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A PKPD Case Study: Achieving Clinically Relevant Exposures of AZD5991 in Oncology Mouse Models
Michael J White1, Letitia Cheatham2, Shenghua Wen2
1AstraZeneca Research and Development Boston: AstraZeneca R&D Boston, Waltham, Massachusetts, USA. michael.white1@astrazeneca.com.
Abstract:
Capturing human equivalent drug exposures preclinically is a key challenge in the translational process. Motivated by the need to recapitulate the pharmacokinetic (PK) profile of the clinical stage Mcl-1 inhibitor AZD5991 in mice, we describe the methodology used to develop a refined mathematical model relating clinically relevant concentration profiles to efficacy. Administration routes were explored to achieve target exposures matching the clinical exposure of AZD5991. Intravenous infusion using vascular access button (VAB) technology was found to best reproduce clinical target exposures of AZD5991 in mice. Exposure-efficacy relationships were evaluated, demonstrating that dissimilar PK profiles result in differences in target engagement and efficacy outcomes. Thus, these data underscore the importance of accurately ascribing key PK metrics in the translational process to enable clinically meaningful predictions of efficacy.
Insights
Accurately modeling preclinical drug exposure is crucial for effective translation. This study developed a mathematical model to match human drug exposure in mice, improving efficacy predictions for Mcl-1 inhibitors.
Area of Science:
- Pharmacology and Toxicology
- Translational Medicine
- Mathematical Modeling
Background:
- Translating preclinical drug data to human efficacy is challenging.
- Accurate recapitulation of human pharmacokinetics (PK) in animal models is essential.
- The Mcl-1 inhibitor AZD5991 requires precise preclinical exposure modeling.
Purpose of the Study:
- To develop a mathematical model for predicting drug efficacy based on PK profiles.
- To establish methods for achieving human equivalent drug exposures in mice.
- To investigate the exposure-efficacy relationship for AZD5991.
Main Methods:
- Development of a refined mathematical model linking drug concentration to efficacy.
- Exploration of various administration routes to achieve target exposures.
- Utilizing vascular access button (VAB) technology for intravenous infusion in mice.
Main Results:
- Intravenous infusion via VAB technology successfully reproduced clinical AZD5991 exposures in mice.
- Dissimilar PK profiles led to significant differences in target engagement and efficacy.
- The developed model demonstrated a relationship between PK metrics and efficacy outcomes.
Conclusions:
- Accurate preclinical pharmacokinetic modeling is vital for predicting clinical efficacy.
- Achieving human equivalent drug exposures in mice enhances translational validity.
- This methodology improves the reliability of efficacy predictions for novel therapeutics.
