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.

Document Type

Article

Publication Date

9-2023

Publication Title

Cancer chemotherapy and pharmacology

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

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

CLINICALTRIALS: GOV: NCT03333824.

Volume

92

Issue

3

First Page

193

Last Page

203

DOI

10.1007/s00280-023-04554-3

ISSN

1432-0843

PubMed ID

37394627

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