Translational and pharmacokinetic-pharmacodynamic application for the clinical development of GDC-0334, a novel TRPA1 inhibitor.

Autor: Chan P; Department of Clinical Pharmacology, Genentech, Inc, South San Francisco, California, USA., Ding HT; Department of Clinical Pharmacology, Genentech, Inc, South San Francisco, California, USA., Liederer BM; Department of Drug Metabolism & Pharmacokinetics, Genentech, Inc, South San Francisco, California, USA., Mao J; Department of Drug Metabolism & Pharmacokinetics, Genentech, Inc, South San Francisco, California, USA., Belloni P; Department of Clinical Sciences, Early Clinical Development, Genentech, Inc, South San Francisco, California, USA., Chen L; Department of Drug Metabolism & Pharmacokinetics, Genentech, Inc, South San Francisco, California, USA., Gao SS; Department of Clinical Imaging, Genentech, Inc, South San Francisco, California, USA., Joseph V; Department of Biomedical Imaging, Genentech, Inc, South San Francisco, California, USA., Yang X; Department of Biostatistics, Early Clinical Development, Genentech, Inc, South San Francisco, California, USA., Lin JS; Department of Clinical Sciences, Early Clinical Development, Genentech, Inc, South San Francisco, California, USA., Mitra MS; Department of Toxicology, Genentech, Inc, South San Francisco, California, USA., Putnam WS; Department of Clinical Pharmacology, Genentech, Inc, South San Francisco, California, USA., Quartino A; Department of Clinical Pharmacology, Genentech, Inc, South San Francisco, California, USA., Bauer RN; Department of Biomarker Development, Early Clinical Development, Genentech, Inc, South San Francisco, California, USA., Pan L; Department of Clinical Pharmacology, Genentech, Inc, South San Francisco, California, USA.
Jazyk: angličtina
Zdroj: Clinical and translational science [Clin Transl Sci] 2021 Sep; Vol. 14 (5), pp. 1945-1954. Date of Electronic Publication: 2021 May 31.
DOI: 10.1111/cts.13049
Abstrakt: GDC-0334 is a novel small molecule inhibitor of transient receptor potential cation channel member A1 (TRPA1), a promising therapeutic target for many nervous system and respiratory diseases. The pharmacokinetic (PK) profile and pharmacodynamic (PD) effects of GDC-0334 were evaluated in this first-in-human (FIH) study. A starting single dose of 25 mg was selected based on integrated preclinical PK, PD, and toxicology data following oral administration of GDC-0334 in guinea pigs, rats, dogs, and monkeys. Human PK and PK-PD of GDC-0334 were characterized after single and multiple oral dosing using a population modeling approach. The ability of GDC-0334 to inhibit dermal blood flow (DBF) induced by topical administration of allyl isothiocyanate (AITC) was evaluated as a target-engagement biomarker. Quantitative models were developed iteratively to refine the parameter estimates of the dose-concentration-effect relationships through stepwise estimation and extrapolation. Human PK analyses revealed that bioavailability, absorption rate constant, and lag time increase when GDC-0334 was administered with food. The inhibitory effect of GDC-0334 on the AITC-induced DBF biomarker exhibited a clear sigmoid-Emax relationship with GDC-0334 plasma concentrations in humans. This study leveraged emerging preclinical and clinical data to enable iterative refinement of GDC-0334 mathematical models throughout the FIH study for dose selection in subsequent cohorts throughout the study. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? GDC-0334 is a novel, small molecule TRPA1 inhibitor and a pharmacokinetic-pharmacodynamic (PK-PD) modeling strategy could be implemented in a systematic and step-wise manner to build and learn from emerging data for early clinical development. WHAT QUESTION DID THIS STUDY ADDRESS? Can noncompartmental and population-based analyses be used to describe the PK and PD characteristics of GDC-0334 in preclinical and clinical studies? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? GDC-0334 exposure generally increased with dose in rats, dogs, and monkeys. The starting dose (25 mg) in the clinical study was determined based on the preclinical data. GDC-0334 exhibited linear PK in humans and the bioavailability was increased with food. The inhibitory effect of GDC-0334 on dermal blood flow induced by the TRPA1 agonist allyl isothiocyanate in humans indicates a clear PK-PD relationship. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? The models developed based on TRPA1 agonist-induced dermal blood flow inhibition data can be used to predict PK-PD relationships in future preclinical and clinical studies evaluating new drug entities that target TRPA1.
(© 2021 Genentech. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)
Databáze: MEDLINE
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