Browsing by Subject "Lamotrigine"

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    Pharmacometric analyses of lamotrigine in special populations: application to pregnant women, younger adult and elderly epilepsy patients
    (2012-12) Polepally, Akshanth R.
    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.
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    Pharmacometrics of antiepileptic drugs: modeling and simulation-based studies of lamotrigine and carbamazepine pharmacokinetics
    (2008-11) Prasittisopin, Baralee
    The population pharmacokinetic modeling plays a pivotal role in quantitative learning about drugs from sparse data collected in clinical studies. It provides crucial information needed for individualization of dosage regimens especially in special population in which the intensive pharmacokinetic studies are of ethical concern. Lamotrigine and carbamazepine are antiepileptic drugs commonly used in elderly patients; however, dosing these drugs is based largely on studies from adult patients. Pharmacokinetic information of these drugs in elderly patients is limited. The aims of the current dissertation were to determine the population pharmacokinetic parameters of lamotrigine and carbamazepine in the community-dwelling elderly patients, and to quantitatively identify factors that have significant effects on these parameters. The further aim was to characterize the time course of carbamazepine deinduction by an enzyme turnover model. Due to the presence of collinearity between covariates during the covariate model development of lamotrigine, the effect of collinearity on power, bias, and precision of the parameter estimates in the population covariate model was further investigated by means of simulations. The population pharmacokinetic models of lamotrigine and carbamazepine were successfully developed and the models adequately described the data sets. The important information of drugs' pharmacokinetics was obtained and it can be beneficial in developing dosing strategies for elderly patients receiving these drugs. The time course of carbamazepine deinduction was well described by an enzyme turnover model. This model allowed the estimation of the half-life of the induced enzymes involving carbamazepine metabolism which is the important parameter for characterizing the time course of carbamazepine deinduction process. The power of selecting the true covariates depends on sample size of the data set, the magnitude of covariate coefficient, and the degrees of correlation. The investigation of the effect of collinearity between two true covariates revealed that an increasing collinearity between two true covariates not only decreases the power of selecting the true covariate model, but also leads to the biased and imprecise parameter estimates. The results from this study improve the understanding of how and to what extent the collinearity affects the parameter estimates in the covariate model building.
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    Quantitative Pharmacological Approaches for Characterizing Lamotrigine Pharmacokinetics in Special Populations of Pregnancy, Postpartum and Breastfeeding Infants to Prospectively Optimize Dosing
    (2020-12) Karanam, Ashwin
    Lamotrigine (LTG) is one of the most prescribed antiseizure medications (ASMs) in women with epilepsy during pregnancy and postpartum. Pregnancy-related physiological changes are expected to alter LTG pharmacokinetics (PK) especially increases in apparent clearance (CL/F), leading to subtherapeutic concentrations and in-turn potential loss of efficacy and/or safety. This necessitates increases in LTG dose during pregnancy to maintain therapeutic LTG concentrations followed by a postpartum reduction in dose to prevent toxicity. In addition, infants born to mothers on LTG therapy are exposed to LTG via breastmilk, necessitating quantitative characterization of rate and extent of LTG exposure in infants and possible relationships with infant neurocognitive and developmental outcomes. Management of LTG therapy in pregnancy and postpartum is thus balancing seizures in mother while minimizing LTG exposure to fetus and infants. These special populations are understudied especially with respect to PK-pharmacodynamic (PK-PD) relationships. This dissertation work aims at characterizing changes to LTG PK in pregnancy, postpartum and in breastfeeding infants. In addition, this thesis explores feasibility of potential LTG dosing algorithms which maximizes exposure and safety during pregnancy. The long-term goal of this research work is to create robust evidence-based guidelines for dosing LTG in both pregnant women with epilepsy and their breastfeeding children.Investigations into CL/F changes in early pregnancy were performed in women with epilepsy maintained on LTG monotherapy who were planning to become pregnant. CL/F increased at the rate of 0.115 L/h for every gestational week with increases in CL/F observed as early as 5 weeks gestational age, often before women themselves know they are pregnant, and continue to increase through gestational week 13. The average increase in clearance by week 13 was approximately 1.6 times the preconception CL/F. Such rapid increases in LTG-CL would necessitate dose-adjustments relatively early in pregnancy. It was also identified that LTG-CL increased by 0.844 L/h for every 1 ng/ml of estradiol however gestational age was a more robust predictor of LTG-CL changes. This may potentially be due to gestational age reflecting additional factors, although neither was robust enough for clinical use owing to significant interpatient variability. We also identified a subpopulation of women who may not experience significance CL/F changes in early gestation however quantification of this group was limited by the small sample size. Our findings highlight the importance of planning and early detection of pregnancy and use of therapeutic drug monitoring (TDM) in this population. LTG CL/F changes in pregnancy and postpartum necessitate dose changes. However, there exists no consensus on dosing recommendations for these populations. Simulation based methods were used to understand the outcomes of LTG dosing changes and different regimens in pregnant women with epilepsy (PWWE) based on published data. We identified that without any dose changes women in the high CL/F change group could experience loss of efficacy as early as 8 weeks gestational age. At least two dose increases during pregnancy would be needed to prevent loss of efficacy. However, using the same two dose increase strategy in women with low CL/F change during gestation could possibly lead to toxic/unsafe LTG concentrations. These results show that a “one size fits all” philosophy does not work well for LTG dosing in PWWE based on current knowledge and reinforces the need for TDM. LTG CL/F was characterized in the largest cohort of PWWE and nonpregnant women with epilepsy (NPWWE) enrolled in the MONEAD study. 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 1.75-fold increase in pregnancy at the end gestation in a majority of the PWWE (91%) compared to no identifiable change in LTG CL/F in the remaining 9% closely reproducing a previous study performed in a smaller population. Clinical covariates available in the study failed to explain the difference in subpopulations. We anticipate 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, LTG CL/F reached baseline values by 3 weeks after birth necessitating dose tapering early in postpartum. After 3 weeks, the CL/F in postpartum PWWE was indistinguishable from NPWWE CL/F confirming that pregnancy related changes do not carry over to postpartum. Infant LTG exposure via breastmilk was quantified in breastfeeding infants exposed to LTG enrolled in the MONEAD study. Median infant LTG concentrations were approximately 28.9% of maternal concentrations with a range of 0.6-90.3% indicating significant infant exposure but also wide between infant variability pointing out the need to accurately characterize infant LTG PK. A physiology-based PK model (PBPK) methodology was utilized to incorporate mechanistic information of LTG disposition in both postpartum mother and infants to characterize LTG exposure with both models having predictions within 1.6-fold of observed levels. These models provide mechanistic understanding of LTG-CL changes in infants and predictions of infant exposures which can be used for exploring exposure-neurocognitive developmental relationships. This PBPK model serves as a framework for understanding PK and quantifying exposure of other commonly used drugs in these special populations and is not limited to the epilepsy therapeutic area. Overall, the studies presented in this thesis characterized the LTG PK in special underrepresented populations of women with epilepsy and their infants including pregnancy and postpartum and breastfed infants. The results of this thesis add robust evidence to inform clinical management of LTG therapy in PWWE.