A PKPD Case Study: Achieving Clinically Relevant Exposures of AZD5991 in Oncology Mouse Models.

Autor: White MJ; AstraZeneca Research and Development Boston: AstraZeneca R&D Boston, Waltham, Massachusetts, USA. michael.white1@astrazeneca.com., Cheatham L; AstraZeneca Research and Development Boston: AstraZeneca R&D Boston, Waltham, Massachusetts, USA., Wen S; AstraZeneca Research and Development Boston: AstraZeneca R&D Boston, Waltham, Massachusetts, USA., Scarfe G; AstraZeneca Research and Development Boston: AstraZeneca R&D Boston, Waltham, Massachusetts, USA., Cidado J; AstraZeneca Research and Development Boston: AstraZeneca R&D Boston, Waltham, Massachusetts, USA., Reimer C; AstraZeneca Research and Development Boston: AstraZeneca R&D Boston, Waltham, Massachusetts, USA., Hariparsad N; AstraZeneca Research and Development Boston: AstraZeneca R&D Boston, Waltham, Massachusetts, USA., Jones RDO; AstraZeneca Research and Development Boston: AstraZeneca R&D Boston, Waltham, Massachusetts, USA., Drew L; AstraZeneca Research and Development Boston: AstraZeneca R&D Boston, Waltham, Massachusetts, USA., McGinnity DF; AstraZeneca Research and Development Boston: AstraZeneca R&D Boston, Waltham, Massachusetts, USA., Vasalou C; AstraZeneca Research and Development Boston: AstraZeneca R&D Boston, Waltham, Massachusetts, USA.
Jazyk: angličtina
Zdroj: The AAPS journal [AAPS J] 2023 Jun 28; Vol. 25 (4), pp. 66. Date of Electronic Publication: 2023 Jun 28.
DOI: 10.1208/s12248-023-00836-z
Abstrakt: 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.
(© 2023. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)
Databáze: MEDLINE
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