Bárbara Costa (1,2,3);Isabel Silva (4); José Carlos Oliveira (4,5); Henrique Reguengo (4,5); Nuno Vale (1,2,3)
1. PerMed Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal; 2. CINTESIS@RISE, Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal; 3. Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto, Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal; 4. Clinical Chemistry, Department of Laboratory Pathology, Hospital Center of the University of Porto (CHUP), Largo Professor Abel Salazar, 4099-313 Porto, Portugal; 5. Unit for Multidisciplinary Research in Biomedicine (UMIB), University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal.
Introduction: The Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved lamotrigine for treating various central nervous system symptoms [1,2], but recent warnings highlight its potential for serious reactions, including hepatotoxicity and cardiac effects [3]. Although rare, hepatotoxicity is a concern, particularly in populations like those with Type 2 Diabetes (T2D) and Non-Alcoholic Fatty Liver Disease (NAFLD) [4,5]. In this study, we investigate the effects of doses outside the therapeutic window to provide insights into the mechanisms underlying drug-induced liver injury (DILI) [6]. Overdosing amplifies the drug’s pharmacological effects, elucidating pathways involved in liver injury [7]. An incomplete understanding of lamotrigine’s mechanisms poses challenges in interpreting secondary effects like DILI or cardiac issues, complicating adverse reaction assessments. Dosing protocols vary by illness, necessitating vigilant healthcare professional monitoring [8,9].
Objectives: Investigate the influence of clinical parameters on lamotrigine pharmacokinetics across various patient populations to enhance therapeutic drug monitoring (TDM) and liver function assessment.
Methods: A retrospective exploratory analysis of 41 lamotrigine-treated patients at Hospital Santo António was conducted to identify changes in blood parameters and correlations among them. Subsequently, a Physiologically Based Pharmacokinetic (PBPK) model for lamotrigine was constructed in GastroPlus, incorporating ADMET predictions and literature data [10]. The model simulated lamotrigine’s pharmacokinetics at varying doses (200 mg, 400 mg, 600 mg, 1200 mg). DILIsym was employed, utilizing SimPops to introduce population variability, crucial for predicting low-frequency events like drug-induced liver injury (DILI), especially in patients with T2D and NAFLD.
Results: The retrospective analysis identified variations in blood parameters, including creatinine, albumin, gamma-glutamyl transferase, total bilirubin, and Vitamin B12 levels, with significant correlations observed. Notably, a strong negative correlation was found between vitamin B12 and creatinine, suggesting potential interactions between lamotrigine, renal function, and nutrient metabolism, which may impact immune system regulation and responsiveness to infection. The PBPK model accurately predicted the distribution and elimination of lamotrigine. The calculated steady-state volume of distribution (Vss) was 1.84 L/kg, which agreed with the values reported in the literature [11,12]. The systemic clearance was estimated at 3.248 L/h, calculated as the product of the fraction of drug unbound in the plasma (fup) and the glomerular filtration rate (GFR). The elimination half-life (t1/2) was estimated to be 27.58 h. Normal ranges include 24 to 35 h and are dose-independent from 30 to 400 mg [12,13]. Peak plasma concentration (Cmax) increased with higher doses, potentially affecting drug efficacy and side effects, while time to reach peak concentration (Tmax) showed variability with dose increments. DILIsym simulations demonstrated dose-dependent changes in plasma concentration profiles and highlighted the potential for drug-induced liver injury (DILI), particularly in specific populations like individuals with TD2 and NAFLD, emphasizing the importance of liver function monitoring. However, none of the simulated individuals met the criteria for severe liver injury (Hy’s law), confirming the overall safety profile of lamotrigine [14]. The study’s limitations include its retrospective nature, small sample size, and reliance on in silico simulations without real-world patient data validation for PBPK and DILIsym simulations. The results of this study have been published for reference [15].
Conclusions: By integrating clinical parameters and physiological pathways, clinicians can identify individuals at high risk of adverse reactions to lamotrigine. Understanding its pharmacokinetics in diverse patients is crucial for improving outcomes and minimizing hepatotoxicity. Timely monitoring and liver assessments are vital, especially in patients with T2D and NAFLD, to ensure safe lamotrigine therapy.
References:
[1] European Medicines Agency. Lamictal—Referral. Available online: https://www.ema.europa.eu/en/medicines/human/referrals/lamictal (accessed on 9 January 2024).
[2] FDA. Lamictal Label—Highlights of Prescribing Information. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020241s045s051lbl.pdf (accessed on 9 January 2024).
[3] FDA. FDA Drug Safety Communication: FDA Warns of Serious Immune System Reaction with Seizure and Mental Health Medicine Lamotrigine (Lamictal). Available online: https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safetycommunication-fda-warns-serious-immune-system-reaction-seizure-and-mental-health (accessed on 9 January 2024).
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[9] Milosheska, D.; Lorber, B.; Vovk, T.; Kastelic, M.; Dolžan, V.; Grabnar, I. Pharmacokinetics of Lamotrigine and Its Metabolite N-2-Glucuronide: Influence of Polymorphism of UDP-Glucuronosyltransferases and Drug Transporters. Br. J. Clin. Pharmacol. 2016, 82, 399–411.
[10] Conner, T.M.; Reed, R.C.; Zhang, T. A Physiologically Based Pharmacokinetic Model for Optimally Profiling Lamotrigine Disposition and Drug–Drug Interactions. Eur. J. Drug Metab. Pharmacokinet. 2018, 44, 389–408.
[11] Cohen, A.F.; Land, G.S.; Breimer, D.D.; Yuen,W.C.;Winton, C.; Peck, A.W. Lamotrigine, a New Anticonvulsant: Pharmacokineticsin Normal Humans. Clin. Pharmacol. Ther. 1987, 42, 535–541.
[12] Yau, MK.; Garnett, WE.; Wargin, WA.; Pellock, JM. A single dose, dose proportionality and bioequivalence study of lamotrigine in normal volunteers. Epilepsia. 1991;32(Suppl 3):8.
[13] Andersen ME. Saturable metabolism and its relationship to toxicity. Crit Rev Toxicol. 1981 May;9(2):105-50. doi: 10.3109/10408448109059563. PMID: 7026174.
[14] Howell, B.A.; Yang, Y.; Kumar, R.; Woodhead, J.L.; Harrill, A.H.; Clewell, H.J.; Andersen, M.E.; Siler, S.Q.; Watkins, P.B. In Vitro to in Vivo Extrapolation and Species Response Comparisons for Drug-Induced Liver Injury (DILI) Using DILIsymTM:A Mechanistic, Mathematical Model of DILI. J. Pharmacokinet. Pharmacodyn. 2012, 39, 527–541
[15] Costa, B.; Silva, I.; Oliveira, J.C.; Reguengo, H.; Vale, N.; Pharmacokinetic Simulation Study: Exploring the Impact of Clinical Parameters on Lamotrigine for Different Patient Populations with Implications for Liver Function Assessment and Therapeutic Drug Monitoring. Sci. Pharm. 2024, 92, 15. https://doi.org/10.3390/scipharm92010015
Reference: PAGE 32 (2024) Abstr 10829 [www.page-meeting.org/?abstract=10829]
Poster: Drug/Disease Modelling - Absorption & PBPK