Abstract 3035: Phase I study to assess the effect of adavosertib (AZD1775) on the pharmacokinetics of substrates of CYP1A2, CYP2C19 and CYP3A4 in patients with advanced solid tumors
Authors: Någård Mats , Ah-See Mei-Lin , So Karen , Strauss James , Wise-Draper Trisha , Safran Howard , Wang Ding , Nadeau Laura , Edenfield William , Lewis Lionel D. , Ottesen Lone , Li Yan , Mugundu Ganesh 
Published: September 2020

Abstract
Background: Adavosertib (AD), a selective WEE1 inhibitor, may alter exposure to compounds metabolized by cytochromes P450 (CYP); this two-period open-label study (NCT03333824) assessed the effect of AD on pharmacokinetics (PK) of probe substrates for CYP1A2 (caffeine; C), CYP2C19 (omeprazole; O) and CYP3A4 (midazolam; M).
Methods: In period 1, patients (pts) with locally advanced or metastatic solid tumors received a cocktail (CKT) of C 200 mg, O 20 mg, M 2 mg (single dose); in period 2, after a 7–14-day washout, pts received AD 225 mg bid on days 1–3 (5 doses), and with CKT on day 3. After CKT and AD administration, 24-hour PK sampling took place for C, O, M and their respective metabolites paraxanthine (P), 5-hydroxyomeprazole (5-HO), and 1′-hydroxymidazolam (1′-HM). Safety was assessed throughout.
Results: Of 33 pts (median age, 60.0 years, range 41–83; F:M, 18:15) receiving CKT, 30 pts were given AD. AD co-administration increased C, O and M exposure by 49%, 80% and 55% (AUC), respectively; AUC0–t increased by 61%, 98% and 55%; Cmax increased by 4%, 46% and 39% (Table 1). AD addition increased 5-HO and 1′-HM exposure by 43% and 54% (AUC), respectively, and by 49% and 58% (AUC0–t) respectively; P exposure was unchanged. AD co-administration decreased Cmax for P and 5-HO by 19% and 7%, respectively, whereas Cmax increased by 33% for 1′-HM. AD addition decreased CL/F and Vz/F for all substrates and increased t1/2 and tmax for most substrates and metabolites; tmax for M and 1′-HM were unchanged. A trend of decreasing metabolite/substrate ratios for AUC, AUC0–t and Cmax was seen with AD co-administration. After receiving AD, 24 (80%) pts reported adverse events (AEs), most commonly diarrhea (16 [53%]), vomiting (9 [30%]) and nausea (8 [27%]). Nineteen (63%) pts had treatment-related AEs (6 [20%] pts with grade ≥3).
Table 1Point estimates of the geometric least-square mean ratios S+AD/S (90% CI), %Median (range) tmax, hMean (SD) t½, hMean (SD) CL/F, L/hMean (SD) Vz/F, LMean MRAUCAUC0–tCmaxAUCAUC0–tCmax−AD+AD−AD+AD−AD+AD−AD+AD−AD+AD−AD+AD−AD+ADCaffeine*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)NAOmeprazole180.2 (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)NAMidazolam155.3 (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)NAParaxanthine†NCNC81.2 (74.6, 88.5)8.0 (4.0–11.8)9.9 (6.0–24.9)7.0 (2.7)12.2 (5.4)NA0.65NC0.540.320.230.165-HO143.0 (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 (4.7NA0.500.460.730.500.530.301′-HM153.5 (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)NA0.410.450.430.440.470.43Patient numbers for cocktail without AD (period 1) were: caffeine (AUC: 22; AUC0–t, Cmax, tmax and t½: 25), omeprazole (AUC and t½: 21; AUC0–t, Cmax and tmax: 27), midazolam (AUC and t½: 22; AUC0–t, Cmax and tmax: 23), paraxanthine (AUC: 10; t½: 14; AUC0–t, Cmax and tmax: 19), 5-HO (AUC: 22; t½: 24; AUC0–t, Cmax and tmax: 28) and 1''-HM (AUC: 20; t½: 22; AUC0–t, Cmax and tmax: 24). Patient numbers for cocktail with AD (period 2) were: caffeine (AUC: 8; AUC0–t and t½: 18; Cmax and tmax: 19), omeprazole (AUC and t½: 15; AUC0–t: 18; Cmax and tmax: 20), midazolam (AUC and t½: 18; AUC0–t, Cmax and tmax: 19), paraxanthine (AUC: 1; t½: 5; AUC0–t: 15; Cmax and tmax: 16), 5-HO (AUC: 13; t½: 17; AUC0–t: 18; Cmax and tmax: 20) and 1''-HM (AUC: 17; t½: 18; AUC0–t, Cmax and tmax: 19). *Caffeine AUC was only reliably characterized in eight patients receiving cocktail with AD in period 2. Caffeine AUC increased in all patients with paired data for both periods for seven patients; results were considered representative of the data; †Paraxanthine AUC was only reliably characterized in 10 patients in period 1 (only cocktail) and one patient in period 2 (cocktail with AD); thus, the treatment comparison for AUC was not considered scientifically meaningful. 1′-HM, 1′-hydroxymidazolam; 5-HO, 5-hydroxyomeprazole; AD, adavosertib; AUC, area under the plasma concentration–time curve from time zero to infinity; AUC0–t, area under the plasma concentration–time curve from time zero to time of last quantifiable concentration; CI, confidence interval; CL/F, apparent clearance; Cmax, maximum plasma drug concentration; MR, metabolic ratio in relation to parent compound; NA, not available; NC, not calculable; S+AD/S, substrate (or compound) + AD compared with substrate or compound alone; SD, standard deviation; tmax, time to reach maximum plasma concentration; t½, terminal half-life; Vz/F, apparent volume of distribution
Conclusions: AD (225 mg bid) is a weak inhibitor of CYP1A2, CYP2C19 and CYP3A4. No new AD-related safety concerns were identified.
Citation Format: Mats Någård, Mei-Lin Ah-See, Karen So, James Strauss, Trisha Wise-Draper, Howard Safran, Ding Wang, Laura Nadeau, William Edenfield, Lionel D. Lewis, Lone Ottesen, Yan Li, Ganesh Mugundu. Phase I study to assess the effect of adavosertib (AZD1775) on the pharmacokinetics of substrates of CYP1A2, CYP2C19 and CYP3A4 in patients with advanced solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3035.