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Translational pharmacokinetic-pharmacodynamic modeling from nonclinical to clinical development: a case study of anticancer drug, crizotinib.

ABSTRACT: Attrition risk related to efficacy is still a major reason why new chemical entities fail in clinical trials despite recently increased understanding of translational pharmacology. Pharmacokinetic-pharmacodynamic (PKPD) analysis is key to translating in vivo drug potency from nonclinical models to patients by providing a quantitative assessment of in vivo drug potency with mechanistic insight of drug action. The pharmaceutical industry is clearly moving toward more mechanistic and quantitative PKPD modeling to have a deeper understanding of translational pharmacology. This paper summarizes an anticancer drug case study describing the translational PKPD modeling of crizotinib, an orally available, potent small molecule inhibitor of multiple tyrosine kinases including anaplastic lymphoma kinase (ALK) and mesenchymal-epithelial transition factor (MET), from nonclinical to clinical development. Overall, the PKPD relationships among crizotinib systemic exposure, ALK or MET inhibition, and tumor growth inhibition (TGI) in human tumor xenograft models were well characterized in a quantitative manner using mathematical modeling: the results suggest that 50% ALK inhibition is required for >50% TGI whereas >90% MET inhibition is required for >50% TGI. Furthermore, >75% ALK inhibition and >95% MET inhibition in patient tumors were projected by PKPD modeling during the clinically recommended dosing regimen, twice daily doses of crizotinib 250 mg (500 mg/day). These simulation results of crizotinib-mediated ALK and MET inhibition appeared consistent with the currently reported clinical responses. In summary, the present paper presents an anticancer drug example to demonstrate that quantitative PKPD modeling can be used for predictive translational pharmacology from nonclinical to clinical development.

SUBMITTER: Yamazaki S

PROVIDER: S-EPMC3675733 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.

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Translational pharmacokinetic-pharmacodynamic modeling from nonclinical to clinical development: a case study of anticancer drug, crizotinib.

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