Taselisib (also known as GDC-0032) is a potent and selective phosphoinositide 3-kinase (PI3K) inhibitor that displays greater selectivity for mutant PI3Kα than wild-type PI3Kα. To better understand the absorption, distribution, metabolism, and excretion properties of taselisib, mass balance studies were conducted following single oral doses of [14C]taselisib in rats, dogs, and humans. Absolute bioavailability (ABA) of taselisib in humans was determined by oral administration of taselisib at the therapeutic dose followed by intravenous dosing of [14C]taselisib as a microtracer. The ABA in humans was 57.4%. Absorption of taselisib was rapid in rats and dogs and moderately slow in humans. The recovery of radioactivity in excreta was high (>96%) in the three species where feces was the major route of excretion. Taselisib was the major circulating component in the three species with no metabolite accounting for >10% of the total drug-derived material. The fraction absorbed of taselisib was 35.9% in rats and 71.4% in dogs. In rats, absorbed drug underwent moderate to extensive metabolism and biliary excretion of taselisib was minor. In dog, biliary excretion and metabolism were major clearance pathways. In humans, 84.2% of the dose was recovered as the parent drug in excreta indicating that metabolism played a minor role in the drug’s clearance. Major metabolism pathways were oxidation and amide hydrolysis in the three species while methylation was another prominent metabolism pathway in dogs. The site of methylation was identified on the triazole moiety. In vitro experiments characterized that the N-methylation was dog-specific and likely mediated by a thiol methyltransferase.

SIGNIFICANCE STATEMENT This study provides a comprehensive description of the absorption, distribution, and metabolism and pharmacokinetic properties of taselisib in preclinical species and humans. This study demonstrated the importance of oral bioavailability results for understanding taselisib’s clearance pathways. The study also describes the identification and characterization of a unique dog-specific N-methylation metabolite of taselisib and the enzyme mediating N-methylation in vitro.

This work received no external funding.

The authors were employees of Genentech, Inc. or F. Hoffmann-La Roche Ltd when this work was completed.

↵1These authors contributed equally.

↵2Current affiliation: Pharmacokinetics and Drug Metabolism, Amgen, Inc., South San Francisco, California.

↵3Current affiliation: Clinical Pharmacology, BeiGene, San Mateo, California.

↵4Current affiliation: Ingredient Research, The Coca-Cola Company, Atlanta, Georgia.

↵5Current affiliation: Clinical Development, ArriVent Biopharma, Burlingame, California.

↵6Current affiliation: Clinical Pharmacology, Seagen, South San Francisco, California.

dx.doi.org/10.1124/dmd.122.001096.

↵This article has supplemental material available at dmd.aspetjournals.org.