Population exposure response analysis of pregabalin in patients with generalized anxiety disorder (GAD)

• Published in: Clinical pharmacology and therapeutics 2004-02, Vol.75 (2), p.P90-P90
• Main Authors: Lockwood, P. A., Kowalski, K. G., Corrigan, B. W.
• Format: Article
• Language: English
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1016/j.clpt.2003.11.345

Purpose To describe the exposure‐response relationship of pregabalin in patients with generalized anxiety disorder (GAD). Methods A subject‐specific random effects model was derived using patient Hamilton Anxiety (HAMA) rating scale data from six placebo controlled GAD studies and maximum likelihood estimation methods, to characterize the individual pregabalin exposure‐response relationship Treatment was up to 8 weeks ranging from 150 to 600mg/day. Covariates were screened using Wald's approximation method. Results Scores were modeled as a continuous response using the logit transformation with additive baseline, placebo and drug effects. Drug effect was described by an Emax model with exposure proportional to average concentration and creatinine clearance, and the placebo effect by a study‐specific monoexponetial function of time with onset characterized by a constant k. Inter‐subject random effects for Emax, k, and the placebo effect (PLA) were multiplicative and an additive residual error model described intra‐subject variability in the logit response. Covariances were estimated for PLA and k. The ED50 estimate was 100mg. Conclusions A decrease in HAMA score was correlated with drug exposure and the time course of the response was attributable to the placebo effect Treating the logit transformed HAMA as a continuous response was a unique application of the logit transform, ensuring simulated outcomes were within the range of the HAMA scale (0–56). Clinical Pharmacology & Therapeutics (2004) 75, P90–P90; doi: 10.1016/j.clpt.2003.11.345