Significant predictors for topiramate pharmacokinetics: a systematic review of population pharmacokinetic studies

Abstract

Background: Topiramate (TPM) is a second-generation antiepileptic drug with a good pharmacokinetic profile; nonetheless, several factors such as age, renal function and concomitant medications have been reported to affect TPM clearance and dosage adjustments are necessary. Several population pharmacokinetic studies of TPM were developed and the results were partially inconsistent, with different predictors for TPM pharmacokinetic parameters and different structural models. Thus, we aimed to systematically summarise clinically significant covariates influencing TPM pharmacokinetics and clinical responses. Methods: PubMed, CINAHL Complete, Science Direct and SCOPUS databases were systematically searched from the date of their inception to May 2021. Studies conducted in humans employing a nonlinear mixed-effects approach were included in this review. Information from retrieved articles were independently extracted using the prespecified data abstraction form. Results: Ten studies were included and most of them characterised TPM pharmacokinetics with a linear one-compartment model. The estimated TPM clearance without covariate effects ranged from 1.15 to 2.25 L/h. Significant predictors for TPM clearance included concomitant medications, weight, age, creatinine clearance and TPM daily dose. Moreover, two studies reported the effect of TPM exposure on cognitive function, with limitations on the generalisability. Conclusions: Significant predictors for TPM clearance that are essential for individualising dosage regimens were concomitant medications, weight, age, creatinine clearance and TPM daily dose. High TPM levels had negative impacts on verbal fluency, working memory, attention and psychomotor speed; however, future studies with broader population characteristics are needed to increase generalisability.

Topiramate dosage optimization for effective antiseizure management via population pharmacokinetic modeling

“…The topiramate V d /F was increased with body weight, where allometric scaling was applied with the exponent of 1. The estimated V d /F was approximately 30% decreased than that of the previous model, but it was a reasonable value compared to the reported V d /F of topiramate 11,12 . The final parameter estimates for CL/F and V d /F were 2.1 ± 0.8 L/h and 82.4 ± 13.3 L for the total samples.…”

“…The estimated V d /F was approximately 30% decreased than that of the previous model, but it was a reasonable value compared to the reported V d /F of topiramate. 11,12 The final parameter estimates for CL/F and V d /F were 2.1 AE 0.8 L/h and 82.4 AE 13.3 L for the total samples. The estimated level of topiramate showed a consistent pattern with the spot serum level (Table 1).…”

Population Pharmacokinetics of Topiramate in Patients with Epilepsy Using Nonparametric Modeling

“…The variability of TPM ke and V in the final model (the coefficient of variation was 104% and 54%, respectively) were considerably high but within the range of previously reported interindividual variability estimated directly within the range (23.6%-175.0% for V and 13.9%-65.0%) using the parametric approach. 33 The high variability reported in this study could be explained by the poor documentation that resulted in many missing dosing histories and sampling times. This resulted in a high residual variability with a gamma value of 5.5.…”

“…Findings of this study are consistent with those of a recent systematic review of 10 population PK studies using parametric approaches. 33 The authors found that concomitant medication, weight, age, sex, creatinine clearance, and daily TPM dose were essential predictors of TPM CL. However, they suggested further investigating the effect of TPM dose on CL because only 1 study has reported the effect.…”

“…This is consistent with the findings of previous studies. [12][13][14][15]33 TPM PK is affected by other concomitant antiseizure medications, including CBZ, PHT, PB, and VPA, because they affect the cytochrome P450 enzyme system, resulting in alterations in TPM metabolism. 7,8,34 However, the effects of VPA on TPM PK when coadministered with TPM are controversial.…”