Pharmacometric analyses of lamotrigine in special populations: application to pregnant women, younger adult and elderly epilepsy patients

Abstract

The pharmacokinetics (PK) of lamotrigine (LTG) is understudied in pregnant women and elderly patients with epilepsy. Both pregnancy and advanced age are expected to result in changes in the LTG PK, which may cause potential loss of efficacy or safety. Optimal dosing of LTG in these special populations requires characterization of PK and its variability among the individuals. This dissertation work aimed at characterizing gestational age-associated changes in LTG PK and seizure control and age-related changes in LTG PK, and exploration of potential benefits of a newly developed LTG formulation over the conventional form in the elderly. The long-term goal of this research work is to create evidence-based guidelines for dosing LTG in both pregnant women and elderly patients with epilepsy. The change in apparent clearance of LTG (CL/F) was quantified with respect to gestational age and postpartum weeks in pregnant women who were maintained on LTG alone or with non-interacting drugs. During pregnancy, we identified two subpopulations of women that exhibited different rates of increase in LTG CL/F. The gestational age-associated increase in CL/F displayed a ten-fold higher rate in subpopulation I (0.120 L/h/week) compared to subpopulation II (0.0115 L/h/week). Such drastic changes in CL/F would require frequent dosage adjustments in subpopulation I. Further investigations revealed heterogeneity in the racial mix between the two subpopulations with a larger prevalence of whites (80%) in subpopulation I than in subpopulation II. We anticipate that race-associated genotypic variations in the activity or induction of UGT1A4 or polymorphisms in estrogen receptors could partly explain the varying degrees of enhanced CL/F between the two groups of pregnant women and may warrant further investigation. In the postpartum period, we calculated that an average duration of 3 weeks is required for LTG CL/F to reach preconception values, and that clinicians may need to taper the dose of LTG to the baseline prescribed dose within that time interval. When exploring seizure frequencies in pregnant women, the seizure rate was low most likely due to effective therapeutic drug monitoring. Future studies with a larger number of patients may provide information on exposure-response and time course changes of seizures in pregnant women. With the creation of a novel stable-labeled intravenous LTG formulation we were able to administer LTG by two routes (i.e., oral and intravenous) simultaneously in younger adults and elderly patients with epilepsy. We also demonstrated a comparable bioequivalence between extended-release and immediate release formulations in terms of steady-state area under the concentration-time curve, trough and average steady-state plasma concentration in elderly patients with epilepsy. We found a comparable absolute bioavailability (75%) of LTG tablets in both younger adult and elderly patients. However, the LTG clearance (CL) was 27% lower on average for elderly patients compared to younger adults. We hypothesize the observed reduction in CL may be caused by a reduced enzyme capacity (or UGT1A4 expression) and/or liver volume in the elderly group. Therefore, we recommend future studies to investigate age-selective differences in UGT1A4 expression. Overall, the studies presented in this thesis characterized the LTG PK in special populations that are underrepresented in clinical studies. We were unable to fully explain some of the PK findings in pregnant women or the elderly due to the lack of information on UGT1A4 genotypes. Therefore, future studies of LTG in these populations should investigate genotypic variations and expression of the main metabolic enzyme UGT1A4.