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Background and Objectives: The commonly used antiseizure medication lamotrigine is a substrate to ATP binding cassette subfamily G member 2 (ABCG2) transporter. The objective of this study was to evaluate the effect of the common loss-of-function polymorphism ABCG2 c.421C>A (rs2231142) on the lamotrigine trough concentrations at steady state in adults with epilepsy., Methods: In two consecutive studies (Study 1, Study 2) in patients on lamotrigine monotherapy, carriers of the variant ABCG2 c.421C>A allele (CA/AA) were considered exposed, and wild-type homozygotes (CC) were considered controls. They were mutually balanced on covariates (age, sex, body weight, several polymorphisms in genes encoding other transporter proteins and lamotrigine-metabolizing enzymes that have been suggested to affect exposure to lamotrigine) to estimate the exposure effect (geometric means ratios, GMRs) in each study separately and overall (individual patient data meta-analysis). The overall estimate was evaluated for sensitivity to residual confounding., Results: In both studies (exposed n = 28 vs. controls n = 103; exposed n = 44 vs. controls n = 153, in Study 1 and Study 2, respectively) and overall (exposed n = 72 vs. controls n = 256), dose-corrected lamotrigine trough concentrations were moderately lower in the exposed patients: frequentist GMR [95% CI] = 0.82 [0.63-1.08]; GMR = 0.69 [0.60-0.81] and GMR = 0.72 [0.63-0.83] in Study 1, Study 2 and overall, respectively; Bayes GMR [95% CrI] = 0.83 [0.68-1.00]; GMR = 0.69 [0.58-0.83] and GMR = 0.75 [0.65-0.86] in Study 1, Study 2 and overall, respectively. Estimates appeared resistant to unmeasured confounding-the E-values for the pooled point estimates were high, and estimates corrected for a strong hypothetical bias were GMR = 0.78 [0.68-0.90] frequentist and GMR = 0.81 [0.70-0.93] Bayes., Conclusion: Polymorphism ABCG2 c.421C>A moderately reduces lamotrigine concentrations in adults with epilepsy., Competing Interests: Declarations. Funding: The studies presented in this report received no funding. Conflict of Interest: None of the authors have any conflict of interest to declare. The authors declare no support from any organization for the submitted work, no other financial relationships with any organizations that might have an interest in the submitted work, and no other relationships or activities that could appear to have influenced the submitted work. Author Contributions: The studies were conceived and designed by Nada Božina, Iva Klarica Domjanović, Ivana Šušak Sporiš and Vladimir Trkulja. Ivana Šušak Sporiš executed and supervised recruitment and management of most of the included patients. Lana Ganoci performed genetic analysis, Mila Lovrić pefromed lamotrigine measurements, and both were supervised by Nada Božina. Data were collected and assembled by Iva Klarica Domjanović, Ivana Šušak Sporiš, Lana Ganoci and Mila Lovrić. The present analysis was performed by Vladimir Trkulja who drafted the manuscript. Data were interpreted by Nada Božina and Vladimir Trkulja. All co-authors provided final approval of the manuscript. Ethics Approval: Both studies presented in this report were approved by the Institutional Ethics Committee (Study 1 – approval class: 8.1.-14/78-2, registration number: 02/21/JG, issued October 7, 2015; Study 2 – approval class: 8.1.-19/12-2, registration number: 02/21 AG, issued November 29, 2018). Consent to Participate: Only patients who signed a written informed consent for (1) genotyping for the pharmacogenes of interest and (2) publication of (anonymized) data for scientific purposes were included in the studies. Consent for Publication: Not applicable. Data Availability Statement: All data/datasets generated for the present analysis are available from the corresponding author upon a reasonable request. Code Availability: Codes used to generate frequentist (SAS for Windows 9.4) and Bayes estimates (R package rstanarm) are available from the corresponding author upon request., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Purpose: To estimate whether epilepsy patients with variant UGT2B7 -161C > T (rs7668258) or UGT1A4*3 c.142 T > G (rs2011425) alleles differ from their wild-type (wt) peers in exposure to lamotrigine., Methods: Consecutive adults on lamotrigine monotherapy or lamotrigine + valproate co-treatment undergoing routine therapeutic drug monitoring, otherwise generally healthy and free of interacting drugs, were genotyped for UGT2B7 -161C > T and UGT1A4*3 c.142 T > G. Heterozygous, variant homozygous, or combined heterozygous/variant homozygous subjects were compared to their wt controls for dose-adjusted lamotrigine troughs with adjustment for age, sex, body weight, rs7668258/rs2011425, polymorphisms of efflux transporter proteins ABCG2 c.421C > A (rs2231142) and ABCB1 1236C > T (rs1128503), and level of exposure to valproate using covariate entropy balancing., Results: Of the 471 included patients, 328 (69.6%) were on monotherapy and 143 were co-treated with valproate. Dose-adjusted lamotrigine troughs in UGT2B7 -161C > T heterozygous (CT, n = 237) or variant homozygous (TT, n = 115) subjects were closely similar to those in their wt controls (CC, n = 119): geometric means ratios (GMRs) (frequentist and Bayes) 1.00 (95%CI 0.86-1.16) and 1.00 (95%CrI 0.83-1.22) for CT vs. CC; and 0.97 (0.81-1.17) and 0.97 (0.80-1.20) for TT vs. CC subjects. Lamotrigine troughs were also closely similar in UGT1A4*3 c.142 T > G variant carriers (n = 106: 102 TG + 4 GG subjects) and wt controls (TT, n = 365): GMR = 0.95 (0.81-1.12) frequentist, 0.96 (0.80-1.16) Bayes. GMRs for variant carriers vs. wt controls were around unity also at different levels of exposure to valproate., Conclusion: Dose-adjusted lamotrigine troughs in epilepsy patients with variant UGT2B7 -161C > T or UGT1A4*3 c.142 T > G alleles are equivalent to those in their respective wt peers., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Concomitant treatment with drugs that inhibit drug metabolising enzymes and/or transporters, such as commonly prescribed statins and nonsteroidal anti-inflammatory drugs (NSAIDs), has been associated with prolonged drug exposure and increased risk of adverse drug reactions (ADRs) due to drug-drug interactions. The risk is further increased in patients with chronic diseases/comorbidities who are more susceptible because of their genetic setup or external factors. In that light, we present a case of a 46-year-old woman who had been experiencing acute renal and hepatic injury and myalgia over two years of concomitant treatment with diclofenac, atorvastatin, simvastatin/fenofibrate, and several other drugs, including pantoprazole and furosemide. Our pharmacogenomic findings supported the suspicion that ADRs, most notably the multi-organ toxicity experienced by our patient, may be owed to drug-drug-gene interactions and increased bioavailability of the prescribed drugs due to slower detoxification capacity and decreased hepatic and renal elimination. We also discuss the importance of CYP polymorphisms in the biotransformation of endogenous substrates such as arachidonic acid and their modulating role in pathophysiological processes. Yet even though the risks of ADRs related to the above mentioned drugs are substantially evidenced in literature, pre-emptive pharmacogenetic analysis has not yet found its way into common clinical practice., (© 2021 Nada Božina, Lana Ganoci, Livija Simičević, Katarina Gvozdanović, Iva Klarica Domjanović, Margareta Fistrek Prlić, Tena Križ, Ana Borić Bilušić, Mario Laganović, and Tamara Božina, published by Sciendo.)

Interindividual variability in drug metabolism is an important cause of adverse drug reactions and variability in drug efficiency. Polymorphisms of cytochrome P450 (CYPs) genes have a significant effect on drug metabolism and toxicity. This review brings an update about how genetic polymorphisms of CYP2C8 and CYP2C9 enzymes affect the disposition and clinical outcomes of ibuprofen and diclofenac, two of the most common pain relievers. The most common side effects associated with the influence of CYP2C8*3 and CYP2C9*2*3 variants on ibuprofen and diclofenac pharmacokinetics are hepatotoxicity and gastrointestinal bleeding. CYP genotyping may therefore identify patients at increased risk of these adverse reactions, and these patients could have their doses adjusted or start receiving another NSAID that does not share the same metabolic pathways with ibuprofen or diclofenac. However, before genotyping is introduced into regular clinical practice, more research is needed to evaluate the effectiveness of this strategy in improving treatment with ibuprofen and diclofenac.