inib were achieved at
approximately 1 hour after dosing and steady-state was reached within 3 days. Mean steady-statelarotrectinib [coefficient of variation (CV%)] for Cmax was 788 (81%) ng/mL and AUC0-24hr was4351 (97%) ng*h/mL.
Absorption
The mean absolute bioavailability of VITRAKVI capsules was 34% (range: 32% to 37%).In healthy subjects, the AUC of VITRAKVI oral solution was similar to that of the capsules andthe Cmax was 36% higher with the oral solution.
Effect of Food
The AUC of larotrectinib was similar and the Cmax was reduced by 35% after oral administrationof a single 100 mg capsule of VITRAKVI to healthy subjects taken with a high-fat meal(approximately 900 calories, 58 grams carbohydrate, 56 grams fat and 43 grams protein)compared to the Cmax and AUC in the fasted state.
Distribution
The mean (CV%) volume of distribution (Vss) of larotrectinib is 48 (38%) L followingintravenous administration of larotrectinib in healthy subjects.
Larotrectinib is 70% bound to human plasma proteins in vitro and binding is independent of drugconcentrations. The blood-to-plasma concentration ratio is 0.9.
Elimination
The mean (CV%) clearance (CL/F) of larotrectinib is 98 (44%) L/h and the half-life is 2.9 hoursfollowing oral administration of VITRAKVI in healthy subjects.
Metabolism
Larotrectinib is metabolized predominantly by CYP3A4. Following oral administration of asingle [14C] radiolabeled 100 mg dose of larotrectinib to healthy subjects, unchanged
larotrectinib constituted 19% and an O-linked glucuronide constituted 26% of the majorcirculating radioactive drug components in plasma.
Excretion
Following oral administration of a single [14C] radiolabeled 100 mg dose of larotrectinib tohealthy subjects, 58% (5% unchanged) of the administered radioactivity was recovered in fecesand 39% (20% unchanged) was recovered in urine.
Specific Populations
Age (range: 28 days to 82 years), sex, and body weight (range: 3.8 kg to 179 kg) had noclinically meaningful effect on the pharmacokinetics of larotrectinib.
Pediatric Patients In pediatric patients, the larotrectinib geometric mean (%CV) AUC0-24hr by age subgroup was:
3348 (66%) ng*h/mL in patients 1 month to < 2 years (n = 9), 4135 (36%) ng*h/mL in patients2 to < 12 years (n = 15), and 3108 (69%) ng*h/mL and in patients 12 to < 18 years (n = 9).
Patients with Renal Impairment
Following oral administration of a single 100 mg dose of VITRAKVI capsules in subjects withend-stage renal disease (e.g., subjects who required dialysis), the AUC0-INF of larotrectinibincreased 1.5-fold and Cmax increased 1.3-fold as compared to that in subjects with normal renalfunction (creatinine clearance ≥ 90 mL/min asestimated by Cockcroft-Gault).
Thepharmacokinetics of VITRAKVI in patients with moderate to severe renal impairment(creatinine clearance ≤ 60 mL/min) have not been studied.
Patients with Hepatic Impairment
Following oral administration of a single 100 mg dose of VITRAKVI capsules, the AUC0-INF oflarotrectinib increased 1.3-fold in subjects with mild hepatic impairment (Child-Pugh A), 2-foldin subjects with moderate hepatic impairment (Child-Pugh B) and 3.2-fold in subjects withsevere hepatic impairment (Child-Pugh C) as compared to that in subjects with normal hepaticfunction. The Cmax was similar in subjects with mild and moderate hepatic impairment and theCmax of larotrectinib increased 1.5-fold in subjects with severe hepatic impairment as compar |
