Population Pharmacokinetic Analysis Of Aripiprazole
Xuejun Chen1, Ekaterina Gibiansky2, Suresh Mallikaarjun1,
1Otsuka Maryland Research Institute, 2440 Research Blvd., Rockville, MD 20850
Aripiprazole, a quinolinone derivative, is being developed as a novel antipsychotic agent. It has a mode of action that differs from those of typical and atypical antipsychotic drugs. A population analysis was performed on data from several Phase II and Phase III studies using NONMEM, to describe the pharmacokinetics of aripiprazole in patients with schizophrenia, to identify predictors of exposure to the drug and to estimate the inter-individual and residual variability of aripiprazole pharmacokinetics. The covariates examined were: gender, age, race, weight (WT), body surface area, body mass index, lean body weight (LBW), smoking, alcohol consumption, concomitant medications, creatinine clearance, total protein, creatine kinase, total bilirubin, alkaline phosphatase, asparate aminotransferase, and alanine aminotransferase. The observed plasma aripiprazole concentrations were described by a linear one-compartment model with the first-order absorption, and log-normally distributed inter-individual variability. The mean pharmacokinetic parameters were: clearance CL/F =3.81 L/h (95% CI=3.61 –4.01), volume of distribution V/F =293 L (95% CI =273-313), absorption rate constant Ka =1.06 h-1 (95% CI =0.807–1.31), and half-life T1/2 =53.3 h (95% CI = 48.6–58.0). The relative standard error (RSE) was ≤ 12% for the structural pharmacokinetic parameters (CL/F, V/F, Ka), ≤ 28% for the parameters on covariates (CLLBW, VAGE, VWT), and was ≤ 19% for the variability parameters (w2CL, w2 V, s2P), except the inter-individual variability in Ka (w2KA, 77.6% RSE). The values for CL/F for patients from the population analysis were in agreement with those for normal healthy volunteers from other studies. The change in CL/F due to LBW (lean body weight) for the 10th to 90th LBW percentiles was <11%, whereas the change in V/F was <31% for the 10th to 90th percentiles of either WT (weight) or age. Overall, no dosage adjustments for covariates are indicated based on this population pharmacokinetic analysis.