Population pharmacokinetics of pregabalin in healthy subjects and patients with post‐herpetic neuralgia or diabetic peripheral neuropathy
Authors: Shoji Satoshi , Suzuki Misaki , Tomono Yoshiro , Bockbrader Howard N. , Matsui Shigeyuki 
Published: February 2011

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Pregabalin has been approved in many countries for partial‐onset seizures, generalized anxiety disorder and a wide variety of pain disorders.• Although pharmacokinetic studies have demonstrated that pregabalin apparent clearance is correlated with estimated creatinine clearance, quantitatively accurate estimation of this relationship is warranted for establishing clinical usage of this drug. WHAT THIS STUDY ADDS • A population pharmacokinetic model was developed from 14 pregabalin clinical trials using the first‐order conditional estimation method, where a one‐compartment model with first‐order absorption and elimination adequately described pregabalin pharmacokinetics.• Based on the developed model, pregabalin systemic exposure in patients with lower renal function (30 ≤ estimated creatinine clearance [CLcr] <60 ml min−1) is expected to be similar to exposure in patients with normal renal function (CLcr≥60) administered twice the dose.• This study indicated that the systemic exposure of pregabalin could be adjusted with reference to the estimated proportional relationship between pregabalin apparent clearance and CLcr regardless of the disease.AIM Pregabalin, a chemical analogue of the mammalian neurotransmitter γ‐aminobutyric acid, has been approved in many countries for partial‐onset seizures, generalized anxiety disorder and various other pain disorders, including neuropathic pain associated with post‐herpetic neuralgia and diabetic peripheral neuropathy and fibromyalgia. The aim of this study was to develop a population pharmacokinetic model and quantify the influence of covariates on the parameters.METHODS This pregabalin population pharmacokinetic analysis was conducted on data from 14 clinical trials involving healthy subjects, subjects with impaired renal function and patients with post‐herpetic neuralgia or diabetic peripheral neuropathy (n= 616). The data analysis was performed using nonlinear mixed effects modelling methodology as implemented by NONMEM.RESULTS A one‐compartment model with first‐order absorption and elimination adequately described pregabalin pharmacokinetics. The model indicated that pregabalin apparent clearance (CL/F) was proportional to estimated creatinine clearance (CLcr). The pregabalin systemic exposure in patients with lower renal function who received pregabalin 150 mg twice daily was almost equal to that of patients with normal renal function administered pregabalin 300 mg twice daily. The systemic exposure stratified by lower or normal renal function was similar between patients with post‐herpetic neuralgia and diabetic peripheral neuropathy.CONCLUSION The developed model identified CLcr and ideal body weight as clinically influential covariates on CL/F and volume of distribution, respectively. This study indicates that renal function accounts for variability in the apparent clearance of pregabalin which is consistent with what is known about the elimination of this drug.