Purpose
Ridaforolimus is an inhibitor of the mammalian target of rapamycin protein, with potent activity in vitro and in vivo. Ridaforolimus is primarily cleared by metabolism via cytochrome P450 3A (CYP3A) and is a P-glycoprotein (P-gp) substrate. Since potential exists for ridaforolimus to be co-administered with agents that affect CYP3A and P-gp activity, this healthy volunteer study was conducted to assess the effect of rifampin or ketoconazole on ridaforolimus pharmacokinetics.
Methods
Part 1: single-dose ridaforolimus 40 mg followed by rifampin 600 mg daily for 21 days and single-dose ridaforolimus 40 mg on day 14. Part 2: single-dose ridaforolimus 5 mg followed by ketoconazole 400 mg daily for 14 days and single-dose ridaforolimus 2 mg on day 2.
Results
Part 1: the geometric mean ratios (GMRs) (90% confidence interval [CI]) for ridaforolimus area under the concentration–time curve to the last time point with a detectable blood concentration (AUC0–∞) and maximum blood concentration (C max) (rifampin + ridaforolimus/ridaforolimus) were 0.57 (0.41, 0.78) and 0.66 (0.49, 0.90), respectively. Both time to C max (T max) and apparent half-life (t 1/2) were similar. Part 2: the GMRs (90% CI) based on dose-normalized AUC0–∞ and C max (ketoconazole + ridaforolimus/ridaforolimus alone) were 8.51 (6.97, 10.39) and 5.35 (4.40, 6.52), respectively. Ridaforolimus apparent t 1/2 was ~1.5-fold increased for ketoconazole + ridaforolimus; however, T max values were similar.
Conclusions
Rifampin and ketoconazole both have a clinically meaningful effect on the pharmacokinetics of ridaforolimus.