Int J Clin Pharm DOI 10.1007/s11096-015-0158-4

CASE REPORT

Rash and multiorgan dysfunction following lamotrigine: could genetic be involved? Alessio Provenzani1 • Manuela Labbozzetta2 • Monica Notarbartolo2 • Paola Poma2 • Piera Polidori1 • Giovanni Vizzini3 • Natale D’Alessandro2

Received: 27 January 2015 / Accepted: 29 June 2015  Koninklijke Nederlandse Maatschappij ter bevordering der Pharmacie 2015

Abstract Case (description) We report the case of a 38-year-old woman treated with lamotrigine who experienced multiorgan dysfunction. The patient received the drug at the dose of 100 mg per day. One week later, the treatment was suspended because of an extensive body rash. Twenty-four hours later, the patient appeared drowsy and stuporous and was hospitalized. On the fifth day, the patient was admitted with a clinical picture of acute multi-organ failure in our Institute, where, she, despite the support of vital functions with vasoactive drugs, continuous hemofiltration and ventilation with oxygen, died. Serum lamotrigine concentration was measured 110 h after its last dose and the drug resulted to be still present at 1 mg/L. The patient was homozygous for the UGT1A4-70C and UGT2B7-161C alleles and heterozygous for the UGT2B7-372A[G polymorphism. Regarding ABCB1 the patient showed the 3435CC, 2677GT and 1236CT genotypes. Conclusion Our results may suggest a role of the UGT2B7-372A[G polymorphism in this reaction.

& Alessio Provenzani [email protected] 1

Clinical Pharmacy Service, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (ISMETT), Via E. Tricomi.5, 90127 Palermo, Italy

2

Area of Pharmacology, Department of Sciences for Health Promotion and Mother-Child Care ‘‘G. D’Alessandro’’, University of Palermo, Via del Vespro 129, 90127 Palermo, Italy

3

Department of Medicine, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (ISMETT), Via E. Tricomi.5, 90127 Palermo, Italy

Keywords ABCB1  Antiepileptic drugs  HLA  Lamotrigine  Multi-organ dysfunction  Pharmacogenetics  Rash  SNPs  UGT1A4  UGT2B7

Impacts on practice •

In this report we describe the case of a 38-year-old woman treated with lamotrigine who experienced multi-organ dysfunction. We call attention regarding the importance of the application of pharmacogenomics together with therapeutic drug monitoring.

Introduction Lamotrigine (LTG) is a phenyltriazine compound that inhibits voltage-gated sodium channels, decreasing the release of glutamate. It is endowed with additional activities and, in addition to treatment of epilepsy, is used also for pain management, and type I bipolar disorders characterized by the prevalence of the depressive component [1]. Rash is a common side effect of LTG therapy, and most frequently occurs during the first 8 weeks of treatment in approximately 3–10 % of new users. However, the incidence of rash associated with hospitalization has been reported to be 0.3 % in adults and 1 % in children [2]. The more rare and severe skin reactions to LTG include druginduced hypersensitivity syndrome (DHS), drug reaction with eosinophilia and systemic symptoms (DRESS), toxic epidermal necrolysis and Stevens-Johnson syndrome [2, 3]. The diagnostic criteria of DHS, which can also be frequently induced by aromatic anticonvulsants, have not been fully established. It has a variable clinical pattern that, beside rash, usually includes fever, lymphadenopathy,

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facial edema, eosinophilia, and abnormalities of liver function. The syndrome can, though rarely, lead to multiorgan dysfunction [3, 4]. DHS is clearly different from LTG dose-dependent toxicity, which manifests mainly with alterations of mental status and neurological and cardiovascular symptoms [5]. It is considered instead to be an idiosyncratic reaction, which results from a chemotoxic and/or immunologically-mediated injury characterized by bio-activation of antiepileptic drugs and histocompatibility complex-mediated activation of T cells. The aromatic antiepileptic agents are metabolized by cytochrome P-450 to arene oxide metabolites, which are normally detoxified by epoxide hydrolase. This enzyme may be genetically lacking or mutated in people who develop DHS [6]. LTG is metabolized mainly by hepatic N-glucuronidation, and hypersensitivity may manifest similarly to that found in aromatic antiepileptic drugs, except that the toxic LTG form has not yet been found. Though, in principle, DHS should be independent from plasma LTG levels [7], it has been suggested that LTG overdose may present with multi-organ involvement, and that at some concentration thresholds the amount of LTG may overwhelm the body’s ability to metabolize the drug, leading to a reaction similar to anticonvulsant DHS [8]. On the other hand, it is known that adhering to recommended dosing guidelines can minimize the risk of LTG-associated rash [7]. Here we report the case of a patient treated with LTG who experienced lethal rash and multi-organ dysfunction. We analyze the possible influence of genetic variations in some pharmacokinetic determinants on such unexpected response to LTG.

Ethical approval Informed, written consent was obtained from the husband.

Case description The patient was a 38-year-old Caucasian woman (65 kg) who had not reported any known allergies or intolerances to drugs. She was treated with alprazolam 0.5 mg/day and paroxetine 20 mg/day for anorexia and depression. Two months later LTG was added at the unusual starting dose of 100 mg/day per day and immediately after insomnia started to occur. This disturbance was treated with valerian at an unspecified dose. One week later LTG was suspended because the appearance of an extensive rash on the trunk and the upper and lower limbs. We do not know which kind of treatment the patient received for this condition. Twentyfour hours later the patient appeared drowsy and stuporous,

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and the day after she was brought to the emergency room and then hospitalized. Forty-eight hours later, the patient was admitted to our Institute, where a clinical picture of acute liver, kidney and respiratory failure was confirmed, and her neurological status degenerated into coma. A few hours later, despite monitoring and support of vital functions with vasoactive drugs (norepinephrine and epinephrine), continuous hemofiltration and ventilation with an inspiratory oxygen fraction of 100 %, she died. The last hematochemical tests showed a significant impairment of the most important liver function parameters, with a maximum AST of 8.820 U/L (normal range [NR] 15–37 U/L), ALT 5.590 U/L (NR 30–65 U/L), ALP 152 (NR 50–136 U/L), total bilirubin 2.4 mg/dL (NR 0.1–1.1 mg/dL), conjugated bilirubin 1.9 mg/dL (NR 0–0.93 mg/dL), albumin 2.2 g/dL (NR 3.5–5 g/dL), C-reactive protein 17.8 mg/L (NR 0–5 mg/L), transferrin 1.26 (NR 2–36 g/L) and ferritin 1.15 (NR 10–150 mcg/L). White blood cell count was 2250/lL (4000–10,000/lL) with 81.5 % neutrophils, 16.4 % lymphocytes, 1.3 % monocytes, 0.01 % eosinophils and 0.4 % basophils. The coagulation parameters were also significantly altered, with a prothrombin time of 63 s (NR 10–15 s) and an INR of 5.4 (NR 0.8–1.2). The serum creatinine and BUN were 2.5 (NR 0.6–1.2 mg/dL) and 61 mg/dL (NR 7–20 mg/dL), respectively. The concentration of serum LTG was measured 110 h after its last administration by QMS Lamotrigine immunoassay (Thermo Fisher Scientific, Inc.) and resulted to be 1 mg/L (NR 2.5–15 mg/L). Furthermore, since the polymorphisms of UGT1A4, UGT2B7 and ABCB1 may contribute to LTG pharmacokinetic variability, six single nucleotide polymorphisms (SNPs), i.e. UGT1A4-70C[A, UGT2B7-161C[T, UGT2B7-372A[G, ABCB1-3435C[T, 2677G[T/A, and 1236C[T, were examined. Using real time polymerase chain reaction (real time PCR) and polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) approaches, we found that the patient was homozygous for the UGT1A4-70C and UGT2B7-161C alleles and heterozygous for the UGT2B7-372A[G polymorphism. With regard to the ABCB1 SNPs, the patient showed the 3435CC, 2677GT and 1236CT genotypes.

Discussion Though our case did not precisely fit the various manifestations described for DHS, its clinical picture appeared to be compatible with such a syndrome. On the other hand, it has been reported that DHS associated with LTG, with respect to other antiepileptic agents, more frequently develops severe rash than eosinophilia and lymphadenopathy [9]. At our best knowledge, the patient did not have any known risk factor for DHS [10], but the dose

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of LTG (100 mg) was not lowered at the start of treatment. Lowering dosages may reduce the incidence of serious rash [6, 7, 10]. Rarely is the use of Valerian associated with liver injury. However, in the literature, severe cases with features of hepatic failure have been described, but usually in association with other potentially hepatotoxic herbals. Moreover, the latency to onset of toxicity varies from 3 to 12 weeks, and it is unlikely that it fits with ours case. [11]. After oral administration, LTG is absorbed rapidly and completely by the gastrointestinal tract. The fraction of LTG bound to serum proteins drug is 55 % and the volume of distribution of the drug is 1.2 L/kg. LTG is excreted by the kidney mostly as an inactive N2-glucuronide conjugate [1, 12]. Its average half-life of elimination is of around 22 h (range 13–30 h) if used in monotherapy, 14 or 70 h if used with enzymatic inductors or sodium valproate, respectively [1, 7]. In clinical practice, despite the fact LTG has several characteristics that would require therapeutic drug monitoring, this is not commonly done [12, 13]. The existence of a clear relationship between LTG blood levels and clinical efficacy is a subject of debate. However, there is agreement that toxicity increases significantly with circulating concentrations of the drug higher than 15 mg/L [1, 7, 12]. LTG exhibits linear pharmacokinetic characteristics [7], and in theory after five half-lives, 3.125 % of the drug should remain. In our case, the presence of circulating LTG (1 mg/L) 110 h after its last administration, and about 3 h of hemofiltration [14], suggests that it had previously achieved levels over the therapeutic range. Also, the multiorgan failure could had significantly contributed to reducing the elimination of lamotrigine and, consequently, to increase its level. However, at the moment, we cannot totally exclude a deliberate or accidental overdose by the patient. Moreover, it been suggested that, beside other factors (e.g., age, concurrent disease, body size, co-medications, pregnancy status, ethnicity), also UGT1A4, UGT2B7 and ABCB1 variants may also influence the pharmacokinetics of LTG and, consequently, explain its inter-individual variability [15–17]. Glucuronidation is catalyzed by the uridine diphosphateglucuronosyltransferase enzymes (UGTs), which consist of two major subfamilies, the UGT1 and UGT2. Among UGT1s, UGT1A4 is of major importance in the conjugation and subsequent elimination of various therapeutic drugs, including LTG [15, 17]. The UGT1A4 gene is highly polymorphic, with 109 SNPs described so far [17, 18]. Allele frequencies of UGT1A4 SNPs differ among ethnic groups [17]. In Caucasians, there are two polymorphisms that lead to amino acid changes, UGT1A4 70C[A (rs#: 6755571) and the UGT1A4 142T[G (rs#: 2011425), with

allelic frequencies of 4.9–8.8 and 8.3–11 %, respectively [17, 19, 20]. They are in linkage disequilibrium and have been associated with reduced in vitro glucuronidation activities against different substrates, including LTG [15, 17, 19, 21–23]. Our patient was homozygous for UGT1A470C, and this cannot account for higher LTG levels, since patients carrying this wild-type genotype would exhibit a higher clearance. For UGT1A4-142T[G, a study concluded that this polymorphism is not an important factor for development of LTG-induced rash, especially in the absence of the 70C[A polymorphism, as in our case [3]. Also, UGT2B7 appears to be of particular significance in drug metabolism. It contributes to the glucuronidation of LTG and other antiepileptic drugs [15]. Several polymorphisms have been detected within the UGT2B7 gene, and they have been associated to changes in glucuronidation activities. The two most common are UGT2B7 161C[T (rs#: 7668258) and 372A[G (rs#: 7662029), with allelic frequencies in Caucasians of 49–56 and 3–13 %, respectively [15, 16, 22, 24–26]. The UGT2B7-161C[T is a promoter polymorphism that may change the level of transcription of the enzyme [16, 27]. However, our patient was homozygous for UGT2B7161C allele and, reportedly, patients carrying this genotype would require a higher LTG dose than those carrying the CT or TT genotypes [16]. As for the more rare UGT2B7-372A[G polymorphism in exon 1, there is little information on its functional consequences. In one study, the 372A allele was found to be associated with an increased morphine glucuronidation activity [16, 26] and, conceivably, the presence of the mutant allele G in our patient might be compatible with a lower activity of the enzyme. With regard to ABCB1 (also known as P-glycoprotein), it is known that this multidrug transporter can determine the disposition of several xenobiotics, possibly, but not incontrovertibly, including LTG [28]. It is also debated whether some SNPs of the ABCB1 gene, such as 1236C[T (rs#: 1128503) at exon 12, 2677G[T/A (rs#: 2032582) at exon 21 and 3435C[T (rs#: 1045642) at exon 26, may cause altered ABCB1 expression and function and influence LTG serum concentrations [29, 30]. In Caucasians, the frequencies of the allelic variants T are of 41, 40–50 and 33–65 % for the polymorphisms at exons 12, 21 and 26, respectively [31]. The few existing studies have focused mainly on the possible influences of ABCB1 polymorphisms on the transport of LTG at the blood–brain barrier and not in other districts. Accordingly, in our case, a higher blood level of the drug might have reflected its lower concentration in the central nervous system, due to the more functional efflux system associated with the wild type 3435CC genotype at exon 26 [29, 30, 32–34]. Indeed, one study found that patients with drug-resistant epilepsy

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were more likely to carry the 3435CC genotype than the TT one [35]. Nevertheless, for the SNPs at exons 12 and 21, our patient showed the 1236CT and 2677GT genotypes, respectively. Also, some data support the validity of simultaneously analyzing the combined effect of the three ABCB1 variants [36, 37]. Unfortunately, the occurrence and severity of DHS from LTG remains difficult to predict genetically. The reaction may well be immune-mediated, but no single major HLArelated genetic risk factor has been identified for the syndrome in patients of European origin, with only a suggestive evidence for HLA-B*58:01, HLA-A*68:01, Cw*07:18, DQB1*06:09 and DRB1*13:01 [38].

Conclusion Overall, our results may suggest a role of the UGT2B7372A[G polymorphism in the reaction experienced by the patient. On the other hand, since inter-individual variability in the therapeutic and toxic response to LTG is an important issue, further large genetic studies, together with a wider application of therapeutic drug monitoring, could prove to be useful in improving the management of the agent. Funding

None.

Conflicts of interest

None to declare.

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Rash and multiorgan dysfunction following lamotrigine: could genetic be involved?

We report the case of a 38-year-old woman treated with lamotrigine who experienced multi-organ dysfunction. The patient received the drug at the dose ...
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