A Feasibility Study of the Multiple-peak Approach for Pharmacokinetic Screening: Population-based Investigation of Valproic Acid Relative Clearance Using Routine Clinical Pharmacokinetic Data

The multiple-peak approach was used to evaluate the effect of age, body mass, dose and gender on the population estimates of valproic acid relative clearance. Routine clinical pharmacokinetic data (n = 474) was collected from 250 patients receiving valproic acid and no other drug. The data was analysed according to a simple steady-state pharmacokinetic model using NONMEM, a computer program designed for population pharmacokinetic analysis allowing pooling of data. The final regression model for relative clearance (CL, mL kg-1 h-1) was: CL = 18.9 x body weight(-0.276) x daily dose(0.142) x gender where gender = 1 for males, 0.877 for females. NONMEM estimates suggested that the rate of valproic acid clearance decreased nonlinearly with increasing body weight in the maturation process, and increased nonlinearly with increasing valproic acid dose (mg kg-1 day-1). The clearance in females was about 11% less than in males. These estimates were similar to those detected from previous studies.