Factors Influencing Topiramate Pharmacokinetics in Adult Patients with Epilepsy: A Population Pharmacokinetic Analysis

Abstract

Background: Topiramate is widely used as an antiepileptic drug (AED) in the treatment of epilepsy. The pharmacokinetics (PK) of topiramate are known to be influenced by various factors such as age, renal function, and concomitant medication. However, these factors have not been thoroughly quantified and remain controversial. The objective of the present study was to identify the factors influencing topiramate PK in a large population of adult patients with epilepsy using population PK analysis. Materials and Methods: Clinical data and blood samples were collected from 553 adult patients with epilepsy treated using topiramate with or without concomitant AEDs. Plasma concentrations of topiramate in a steady state were determined by liquid chromatography-tandem mass spectrometry. Nonlinear mixed effects modeling software (NONMEM, version 7.2) was used to fit the plasma concentration to a one-compartment PK model. Demographic and clinical variables tested as potential covariates were age, sex, body weight, height, serum creatinine, creatinine clearance (CLcr), total bilirubin, prothrombin time, albumin, aspartate transaminase (AST), alanine transaminase (ALT), daily dose (DOSE), and concomitant medications (phenytoin [PHT], clobazam, carbamazepine [CBZ], valproic acid, lamotrigine, levetiracetam, oxcarbazepine [OXC], pregabalin, clonazepam, and phenobarbital [PB]). In addition, the efficacy and adverse events of topiramate were analyzed according to the level of daily dose per body weight and plasma concentration. Results: The final PK model was CL/F (L/h) = (1.17 + 1.36×PHT + 1.02×CBZ + 0.621×OXC + 0.488×PB) × (CLcr/90)0.289 × (DOSE/100)0.0894 (1 in patients co−medicated with each drug, 0 in otherwise) and V/F (L) = 108 × (WT/62). For a typical patient with CLcr of 90 mL/min and DOSE of 100 mg, the CL/F was expected to be 1.17 L/h. Co−medication with PHT, CBZ, OXC, and PB increased the CL/F to 2.53 (1.17+1.36) L/h, 2.19 (1.17 + 1.02) L/h, 1.791 (1.17+0.621) L/h, and 1.658 (1.17+0.488) L/h, respectively, which was 116%, 87%, 53%, and 42% higher, respectively, than in patients without co-medication. Two hundred sixty-four patients (48%) were seizure free, 236 (43%) had at least 50% seizure reduction, and 52 (9%) had less than 50% seizure reduction. One hundred thirty-eight patients (25%) reported adverse events, including memory impairment, dizziness, anomia, weight loss, paresthesia, and appetite loss. The efficacy and adverse events of topiramate did not show any clinically relevant relationship with the daily dose per body weight or plasma concentration. Conclusion: The apparent clearance of topiramate increased with co-medication of PHT, CBZ, OXC, and PB. This population PK model can be applied for optimizing topiramate dosage regimens in actual clinical practice, especially for the patients on polytherapy with PHT, CBZ, OXC, and PB. Individualization of therapeutic dose and plasma concentration is needed for epilepsy patients treated with topiramate.