Population‐Based Investigation of Valproic Acid Relative Clearance Using Nonlinear Mixed Effects Modeling: Influence of Drug‐Drug Interaction and Patient Characteristics

Abstract

Nonlinear mixed effects modeling (NONMEM) was used to estimate the effects of drug-drug interaction on valproic acid relative clearance values using 792 serum levels gathered from 400 pediatric and adult patients with epilepsy (age range, 0.3-54.8 years) during their clinical routine care. Patients received valproic acid as monopharmacy or in combination with either the antiepileptic drugs, phenobarbital, or carbamazepine. The final model describing valproic acid relative clearance was CL (mL/hr/kg) = 15.6.TBW (kg)-0.252.DOSE (mg/kg/day)0.183.0.898GEN.COPB.COCBZ, where COPB equals 1.10 if the patient is treated with phenobarbital, a value of unity otherwise, and COCBZ equals 0.769.DOSE (mg/kg/day)0.179 if the patient is treated with carbamazepine, a value of unity otherwise. Valproic acid relative clearance was highest in the very young and decreased in a weight-related fashion in children, with minimal changes observed in adults. This pattern was consistent whether valproic acid was administered alone or coadministered with phenobarbital or carbamazepine. When valproic acid was coadministered with phenobarbital or carbamazepine, valproic acid relative clearance increased as compared with that in monopharmacy. Its magnitude in the presence of carbamazepine increased in a valproic acid daily dose-related fashion. Concomitant administration of phenobarbital and valproic acid resulted in a 10% increase on valproic acid relative clearance. The clearance in female patients was approximately 10% less than that in male patients.

Population pharmacokinetic of antiepileptic drugs in different populations

“…There is a very close correlation between total body weight and age of the patient, especially in the children population, but also in heterogeneous populations [6,16]. However, our research clearly showed that the age within the subpopulations of children and adults was not important characteristic that influenced the clearance of valproate which is in accordance with reports by other authors [15,[18][19][20]23]. Moreover, some researchers have noted that body weight is a better indicator of metabolic capacity and general physiological condition of the body then age [21,24].…”

“…In agreement with our findings, results of numerous studies have shown that the relative clearance of valproate is increased in concomitant therapy with carbamazepine [15][16][17][18][19]. In children the increase in VPA clearance ranged from 35.9% to 61% [16,18].…”

“…The linear relationship of TBW and age with CL of valproate was shown in the study. The facts that age and total body weight are the important factors that influence a change of VPA CL in children and also in heterogeneous patient populations were in accordance with reports of other authors [15][16][17].…”

“…Total body weight is an important cause of interindividual variability of pharmacokinetics of valproate, particularly in the children populations. The significant influence of this factor has been confirmed in studies by other authors that reports point to the possibility of both linear and non-linear increase in VPA clearance with increasing body weight of patients in different populations [15,16,[18][19][20][21]. Also, numerous studies have showed the existence of a linear increase of VPA clearance with body weight in mixed populations of children and adults [6,22].…”

Levetiracetam, a New Antiepileptic Agent: Lack of In Vitro and In Vivo Pharmacokinetic Interaction with Valproic Acid

“…Conversely, because of its extensive transformation, the disposition of VPA can be affected by coadministered drugs; particularly the AEDs that induce UGTs may accelerate the metabolic elimination of VPA. PB, PHT, and CBZ can double the clearance of VPA (2,9,10). Conversely, felbamate (FBM) inhibits the ␤-oxidation pathway of VPA, causing a significant increase in its plasma concentrations (11).…”