Factors influencing topiramate clearance in adult patients with epilepsy: A population pharmacokinetic analysis

PURPOSE To identify the factors influencing topiramate pharmacokinetics (PK) in a large population of adult patients with epilepsy using population PK analysis. METHODS Clinical data and blood samples were collected from 550 adult patients with epilepsy treated using topiramate. 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]). RESULTS The final PK model was CL/F (L/h)=(1.16+1.36 × PHT+1.01 × CBZ+0.643 × OXC+0.476 × PB)×(CLcr/90)(0.310)×(DOSE/100)(0.0929) (1 in patients co-medicated with each drug, 0 in otherwise) and V/F (L)=109 × (WT/62). For a typical patient with CLcr of 90 mL/min and DOSE of 100mg, co-medication with PHT, CBZ, OXC, and PB increased the CL/F to 2.52 (1.16+1.36)L/h, 2.17 (1.16+1.01)L/h, 1.803 (1.16+0.643)L/h, and 1.636 (1.16+0.476)L/h, respectively, which was 117, 87, 55, and 41% higher, respectively, than in patients without co-medication. 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.