Pharmacokinetic assessments
Pharmacokinetic parameter estimates for substrates of CYP1A2 (caffeine), CYP2C19 (omeprazole), and CYP3A (midazolam) and their metabolites (paraxanthine, 5-HO, and 1ʹ-HM, respectively) in the presence and absence of adavosertib are shown in Table Pharmacokinetic parameter estimates for substrates of CYP1A2 (caffeine), CYP2C19 (omeprazole), and CYP3A (midazolam) and their metabolites (paraxanthine, 5-HO, and 1ʹ-HM, respectively) in the presence and absence of adavosertib 225 mg bid (pharmacokinetic analysis set)149.1(131.3–169.3)160.8(143.3–180.5)103.8(92.2–116.9)0.5(0.3–3.0)0.7(0.3–3.0)6.4(3.8)13.5(6.8)5.7(2.5)3.8(1.9)39.3(15.0)37.9(12.1)180.2(145.7–222.9)198.1(160.3–244.7)145.5(114.0–185.7)3.0(0.7–6.0)3.9(0.5–8.0)2.0(1.0)2.5(1.3)13.3(10.5)7.6(7.3)28.3(16.6)19.8(10.1)155.3(138.6–173.9)155.2(140.5–171.5)138.5(118.9–161.3)0.5(0.2–1.0)0.5(0.2–1.0)5.5(2.6)6.6(3.0)59.0(34.3)39.7(14.5)409.9(211.5)364.1(182.7)81.2(74.6–88.5)8.0(4.0–11.8)9.9(6.0–24.9)7.0(2.7)12.2(5.4)143.0(123.8–165.0)148.8(129.6–170.8)92.9(78.6–109.8)3.0(0.7–6.0)4.0(1.8–7.8)2.7(1.7)4.5(4.7)153.5(131.0–179.8)158.2(139.1–180.0)133.4(106.5–167.1)0.5(0.3–2.1)0.5(0.2–1.0)7.2(6.1)7.6(7.1)Patient numbers for cocktail without AD (period 1) were: caffeine (AUC: 22; AUCCo-administration of adavosertib increased caffeine total exposure by 49% (AUCParaxanthine AUCCo-administration of adavosertib increased omeprazole total exposure by 80% (AUCCo-administration of adavosertib increased midazolam total exposure by 55% (AUCThe individual and geometric mean AUCIndividual and geometric mean AUCThe geometric mean plasma concentrations of caffeine, omeprazole, and midazolam versus time, with and without adavosertib, are shown in Fig. Geometric mean (± SD) plasma concentration of The PK parameters of adavosertib following co-administration of cocktail are shown in Table Summary of pharmacokinetic parameters of adavosertib following co-administration of cocktail (pharmacokinetic analysis set)12,720(3796)1490(398)602(219)1065(319)ND(ND)38.0(12.11)85.7(24.3)11,970(6950, 18,200)1415(853, 2120)563(344, 1050)991(580, 1540)3.0(0.75, 6.00)36.9(24.3, 63.5)79.8(54.3, 135.8)Treatment: adavosertib + cocktail: caffeine (200 mg tablet), omeprazole (20 mg capsule), and midazolam (1 mL of 2 mg/mL syrup formulation) on day 3. CV calculated as 100 x √[exp(s