Single-Dose Pharmacokinetics and Tolerability of the Oral Epidermal Growth Factor Receptor Inhibitor Mobocertinib (TAK-788) in Healthy Volunteers: Low-Fat Meal Effect and Relative Bioavailability of 2 Capsule Products.

Abstract

Mobocertinib (TAK-788) is a tyrosine kinase inhibitor under investigation for treatment of non-small cell lung cancer with activating EGFR exon 20 insertions. This study examined the safety; tolerability; pharmacokinetics (PK), including food effects; and bioavailability of mobocertinib in healthy volunteers. In part 1, fasted volunteers were randomized to placebo or mobocertinib in single-ascending-dose cohorts (20-160 mg). In part 2, mobocertinib (120/160 mg) was administered on day 1 of periods 1 and 2 under fasted or low-fat meal conditions (2-period, 2-sequence crossover design). In part 3, fasted volunteers received mobocertinib 160 mg in 1 of 2 capsule products on day 1 of periods 1 and 2 with 7-day washout. Safety and PK parameters were assessed. Sixty-nine volunteers were enrolled (mean age, 29 years; 75% male). The most common adverse events (AEs; ≥10% of volunteers) were gastrointestinal AEs (25%-50%) and headache (8%-31%). No serious AEs were reported. A low-fat meal did not affect the PK of mobocertinib or its active metabolites. The geometric mean terminal disposition phase half-life (20 hours) supported once-daily dosing. The 2 capsule products were bioequivalent. These data guided dosing and supported administration of mobocertinib without regard to low-fat meal intake in ongoing and planned clinical studies.

• Authors: Steven Zhang, Shu Jin, Celina Griffin, Zhongling Feng, Jianchang Lin, Mike Baratta, Rachael Brake, Karthik Venkatakrishnan, Neeraj Gupta
• Journal: Clinical pharmacology in drug development (Clin Pharmacol Drug Dev) Vol. 10 Issue 9 Pg. 1028-1043 (09 2021) ISSN: 2160-7648 [Electronic] United States
• PMID: 34118178 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.

Chemical References

• Aniline Compounds
• Indoles
• Protein Kinase Inhibitors
• Pyrimidines
• mobocertinib

Topics

• Administration, Oral
• Adolescent
• Adult
• Aniline Compounds (administration & dosage, adverse effects, pharmacokinetics)
• Biological Availability
• Cohort Studies
• Cross-Over Studies
• Dose-Response Relationship, Drug
• Double-Blind Method
• Female
• Food-Drug Interactions
• Half-Life
• Humans
• Indoles (administration & dosage, adverse effects, pharmacokinetics)
• Male
• Middle Aged
• Protein Kinase Inhibitors (administration & dosage, adverse effects, pharmacokinetics)
• Pyrimidines (administration & dosage, adverse effects, pharmacokinetics)
• Therapeutic Equivalency
• Young Adult