Phase I Study to Assess the Effect of Adavosertib (AZD1775) on the Pharmacokinetics of Substrates of CYP1A2, CYP2C19, and CYP3A in Patients with Advanced Solid Tumors

Overview

Journal Cancer Chemother Pharmacol

Specialty Oncology

Date 2023 Jul 2

PMID 37394627

Authors

Mats Nagard

Mei-Lin Ah-See

James Strauss

Trisha Wise-Draper

Howard P Safran

Laura Nadeau

William J Edenfield

Lionel D Lewis

Lone H Ottesen

Yan Li

Ganesh M Mugundu

Affiliations

Soon will be listed here.

Abstract

Purpose: Adavosertib may alter exposure to substrates of the cytochrome P450 (CYP) family of enzymes. This study assessed its effect on the pharmacokinetics of a cocktail of probe substrates for CYP3A (midazolam), CYP2C19 (omeprazole), and CYP1A2 (caffeine).

Methods: Period 1: patients with locally advanced or metastatic solid tumors received 'cocktail': caffeine 200 mg, omeprazole 20 mg, and midazolam 2 mg (single dose); period 2: after 7- to 14-day washout, patients received adavosertib 225 mg twice daily on days 1-3 (five doses), with cocktail on day 3. After cocktail alone or in combination with adavosertib administration, 24-h pharmacokinetic sampling occurred for probe substrates and their respective metabolites paraxanthine, 5-hydroxyomeprazole (5-HO), and 1'-hydroxymidazolam (1'-HM). Safety was assessed throughout.

Results: Of 33 patients (median age 60.0 years, range 41-83) receiving cocktail, 30 received adavosertib. Adavosertib co-administration increased caffeine, omeprazole, and midazolam exposure by 49%, 80%, and 55% (AUC), respectively; AUC increased by 61%, 98%, and 55%. Maximum plasma drug concentration (C) increased by 4%, 46%, and 39%. Adavosertib co-administration increased 5-HO and 1'-HM exposure by 43% and 54% (AUC) and 49% and 58% (AUC0-t), respectively; paraxanthine exposure was unchanged. Adavosertib co-administration decreased C for paraxanthine and 5-HO by 19% and 7%; C increased by 33% for 1'-HM. After receiving adavosertib, 19 (63%) patients had treatment-related adverse events (six [20%] grade ≥ 3).

Conclusion: Adavosertib (225 mg bid) is a weak inhibitor of CYP1A2, CYP2C19, and CYP3A.

Clinicaltrials: GOV: NCT03333824.

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