Thank you for sharing how to access the publication with AAPS credentials. Got the publication!!
This older publication might be of interest.
Liston, Dane R., and Myrtle Davis. "Clinically relevant concentrations of anticancer drugs: a guide for nonclinical studies." Clinical cancer research 23.14 (2017): 3489-3498.
Abstract
Approved and marketed drugs are frequently studied in nonclinical models to evaluate the potential application to additional disease indications or to gain insight about molecular mechanisms of action. A survey of the literature reveals that nonclinical experimental designs (in vitro or in vivo) often include evaluation of drug concentrations or doses that are much higher than what can be achieved in patients (i.e., above the maximally tolerated dose or much higher than the clinically relevant exposures). The results obtained with these high concentrations may be particularly helpful in elucidating off-target effects and toxicities, but it is critical to have a dose–response curve that includes the minimally effective or clinically effective concentration for comparison. We have reviewed the clinical literature and drug product labels for all small molecules and biological agents approved by the FDA for use in oncology to identify and compile the available pharmacokinetic parameters. The data summarized here can serve as a guide for selection of in vitro concentrations and in vivo plasma exposures for evaluation of drug effects in nonclinical studies. Inclusion of drug concentrations or exposures that are relevant to those observed in clinical practice can improve translation of nonclinical mechanism of action findings into potentially relevant clinical effects. Clin Cancer Res; 23(14); 3489–98. ©2017 AACR.
https://aacrjournals.org/clincancerres/article/23/14/3489/122969/Clinically-Relevant-Concentrations-of-Anticancer
Best,
Tsung
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Tsung Tan
Drug Delivery and Infusion Department Manager
Primetech Corporation
Tokyo
[email protected]
Disclaimer: Opinions expressed are solely my own and do not express the views or opinions of my employer.
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Original Message:
Sent: 07-10-2023 08:40
From: Ho-Leung Fung
Subject: New AAPS Journal article: A PKPD Case Study: Achieving Clinically Relevant Exposures of AZD5991 in Oncology Mouse Models
| https://link.springer.com/article/10.1208/s12248-023-00836-z |
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.
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Ho-Leung Fung Ph.D., FAAPS
Editor-in-Chief
University at Buffalo
Sarasota FL
[email protected]
Disclaimer: Opinions expressed are solely my own and do not express the views or opinions of my employer.
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