Population pharmacokinetics of phenobarbital in Caucasian patients with epilepsy

• Published in: European journal of pharmaceutical sciences Vol. 153; p. 105484
• Main Authors: Teixeira-da-Silva, Paulo, Santos-Buelga, Dolores, Otero, María José, García, María José
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01-10-2020
• Subjects: Epilepsy; NONMEM; Phenobarbital; Population pharmacokinetic; Therapeutic drug monitoring; Therapeutic drug monitoring; Phenobarbital; Epilepsy; Population pharmacokinetic; NONMEM
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/j.ejps.2020.105484

•The PopPK analysis was performed using a non-linear mixed-effect modelling approach.•The final model presents acceptable estimation errors in all parameters.•BSA and interactions with PHT and VPA should be incorporated into dosing decisions.•This PopPK, using Bayesian algorithms, could help establish an optimal dosage regimen.
The present study aimed to establish a population pharmacokinetic (PopPK) model of Phenobarbital (PB) in Caucasian patients with epilepsy included in a Therapeutic Drug Monitoring program. In total, 855 PB serum concentrations (steady-state trough concentrations) were retrospectively collected during routine clinical monitoring of 395 patients over 15 years of age with epilepsy. The PopPK analysis was performed with NONMEM using a non-linear mixed-effect modelling approach. The influence of demographic, anthropometric, treatment, and comedication variables on the apparent clearance (CL/F) of PB were analysed. Goodness of fit plots and the bootstrap method were performed to evaluate the final model. External validation was carried out using an independent group of patients (107 patients, 178 blood samples). A one-compartment model with first-order absorption and elimination successfully described the data. In the final model, CL/F included body surface area (BSA) and comedication with phenytoin (PHT) and valproic acid (VPA), resulting in the following equation:
CL/F[L/h]=(0.236+(0.115×(BSA−1.7)))×(0.822PHT)×(0.711VPA)
The model presents acceptable estimation errors in the parameters of fixed (<12%) and random effects (<13%), and of the shrinkage values (<21%). Internal and external validations demonstrated the good predictability of the final model. A PopPK model of PB in Caucasian patients over 15 years of age was successfully established, which can be used to estimate phenobarbital CL/F. BSA and drug–drug interactions with PHT and VPA should be incorporated into dosing decisions. This PopPK, using Bayesian algorithms, could help establish an optimal dosage regimen in routine patient care.
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