Najia Rahim1, Ian Haworth
1Dow University of Health Sciences, 2 University of Southern California
Introduction: Lamotrigine is an antiepileptic drug that is mainly eliminated via metabolic degradation by uridine diphosphate glucuronosyltransferase (UGT) enzymes. This drug is approved for use in combination with valproic acid in patients with refractory epilepsy (1). However, valproic acid is an inhibitor of UGTs and can reduce lamotrigine clearance (2). Conversely, co-administration of lamotrigine and rifampicin decreases lamotrigine exposure (3). Also, certain patient populations, including older people, pregnant women, and those with hepatic impairment, may be exposed to higher levels of lamotrigine than healthy adults due to effects on clearance, which could lead to adverse effects or harm to organs (4, 5). To avoid these types of circumstances, it is widely encouraged to rationalize lamotrigine use in cases with hepatic impairment or with possible drug-drug interactions (DDIs). In this study, a physiologically based pharmacokinetic (PBPK) model was used to investigate lamotrigine exposure in such clinical situations using a detailed mechanistic approach. Objectives: The aims of the study are to build a PBPK model for lamotrigine in patients with hepatic impairment, and to develop a PBPK model for valproic acid and use DDI models to predict the impact of valproic acid or rifampicin on the pharmacokinetics of lamotrigine. Methods: The PBPK lamotrigine model was developed in GastroPlusTM. Physicochemical properties and pharmacokinetic data were extracted from literature and reported clinical trials, including for one intravenous dose and multiple oral doses in the range of 25-300 mg (6-12). The model incorporated three metabolizing enzymes, UGT1A3, UGT1A4, and UGT2B7. To include nonlinear kinetics due to saturation of UGTs in the liver and kidney, Michaelis-Menten parameters (Vmax and Km) were used in the model (13). Influx and efflux transporters were also incorporated to reproduce the observed concentration-time profiles. The PBPK valproic acid model was developed and validated using several clinical studies, including intravenous (800 mg) and oral (dose range: 250-1000 mg) administration (14-17). Hepatic impairment was simulated by adjusting disease-specific parameters, and co-administration of valproic acid with lamotrigine was simulated using the DDI module of GastroPlusTM. A similar approach was used for the rifampicin DDI with lamotrigine, using the standard rifampicin PBPK model in GastroPlusTM. Pharmacokinetic predictions in virtual populations were compared with clinical observations from selected trials via visual inspection and based on fold error (FE). Results: The PBPK lamotrigine model was validated based on ranges of FE for Cmax and AUC of 0.72-1.07 and 0.88-1.27, respectively. Most predicted values fell within the acceptable limit of 20% of the observed values. The model was extrapolated to predict the pharmacokinetics of lamotrigine following oral administration of a 100 mg dose in patients with hepatic impairment. The observed to predicted Cmax and AUC ratios were 0.89-0.97 and 0.89-0.96, respectively. The PBPK model accurately predicted lamotrigine exposure in the virtual population with hepatic impairment of Child Pugh classes A and B, but not for Child Pugh C impairment. Mild hepatic impairment had a minor impact on lamotrigine exposure; however, the effects of moderate to severe hepatic impairment on lamotrigine exposure were pronounced. The PBPK model for valproic acid was validated using data from clinical studies, and had FE ranges for AUC and Cmax of 0.76-1.27 and 0.9-1.26, respectively. Use of the PBPK models for lamotrigine and valproic acid in the DDI module of GastroPlusTM predicted an increase in lamotrigine exposure by 1.96- to 2.16-fold caused by valproic acid co-administration, reflecting UGT inhibition by valproic acid (UGT1A4 inhibitor), in alignment with clinical data (18). Co-administration of rifampicin (using the standard PBPK model for this drug in GastroPlusTM) reduced lamotrigine exposure by 0.61-fold, reflecting the UGT induction effect of rifampicin (3). Conclusions: Development of PBPK models of lamotrigine and valproic acid permitted prediction of exposure to lamotrigine under different conditions. This approach can be extended to utilization of lamotrigine in different patient populations, including malnourished patients, and may be useful for choosing dosage regimens in these patients.
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Reference: PAGE 33 (2025) Abstr 11640 [www.page-meeting.org/?abstract=11640]
Poster: Drug/Disease Modelling - Other Topics