Background
Valproate inhibits clearance of lamotrigine and greatly increases its concentrations. We assessed whether this effect was moderated by a polymorphism (ABCG2 c.421C>A) of the breast cancer ...resistance protein.
Methods
In two consecutive independent studies in adults with epilepsy on lamotrigine monotherapy or cotreated with valproate: (i) Exposure to valproate was considered treatment, (ii) dose‐adjusted lamotrigine troughs at steady state were the outcome, and (iii) ABCG2 c.421C>A genotype (wild‐type wt homozygosity or variant carriage) was the tested moderator. We used entropy balancing (primary analysis) and exact/optimal full matching (secondary analysis) to control for confounding, including polymorphisms (and linked polymorphisms) suggested to affect exposure to lamotrigine (UGT1A4*3 c.142T>G, rs2011425; UGT2B7–161C>T, rs7668258; ABCB1 1236C>T, rs1128503) to generate frequentist and Bayesian estimates of valproate effects (geometric means ratios GMR).
Results
The two studies yielded consistent results (replicated); hence, we analyzed combined data (total N = 471, 140 treated, 331 controls, 378 ABCG2 c.421C>A wt subjects, 93 variant carriers). Primary analysis: in variant carriers, valproate effect (GMR) on lamotrigine (treated, n = 21 vs. controls, n = 72) was around 60% higher than in wt subjects (treated, n = 119 vs. controls, n = 259)—ratio of GMRs 1.61 (95%CI 1.23–2.11) (frequentist) and 1.63 (95%CrI 1.26–2.10) (Bayes). Similar differences in valproate effects between variant carriers and wt subjects were found in the secondary analysis (valproate troughs up to 364 μmol/L vs. no valproate; or valproate ≥364 μmol/L vs. no valproate). Susceptibility of the estimates to unmeasured confounding was low.
Conclusion
Data suggest that polymorphism rs2231142 moderates the effect of valproate on exposure to lamotrigine.
To estimate the effect size of concomitant antiepileptic therapy on the concentrations of lamotrigine, a drug often prescribed in combination with other antiepileptic drugs (AED), which can act as ...enzyme inducers or inhibitors.
A total of 304 patients with epilepsy, aged 18-70 years, were divided into a lamotrigine monotherapy group and groups receiving lamotrigine with AEDs that act as enzyme inducers, enzyme inhibitors, or both. We compared lamotrigine monotherapy serum concentrations with those where lamotrigine was administered with a metabolic inhibitor valproate, metabolic inducers carbamazepine, oxcarbazepine, phenobarbital, phenytoin, or topiramate, and both an inducer and an inhibitor.
Comparison of trough lamotrigine monotherapy concentrations and lamotrigine polytherapy concentrations showed an almost similar median concentration in case of drug-inducers, and higher lamotrigine concentration in case of comedication with valproate as an inhibitor. A significant difference was confirmed after dose correction (P<0.001). Significant positive correlations of lamotrigine trough serum concentrations with valproate were observed before and after the dose correction (r=0.480, P<0.001 and r=0.561, P<0.001, respectively). Positive correlations between the dose-corrected lamotrigine trough concentration and carbamazepine (r=0.439; PP<0.001) or monohydroxy metabolite of oxcarbazepine (MHD) (r=0.675; PP<0.001) were also significant.
Higher valproate levels resulted in higher inhibition potency and higher lamotrigine levels. Increased dose-corrected concentrations of inducers carbamazepine and MHD, after the process of induction was finished, did not lower lamotrigine concentrations. These findings can be of clinical significance for optimal AED dosing.
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.
Organic anion-transporting polypeptide 1B1 (OATP1B1) and the ATP-binding cassette subfamily G member 2, ABCG2, are important transporters involved in the transport of endogenous substrates and ...xenobiotics, including drugs. Genetic polymorphisms of these transporters have effect on transporter activity. There is significant interethnic variability in the frequency of allele variants.
To determined allele and genotype frequencies of ABCG2 and SLCO1B1 genes in Croatian populations of European descent.
A total of 905 subjects (482 women) were included. Genotyping for ABCG2 c.421C > A (rs2231142) and for SLCO1B1 c.521T > C (rs4149056), was performed by real-time polymerase chain reaction (PCR) using TaqMan
®
DME Genotyping Assays.
For ABCG2 c.421C > A, the frequency of CC, CA and AA genotypes was 81.4%, 17.8% and 0.8% respectively. The frequency of variant ABCG2 421 A allele was 9.7%. For SLCO1B1 c.521T > C, the frequency of TT, TC and CC genotypes was 61.7%, 34.8% and 3.5% respectively. The frequency of variant SLCO1B1 521 C allele was 20.9%.
The frequency of the ABCG2 and SLCO1B1 allelic variants and genotypes in the Croatian population is in accordance with other European populations. Pharmacogenetic analysis can serve to individualise drug therapy and minimise the risk of developing adverse drug reactions.
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.
Older people are increasingly susceptible to adverse drug reactions (ADRs) or therapeutic failure. This could be mediated by considerable polypharmacy, which increases the possibility of drug-drug ...and drug-gene interactions. Precision medicine, based on individual genetic variations, enables the screening of patients at risk for ADRs and the implementation of personalized treatment regimens. It combines genetic and genomic data with environmental and clinical factors in order to tailor prevention and disease-management strategies, including pharmacotherapy. The identification of genetic factors that influence drug absorption, distribution, metabolism, excretion, and action at the drug target level allows individualized therapy. Positive pharmacogenomic findings have been reported for the majority of cardiovascular drugs (CVD), suggesting that pre-emptive testing can improve efficacy and minimize the toxicity risk. Gene variants related to drug metabolism and transport variability or pharmacodynamics of major CVD have been translated into dosing recommendations. Pharmacogenetics consortia have issued guidelines for oral anticoagulants, antiplatelet agents, statins, and some beta-blockers. Since the majority of pharmacogenetics recommendations are based on the assessment of single drug-gene interactions, it is imperative to develop tools for the prediction of multiple drug-drug-gene interactions, which are common in the elderly with comorbidity. The availability of genomic testing has grown, but its clinical application is still insufficient.
Aims
To investigate the impact of glucuronidation enzyme (UGT1A4*3 142T>G, UGT1A4*2 70C>A, UGT2B7 –161C>T) and transporter (MDR1/ABCB1 1236C>T, ABCG2 421C>A) polymorphisms on steady‐state disposition ...of lamotrigine and on the lamotrigine–valproate interaction.
Methods
Adults with epilepsy on lamotrigine monotherapy (n = 131) or lamotrigine + valproate treatment (n = 74) were genotyped and steady‐state lamotrigine and valproate morning troughs were determined as a part of routine therapeutic drug monitoring.
Results
No effect of UGT and MDR1/ABCB1 polymorphisms was observed. In the entire cohort, ABCG2 421A allele had no effect however an interaction between the variant allele and valproate was observed: (i) in lamotrigine‐only patients, variant allele (vs. wild type homozygosity) was independently (adjustments: age, sex, body mass index, lamotrigine dose, other polymorphisms) associated with mildly lower lamotrigine troughs geometric means ratio (GMR) = 0.76, 95% confidence interval (CI) 0.59–0.98, whereas in lamotrigine + valproate patients it was associated with higher troughs (GMR = 1.72, 95%CI 1.14–2.62); (ii) valproate cotreatment was overall associated with markedly higher troughs vs. lamotrigine monotherapy (GMR = 3.49, 95%CI 2.73–4.44), but more so in variant allele carriers (GMR = 5.24, 95%CI 3.38–8.15) than in wild type homozygotes (GMR = 2.32, 95%CI 1.89–2.83); (iii) variant allele effects in two treatment subsets and valproate effects in two genotype subsets differed by 2.36‐fold (95%CI 1.39–3.67); (iv) increase in lamotrigine troughs associated with increasing valproate troughs was greater in variant allele carriers than in wild type homozygotes, i.e. variant allele effect increased with increasing valproate troughs.
Conclusion
This study is first to indicate a potentially relevant interaction between ABCG2 421C>A polymorphism and valproate in their effects on lamotrigine disposition.
Seizure control with antiepileptic drugs (AEDs) as well as susceptibility to adverse drug reactions varies among individuals with epilepsy. This interindividual variability is partly determined by ...genetic factors. However, genetic testing to predict the efficacy and toxicity of AEDs is limited and genetic variability is, as yet, largely unexplainable. Accordingly, genetic testing can only be advised in a very limited number of cases in clinical routine. Currently, by applying different methodologies, many trials have been undertaken to evaluate cost benefits of preventive pharmacogenetic analysis for patients. There is significant progress in sequencing technologies, and focus is on next-generation sequencing-based methods, like exome and genome sequencing. In this review, an overview of the current scientific knowledge considering the pharmacogenetics of AEDs is given.
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.
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.
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