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Strategy for CYP3A Induction Risk Assessment from Preclinical Signal to Human: a Case Example of a Late-Stage
Jialin Mao1, Peter Fan2,3, Susan Wong2
1Department of Drug Metabolism and Pharmacokinetics, Genentech, A Member of the Roche Group, 1 DNA Way, South San Francisco, California, 94080, USA. mao.jialin@gene.com.
Purpose:
The exposure of G2917 decreased by four-fold at oral doses of 100 mg/kg twice daily for seven days in cynomolgus monkeys. Additional investigative work was conducted to understand: (1) the causes for the significant reduction in G2917 exposure in monkeys; (2) the extrapolation of in vitro induction data to in vivo findings in monkeys, and (3) the relevance of this pre-clinical finding to humans at the projected human efficacious dose.
Methods:
Pharmacokinetic and induction potency (in vitro and in vivo) of G2917 in monkeys, and the in vitro human induction potency were studied. The hepatic CYP3A biomarkers 4β-hydroxycholesterol (4β-HC) and 6β-hydroxycortisol/cortisol ratio (6β-OHC/C) were monitored in in vivo studies. The static mechanistic model was used to quantitatively understand the in vitro-in vivo extrapolation (IVIVE) on the magnitude of induction retrospectively. Physiologically based pharmacokinetic (PBPK) modeling was used to predict the human pharmacokinetics and induction-based drug-drug interactions (DDI).
Results:
All in vitro and in vivo data indicate that the significant reduction in exposure of G2917 in monkeys is caused by auto-induction of CYP3A. The mechanistic understanding of IVIVE of G2917 induction in monkey provides higher confidence in the induction risk prediction in human using the PBPK modeling. PBPK model analysis predicted minimum auto-induction and DDI liability in humans at the predicted efficacious dose.
Conclusions:
The learning of this example provided a strategy to address the human CYP3A induction risk prospectively when there is an auto-induction finding in preclinical toxicology study.
Insights
Drug G2917 significantly reduced monkey exposure due to CYP3A auto-induction. Physiologically based pharmacokinetic modeling suggests minimal risk in humans, offering a strategy for prospective risk assessment.
Area of Science:
- Pharmacology
- Drug Metabolism
- Toxicology
Background:
- Drug exposure can be significantly altered by metabolic processes.
- Cytochrome P450 3A (CYP3A) induction is a key factor in drug-drug interactions and altered pharmacokinetics.
- Preclinical findings require careful extrapolation to predict human safety and efficacy.
Purpose of the Study:
- Investigate the cause of a four-fold decrease in G2917 exposure in cynomolgus monkeys.
- Extrapolate in vitro induction data to in vivo findings in monkeys.
- Assess the relevance of preclinical findings to human efficacy and safety at projected doses.
Main Methods:
- Pharmacokinetic and induction potency studies (in vitro and in vivo) in monkeys.
- Monitoring of hepatic CYP3A biomarkers (4β-HC, 6β-OHC/C).
- In vitro-in vivo extrapolation (IVIVE) using a static mechanistic model and physiologically based pharmacokinetic (PBPK) modeling.
Main Results:
- In vitro and in vivo data confirmed CYP3A auto-induction as the cause of reduced G2917 exposure in monkeys.
- IVIVE provided confidence in predicting induction risk in humans via PBPK modeling.
- PBPK analysis predicted minimal auto-induction and drug-drug interaction (DDI) liability in humans at efficacious doses.
Conclusions:
- The study identified CYP3A auto-induction as the mechanism for decreased G2917 exposure in monkeys.
- PBPK modeling offers a reliable method for predicting human induction risk and DDI.
- This case provides a strategy for prospective assessment of human CYP3A induction risk from preclinical auto-induction findings.
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