The effect of hepatic insufficiency on the pharmacokinetics of ridaforolimus.

Abstract

e13001 Background: Ridaforolimus (RIDA) (AP23573; MK-8669), a unique rapamycin analog and a potent inhibitor of mTOR signaling, is being developed for the treatment of solid tumors. The study aims were to assess the safety and whole blood pharmacokinetics following single 10 mg doses of RIDA in patients with moderate hepatic insufficiency (Child-Pugh [CP] score of 7-9). Methods: This was an open-label study comparing the pharmacokinetics after administration of a 10 mg single dose of RIDA to patients with moderate hepatic insufficiency (assessed by the CP scale) with healthy matched controls. Nineteen (19) males and females of non-childbearing potential were enrolled: ten (10) patients with moderate hepatic insufficiency (CP score of 7-9) and 9 healthy matched control subjects (race, age [±5 years], gender, BMI [±3.3 units]). Results: A summary of the blood pharmacokinetic parameters of RIDA administered to patients with moderate hepatic insufficiency and to healthy matched control subjects is presented below. RIDA was generally well tolerated and no patients were discontinued due to drug-related AEs. Conclusions: RIDA exposure in patients with moderate hepatic insufficiency was approximately 2-fold higher than in healthy matched controls. Since RIDA is being studied in phase III at the maximally tolerated dose of 40 mg, this finding is likely to be clinically meaningful and caution should be exercised when dosing patients with moderate hepatic insufficiency. Moderate hepatic insufficiency Healthy matched control Moderate hepatic insufficiency/ healthy matched control Pharmacokinetic parameter N# GM 95% CI N GM 95% CI GMR 90% CI AUC0-∞ † (ng/ml·hr) 10 1168 (669, 2,039) 9 589 (315, 1,100) 1.98 (1.06, 3.71) Cmax † (ng/ml) 10 53.9 (25.5, 114.2) 9 41.4 (17.8, 96.0) 1.30 (0.56, 3.03) Tmax ‡ (hr) 10 6.0 (3.0, 8.0) 9 4.0 (4.0, 8.0) Apparent t1/2 § (hr) 10 111.4 28.0 9 75.0 41.0 Abbreviations: GM, geometric mean; GMR, geometric mean ratio; CI, confidence interval. † Geometric mean computed from least squares estimate from an ANCOVA performed on the natural-log transformed values. ‡ Median [Min, Max] reported for Tmax. § Harmonic mean, jack-knife standard deviation (SD) reported for t1/2. # AN 0003 who discontinued had sufficient PK to be included in the primary analysis.