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

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_0-12), respectively; AUC_0-t increased by 61%, 98%, and 55%. Maximum plasma drug concentration (C_max) increased by 4%, 46%, and 39%. Adavosertib co-administration increased 5-HO and 1'-HM exposure by 43% and 54% (AUC_0-12) and 49% and 58% (AUC0-t), respectively; paraxanthine exposure was unchanged. Adavosertib co-administration decreased C_max for paraxanthine and 5-HO by 19% and 7%; C_max 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.

Keywords: AZD1775; Adavosertib; CYP1A2; CYP2C19; CYP3A; Pharmacokinetics.

Fig. 1

a Study design and b patient disposition flow chart. This manuscript focuses on pharmacokinetic data from part A of NCT03333824; part B of NCT03333824 is an investigation of the effect of adavosertib on the QT interval, results of which are reported separately. *Informed consent received; ^†A number of patients enrolled more than once; there were 49 unique enrollments; ^‡Study treatment refers to treatment with either cocktail or adavosertib; ^§One each as a result of death (pancreatic cancer), study termination by the sponsor, and withdrawal by the patient. bid twice daily

Fig. 2

Individual and geometric mean AUC_0–t and C_max of a caffeine, b omeprazole, and c midazolam alone versus each cocktail drug plus adavosertib, and d individual and geometric mean of adavosertib plus cocktail (part A) versus adavosertib alone (part B). *Individual patient and geometric mean AUC_0–t and C_max in the presence and absence of adavosertib 225 mg bid for caffeine (n = 25), omeprazole (n = 27), and midazolam (n = 23); ^†Adavosertib + cocktail: caffeine (200 mg tablet), omeprazole (20 mg capsule), and midazolam (1 mL of 2 mg/mL syrup formulation) on day 3 and adavosertib 225 mg (3 × 75 mg capsules) on day 3 (part A). Adavosertib: adavosertib 225 mg (3 × 75 mg capsules) bid on days 1 and 2 and once on day 3 (part B/pharmacodynamic study). AUC_0–12 area under the plasma concentration–time curve from time zero to 12 h, AUC_0–t area under the plasma concentration–time curve from time zero to time of the last quantifiable concentration, C_max maximum plasma drug concentration

Fig. 3

Geometric mean (± SD) plasma concentration of a caffeine, b omeprazole, and c midazolam ± adavosertib versus time. Exponential of (mean of log concentration ± SD of log concentration). Probe cocktail: caffeine (200 mg tablet), omeprazole (20 mg capsule), and midazolam (1 mL of 2 mg/mL syrup formulation) on day − 8. Adavosertib + cocktail: cocktail and adavosertib 225 mg (3 × 75 mg capsules) on day 3. SD standard deviation