variability in AUC/Dose of CYP2C8 substrates in healthy volunteers using the Monte Carlo simulation. Inter-individual variability in the hepatic intrinsic clearance of CYP2C8 substrates (CL) was estimated from the inter-individual variability in pharmacokinetics of pioglitazone, which is a major CYP2C8 substrate. The coefficient of variation (CV) of CL was estimated to be 40%. Using this value, the CVs of AUC/Dose of other major CYP2C8 substrates, rosiglitazone and amodiaquine, were predicted to validate the estimated CV of CL. As a result, the reported CVs of both substrates were within the 2.5-97.5 percentile range of the predicted CVs. Furthermore, the CVs of AUC/Dose of the CYP2C8 substrates loperamide and chloroquine, which are affected by renal clearance, were also successfully predicted. Combining this value with previously reported CVs of other CYPs, we were able to successfully predict the inter-individual variability in pharmacokinetics of various drugs in clinical.

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Prediction of inter-individual variability on the pharmacokinetics of CYP1A2 substrates in non-smoking healthy volunteers

Cited by 3 publications

References 87 publications

Ritonavir-Boosted Exposure of Kinase Inhibitors: an Open Label, Cross-over Pharmacokinetic Proof-of-Concept Trial with Erlotinib

Ritonavir-Boosted Exposure of Kinase Inhibitors: an Open Label, Cross-over Pharmacokinetic Proof-of-Concept Trial with Erlotinib

Application of a PBPK Model Incorporating the Interplay Between Transporters and Drug‐Metabolizing Enzymes for the Precise Prediction of Drug Toxicity

Prediction of inter-individual variability on the pharmacokinetics of CYP2C8 substrates in human

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