Table 3.

Summary of sonidegib pharmacokinetic parameters after a single dose on day 1 of pharmacokinetic run-in and repeated doses on day 15 of cycle 1

Pharmacokinetic run-in
Dose, mgNCmax, ng/mL mean (SD; CV%)AUC0–168 h ng × h/mL Mean (SD; CV%)Tmax, ha Median (min–max)
100 once daily685.8 (52.3; 61)1,880 (1,150; 61)2 (1–24)
200 once daily6160 (115; 72)3,670 (2,130; 58)2 (2–48)
400 once daily5267 (239; 90)7,450 (8,530; 115)4 (4–4)
800 once dailyb25430 (381; 89)7,870 (6,950; 88)4 (1–27)
1,000 once daily11322 (258; 80)7,400 (6,340; 86)2 (1–4)
1,500 once daily9376 (199; 53)12,600 (7,110; 56)4 (2–24)
3,000 once daily10429 (237, 55)11,800 (11,200; 95)2 (1–8)
250 twice dailyb14150 (111; 74)3,220 (2,320; 72)2 (1–4)
400 twice daily8334 (300; 90)7,530 (7020; 93)4 (2–4)
750 twice daily8226 (180; 80)6,920 (7110; 103)3 (1–23)
Day 15, cycle 1
Dose, mgncCmax, ng/mL Mean (SD; CV%)AUC0–24 h, ng × h/mLc Mean (SD; CV%)Tmax, ha Median (min–max)
100 once daily3155 (63.4; 41)2,690 (1,340; 50)4 (2–6)
200 once daily5269 (163; 61)5,920 (3,890; 66)4 (0-6)
400 once daily4558 (286; 51)10,200 (5,880; 58)13 (1–24)
800 once dailyb20840 (457; 54)12,800 (6,350; 50)2 (1–6)
1,000 once daily81,230 (1400; 113)15,200 (18,500; 122)4 (2–6)
1,500 once daily81,320 (657; 50)27,400 (14,300; 52)5 (2–24)
3,000 once daily61,670 (1050, 62)24,600 (8770; 36)3 (0–21)
250 twice dailyb13807 (353; 44)14,500 (4780; 33)2 (0–6)
400 twice daily7864 (333; 39)13,800 (6390; 46)2 (0–8)
750 twice daily81570 (1020; 65)26,900 (17,300; 64)4 (0–8)

Abbreviations: AUC0–168 h, area under the plasma concentration–time curve from time zero to 168 hours; AUC0–24 h, area under the plasma concentration–time curve from time zero to 24 hours; Cmax, maximum plasma drug concentration; Tmax, time to reach Cmax. AUC0–24 h for twice-daily doses are calculated as 2*AUC0–12 h.

  • a Values are median (range) and arithmetic mean (SD; CV%) for all other parameters.

  • b Bold values represent maximum tolerated dose for once-daily and twice-daily doses.

  • c AUC analysis on cycle 1, day 15 included 3, 3, 4, 16, 6, 3, 4, 12, 5, and 6 patients from the 100, 200, 400, 800, 1,000, 1,500, and 3,000 mg once-daily and 250, 400, and 750 mg twice-daily dose cohorts, respectively.