A study of dose-proportionality in the pharmacokinetics of the oral direct renin inhibitor aliskiren in healthy subjects

Objective: To evaluate the dose-proportionality of the pharmacokinetics of aliskiren, the first in a new class of orally active direct renin inhibitors approved for the treatment of hypertension. Methods: This was an open-label, single-center, single-dose, randomized, 4-period crossover study. Following a 21-day screening period, 32 healthy male or female subjects (ages 18 - 45 years) were randomized to 1 of 4 aliskiren dosing sequence groups (8 subjects per group): 75, 150, 300 and 600 mg. Blood samples were obtained for determination of plasma aliskiren concentrations (HPLC/MS/MS) for 96 h post dose. Log-transformed pharmacokinetic parameters AUC and C-max were analyzed to determine dose-proportionality using the power model, parameter= A*(Dose)(beta), where A = intercept and P = dose-proportionality coefficient. The predefined dose-proportionality criteria over the dose range 75 - 600 mg were 90% confidence intervals (CI) for beta contained within the range 0.89 - 1.11. Results: AUC and C-max values increased with increasing doses of aliskiren. Both AUC and C-max were associated with high variability (coefficient of variation 55 - 64% for AUC and 59 - 117% for C-max). The estimated proportionality coefficients (P) for AUC(0-infinity), AUC(0-t) and C-max were 1.18 (90% CI 1.10, 1.25), 1.29 (90% CI 1.22, 1.36) and 1.42 (90% CI 1.31, 1.52), respectively. Dose-proportionality was, therefore, not demonstrated across the entire 8-fold dose range. For the clinical dose range of 150 - 300 mg, increases of 2.3- and 2.6-fold were observed for AUC and C-max, respectively. All doses of aliskiren were well tolerated. Conclusions: Exposure to aliskiren was greater than proportional over the dose range of 75 - 600 mg. Over the therapeutic dose range of 150 - 300 mg approved for the treatment of hypertension, AUC and C-max increased by 2.3- and 2.6-fold, respectively. The pharmacokinetics of aliskiren show relatively high intersubject variability.