Serum Concentrations of Pregabalin in Patients With Epilepsy: The Influence of Dose, Age, and Comedication

Abstract

Pregabalin (PGB) is a new antiepileptic drug (AED) approved for adjunctive therapy for partial seizures with and without generalized tonic-clonic seizures and for the treatment of peripheral neuropathic pain in adults. PGB does not bind to plasma proteins and is excreted predominantly unchanged by the kidneys. Previous studies indicated that PGB shows no relevant interactions with other AEDs. The aim of this study was to investigate the influence of PGB dose, patient age, and comedication on the serum concentration of PGB. In total, 198 samples of 167 (adult) inpatients who fulfilled the inclusion criteria (eg, trough concentration, body weight available) were investigated. A patient was considered twice only if the comedication had been changed. The PGB serum concentration (mg/L) in relation to PGB dose/body weight (mg/kg) per day (level-to-dose ratio, LDR, [(mg/L)/(mg/kg)=kg/L]) was calculated and compared for the most frequent drug combinations (n=97). Analysis of covariance (using age as covariate) carried out on the log-transformed data showed that comedication had a slight but significant (P = 0.02) effect on PGB serum concentrations. The median LDR of PGB was 0.29 for PGB + oxcarbazepine (n=16), 0.31 for PGB + carbamazepine (n=20), 0.35 for PGB + levetiracetam (n=11), 0.35 for PGB + lamotrigine (n=15), and 0.39 for PGB + valproic acid + lamotrigine (n=35). Regression analysis including all 198 samples indicated (in accordance with analysis of covariance) that PGB concentrations were lower in combination with enzyme-inducing AEDs (phenytoin, carbamazepine, oxcarbazepine) and were age-dependent (higher in older patients). The PGB dose-concentration relationship was nearly linear (r=0.68, P<0.0001). However, patients on the same PGB dosage per body weight had rather different PGB trough concentrations, which could be explained only in part by age and comedication. The increase of PGB serum concentrations in older patients is in accordance with expectations for drugs that are predominantly renally excreted. Unexpectedly and in contrast to other studies, our data indicate that comedication with enzyme-inducing antiepileptic drugs (eg, carbamazepine) can moderately decrease PGB serum concentrations (about 20% to 30%). Further studies should clarify the effect of age and interactions on PGB concentrations.