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Clinical Trial
. 2021 Sep;14(5):1945-1954.
doi: 10.1111/cts.13049. Epub 2021 May 31.

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

Phyllis Chan  1 , Han Ting Ding  1 , Bianca M Liederer  2 , Jialin Mao  2 , Paula Belloni  3 , Liuxi Chen  2 , Simon S Gao  4 , Victory Joseph  5 , Xiaoying Yang  6 , Joseph S Lin  3 , Mayur S Mitra  7 , Wendy S Putnam  1 , Angelica Quartino  1 , Rebecca N Bauer  8 , Lin Pan  1
Affiliations
Clinical Trial

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

Phyllis Chan et al. Clin Transl Sci. 2021 Sep.

Abstract

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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Conflict of interest statement

All authors are current or former employees and stockholders of Genentech/Roche.

Figures

FIGURE 1
FIGURE 1
Plasma concentration‐time profiles of GDC‐0334 in humans after single ascending dose under fasting condition show increasing GDC‐0334 plasma concentrations associated with the ascending dose levels. Symbols = arithmetic mean +/‐ SD per nominal sampling time per treatment group; lines = PK‐time profile per treatment group. The inset figure only displays data up to 48 h postdose. PK, pharmacokinetic
FIGURE 2
FIGURE 2
Observed pharmacokinetic‐pharmacodynamic (PK‐PD) relationship from the clinical study demonstrates the inhibition of allyl isothiocyanate (AITC)‐induced dermal blood is dose proportional to the plasma concentrations of GDC‐0334. DBF, dermal blood flow; AUC0–10 min, area under the curve from time 0 to 10 min; SCR, baseline data from screening period; SAD, single ascending dose; MAD, multiple ascending dose; ss, steady state; solid black line, nonlinear regression curve fit line. Data partially published previously: ©2020 Balestrini et al., J Exp Med. 2021; 218(4):e2021637
FIGURE 3
FIGURE 3
Prediction‐corrected visual predictive check of final pharmacokinetic‐pharmacodynamic (PK‐PD) model. Observed data (gray circles), observed median (red crosses), observed 5th and 95th percentiles (blue crosses); 95% prediction interval (PI; 1000 replicates) of median (red shaded areas); 95% PI for 5th and 95th percentiles not displayed due to large PI; n = sample size (by allyl isothiocyanate [AITC] application location, arm, occasion, and subject), bracket = inclusive, parenthesis = exclusive
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