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Effect of comedication on lamotrigine clearance in Korean epilepsy patients
Clinica Chimica Acta 438 (2015) 269–273
Contents lists available at ScienceDirect
Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim
Effect of comedication on lamotrigine clearance in Korean epilepsy patients Hee-Jung Kim a,1, Tae-Eun Kim b,d,1, Eun Yeon Joo c, Dae-Won Seo c,⁎, Soo-Youn Lee a,b,⁎⁎, Seung Bong Hong c a
Department of Laboratory Medicine & Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea Department of Clinical Pharmacology & Therapeutics, Samsung Medical Center, Seoul, Republic of Korea Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Seoul, Republic of Korea d Department of Clinical Pharmacology, Konkuk University Medical Center, Seoul, Republic of Korea b c
a r t i c l e
i n f o
Article history: Received 23 June 2014 Received in revised form 2 September 2014 Accepted 2 September 2014 Available online 8 September 2014 Keywords: Epilepsy Comedication Korean Lamotrigine Pharmacokinetics Clearance
a b s t r a c t Background: Lamotrigine (LTG) is a widely used antiepileptic-drug (AED) for the treatment of epilepsy. We investigated the effect of AED comedication on LTG clearance in Korean patients with epilepsy. Methods: The authors reviewed the medical charts for all patients ≥ 18 years who have received LTG as monotherapy or adjunctive therapy. Data collected included LTG levels, dosage, treatment duration, concomitant AEDs and specific side effects. LTG clearance was estimated according to comedication. Results: A total of 580 blood samples from 548 patients were analyzed. LTG clearance in the enzyme-inducing AED (EIAED) coadministration group was the highest (0.050 l/kg/h), followed by the LTG monotherapy group (0.028 l/kg/h), the coadministration group of both valproate (VPA) and EIAED (0.024 l/kg/h) and the VPA coadministration group (0.018 l/kg/h). When LTG was administered with both VPA and EIAED, the multiple EIAED group had higher LTG clearance than the single EIAED group. Conclusions: Concomitant administration of valproate reduced LTG clearance by approximately 35%, while EIAEDs increased LTG clearance by 80%. These relationships indicate the importance of considering the effects of comedication on LTG clearance when determining LTG dosage. © 2014 Published by Elsevier B.V.
1. Introduction Lamotrigine (LTG) is a widely used antiepileptic drug (AED) for the treatment of new-onset as well as refractory epilepsy [1,2]. LTG was introduced as adjunctive treatment for partial seizures in Europe in 1991 and in the United States in 1994. At the present time, it is indicated as adjunctive therapy in the treatment of Lennox–Gastaut syndrome, generalized seizures, and partial seizures in adults and children 2 years and older, and as monotherapy in adults with partial seizures [3]. Furthermore, there is an increasing interest in its properties for treating bipolar disorders [4]. LTG is metabolized mainly in the liver by glucuronidation and excreted renally as a glucuronide conjugate [5]. The coadministration of hepatic enzyme-inducing AED (EIAED), such as phenytoin, carbamazepine, phenobarbital or primidone, significantly increases the systemic clearance of LTG [6,7], while valproate (VPA), a known inhibitor of glucuronidation, significantly reduces the elimination of LTG [6–8]. LTG is rapidly absorbed and reaches peak serum concentrations 1 to 5 h after administration [3]. The mean half-life of LTG ranges from ⁎ Corresponding author. ⁎⁎ Correspondence to: S.-Y. Lee, Department of Laboratory Medicine & Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 135-710, Republic of Korea. Tel: +82 2 3410 2702; fax: +82 2 3410 2719. E-mail address: [email protected] (S.-Y. Lee). 1 These authors contributed equally to this work.
http://dx.doi.org/10.1016/j.cca.2014.09.004 0009-8981/© 2014 Published by Elsevier B.V.
25 to 33 h in healthy volunteers taking only LTG, 59 to 70 h in healthy volunteers comedicated with VPA, and 13 to 14 h in patients comedicated with an EIAED [3]. Although plasma LTG levels are described in many publications, a therapeutic range for LTG is not well established. Therapeutic serum concentrations range from 1–3 mg/l or 1–4 mg/l were originally proposed based on preclinical data [9–11]. However, later studies suggested that these concentrations may have been too low, and showed that some patients tolerated concentrations above 10 mg/l with greater efficacy and without clinical toxicity [12]. Morris et al. advised a plasma LTG level of 3–14 mg/l [13,14]. 2. Materials and methods 2.1. Patients This study was approved by the medical ethics committee for Samsung Medical Center. The authors reviewed the medical charts for all patients ≥ 18 years seen at the Epilepsy Center in the Samsung Medical Center, who received LTG as monotherapy or adjunctive therapy and had their weight and LTG serum concentrations levels recorded. Patients who were being titrated or who were noncompliant were excluded from the study, as were patients with levels below the quantification limit, as it suggested potential noncompliance. The patients with hepatic or renal dysfunction were also excluded.
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H.-J. Kim et al. / Clinica Chimica Acta 438 (2015) 269–273
2.2. Serum LTG concentrations
3.2. Effect of comedication on the pharmacokinetics of lamotrigine
AED blood levels were obtained for every patient at least 10 h after dose administration. Patients were treated with stable doses for a period of at least 3 weeks before blood levels were obtained. When N 1 LTG level was observed in a patient while taking the same drug combination and LTG dosage, the levels were averaged. Serum LTG concentrations were measured by high-performance liquid chromatography (Agilent 1200 Series, Agilent) and with a Chromsystems kit. The linear assay range was 0.5–50 mg/l (r2 N 0.99). The intra- and inter-assay imprecisions were coefficients of variation less than 10%. The weight-corrected hourly rate of clearance was calculated as follows:
3. Results
All patients were divided into subgroups based on comedication. LTG monotherapy group, LTG plus VPA group, LTG plus both EIAED and VPA group and LTG plus EIAED group included 248, 131, 61 and 108 patients, respectively. LTG doses were not significantly different among 4 subgroups except for between LTG plus VPA group and LTG plus EIAED group (p = 0.016) (Table 2). LTG clearance was significantly different between the groups; LTG clearance in the EIAED coadministration group was the highest, followed by the LTG monotherapy group and the combination group of VPA and EIAED. The LTG clearance was the lowest in the LTG and VPA combination group (Table 2). The mean LTG clearance of the VPA coadministration group (0.018 l/kg/h) was significantly lower than the LTG monotherapy group (0.028 l/kg/h), while the EIAED coadministration group (0.050 l/kg/h) showed significantly higher LTG clearance than the LTG monotherapy group. However, the mean LTG clearance of the VPA and EIAED coadministration group (0.024 l/kg/h) was not significantly different from that of the LTG monotherapy group. In addition, although the mean LTG clearance of the VPA and EIAED coadministration group was higher than the VPA coadministration group (0.018 l/kg/h), this difference was not significant (Table 2, Fig. 1). For EIAED coadministration groups with or without VPA, LTG clearances were analyzed according to each EIAED and compared according to the number of coadministered EIAEDs (Table 3). When a single EIAED was coadministered, phenytoin exhibited the highest increase of LTG clearance followed by carbamazepine and phenobarbital. However, the effects of phenytoin were not distinguishable from other EIAEDs when multiple EIAEDs were coadministered. When comparing LTG clearance according to the number of EIAEDs, different results were observed depending on whether or not VPA was administered concurrently. When EIAED was coadministered without VPA, there was no significant difference in LTG clearance between the single EIAED group and the multiple EIAED group. However, when both EIAEDs and VPA were administered with LTG, the LTG clearance of the multiple EIAED group was significantly higher than that of the single EIAED group.
3.1. Patient demographics and pharmacokinetic parameters
3.3. Predictive model of LTG serum concentrations
A total of 580 blood samples from 548 patients were obtained, yielding 548 LTG levels for analysis. The patient group consisted of 251 males and 297 females with a mean age of 34.9 ± 12.8 years (range 18.0–83.2) and mean weight of 63.6 ± 12.5 kg (range 35.8–117.4) (Table 1). The average LTG dose and treatment period were 2.98 mg/kg/day and 627 days, respectively. All patients were treated for N 21 days to ensure steady-state. The mean concentration at steady state (Css) was 5.57 ± 3.91 mg/l and the mean clearance was 0.030 ± 0.029 l/kg/h (Table 1).
LTG daily dose, body weight and comedication of VPA and EIAED were predictors of LTG serum concentration. Age and sex did not appear to impact LTG levels. LTG daily dose was the most significant predictor of LTG serum concentration (β = 0.570, Fig. 2), followed by comedication of VPA (β = 0.428), EIAED (β = −0.289) and body weight (β = 0.021). The final model is shown below, with an r2 = 0.541: LTG serum concentration = 4.397–0.049 ∗ body weight + 0.021 ∗ daily LTG dose + 3.6 ∗ CMVPA − 2.516 ∗ CMEIAED
CL ðl=kg=hÞ ¼ weight−adjusted daily dose ðmg=kgÞ= ðsteady state serum concentration Þðmg=lÞ 24 ðhÞÞ: 2.3. Statistical analysis Four treatment groups were established to investigate each AED comedication effect: LTG monotherapy group, LTG plus VPA group, LTG plus both EIAED and VPA group and LTG plus EIAED group. LTG daily doses, steady-state concentrations and clearances were analyzed according to treatment group, and LTG clearances were compared between treatment groups using an ANOVA test and adjusting for multiplicity with the Tukey method. The Mann–Whitney U test was used to compare LTG clearance between the group with one EIAED coadministration and the group with multiple EIAED coadministration. A predictive model for LTG serum concentration was created using multiple regression analysis, with daily dose of LTG, age, weight, and comedication of VPA or EIAED as independent variables. The model estimation proceeded backwards. IBM SPSS Statistics™ 21 (Datasolution Inc., ver 21) was used for statistical analysis with a 2-sided level of statistical significance set at 0.05.
Table 1 Summary of patient characteristics.
3.4. Toxic effects of high levels of LTG
Number of patients
548
Female/male Age (year)⁎ Body weight (kg)⁎ LTG Dose (mg/kg/day)⁎ LTG treatment period (days)⁎
297/251 34.9 ± 12.8 63.6 ± 12.5 2.98 ± 1.86 627 ± 653
Number of patients according to type of epilepsy Localization-related Generalized Undetermined whether focal or generalized
391 123 34
LTG = Lamotrigine. ⁎ Mean ± SD.
- CMVPA: 1 if VPA was coadministered and 0 if VPA was not coadministered - CMEIAED: 1 if any EIAED was coadministered and 0 if no EIAEDs were coadministered.
Of the 548 patients in this study, 22 patients had LTG levels N 14 mg/l (range, 14.1–27.9 mg/l) (data not shown). Among these patients, 2 patients experienced side effects of LTG. One patient with an LTG level of 15.0 mg/l developed tremors, thus the LTG dose was reduced. Another patient with 16.9 mg/l developed mild tremors, which did not lead to a dosage change or discontinuation of LTG. On the other hand, three patients with LTG levels of 15.7, 20.0 and 27.9 mg/l did not have any side effects, but their seizures were not well-controlled. Thus, their dosage of LTG was increased or another antiepileptic drug was added to their treatment. Meanwhile, four out of 526 patients with lower LTG levels also experienced side effects of headache, nausea, vomiting and tremor.
H.-J. Kim et al. / Clinica Chimica Acta 438 (2015) 269–273
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Table 2 Summary of lamotrigine pharmacokinetic parameters. Parameters
All data
Number of patients Dose LTG, mg/kg/day⁎ Css, mg/l⁎ CL, l/Kg/h⁎
548 2.98 ± 1.86 5.57 ± 3.91 0.030 ± 0.029
Treatment group LTG
LTG + VPA
LTG + VPA + EIAED
LTG + EIAED
248 2.95 ± 1.99 4.99 ± 3.19 0.028 ± 0.019
131 2.71 ± 1.56 8.46 ± 4.73 0.018 ± 0.034
61 2.85 ± 1.50 5.65 ± 3.39 0.024 ± 0.012
108 3.43 ± 2.04 3.36 ± 2.23 0.050 ± 0.035
0.025 b0.001 b0.001
LTG = lamotrigine; Css = concentration at steady state; CL = clearance; VPA = valproate; EIAED = enzyme-inducing anti-epileptic drugs. ⁎ Mean ± SD.
4. Discussion The present study found that the combination of LTG and VPA decreased LTG clearance by 36% compared to LTG monotherapy. When one or more of EIAEDs were combined with LTG, LTG clearance increased by approximately 80%. The clearance of LTG in combination with EIAED(s) but without VPA was therefore approximately 3 times higher than the LTG clearance with VPA but without an EIAED. When both EIAED and VPA are combined with LTG simultaneously, their effects appear to cancel each other out, resulting in an LTG clearance similar to monotherapy. The synergistic enzyme-inducing effect of multiple EIAEDs was observed only when VPA was administered concurrently. Though several previous studies had classified comedication of EIAED by the number of inducers or by the combinations of different inducers [15–18], the effect of VPA coadministration had not yet been
Fig. 1. Distribution of lamotrigine serum concentrations according to comedication group. LTG, lamotrigine; VPA, valproate; EIAED, enzyme inducing anti-epileptic drugs; NS, not significant.
identified. One possible explanation for this is that without VPA, the inducing effect of multiple EIAEDs reached a plateau; however, with coadministration of VPA, enzyme activity which had been inhibited by VPA could be further induced by multiple EIAEDs, leading to higher LTG clearance than a single EIAED. As expected, among all the patient-related variables, LTG daily dose had the most significant influence on LTG serum concentrations. Comedication of VPA or EIAED also changed LTG serum concentrations, with VPA having a greater effect than EIAED (β = 0.428 vs. − 0.289). The predictive model in this study was mostly in line with a previous research [6], although the previous model found that age was a contributing factor, while our study showed that gender and age were not related to serum LTG levels. In addition, EIAEDs were not differentiated in this study, while the previous study evaluated each EIAED separately. The model fit in this study was better than the previous study in that it had a higher r2 (0.541 vs. 0.38). LTG clearance observed in Korean epilepsy patients in our study was generally lower than LTG clearance in Caucasians [6–8], which is similar to a previous study that found that LTG clearance in Japanese subjects was lower than Caucasians [15]. In the present study, concomitant administration of VPA reduced LTG clearance by approximately 36%. Compared to our study, previous studies conducted mostly in Caucasian populations reported higher LTG clearance in monotherapy and a 50 to 60% reduction in LTG clearance after coadministration of LTG and VPA [6–8,19]. On the other hand, EIAEDs increased LTG clearance by approximately 80%, which is similar to the aforementioned studies conducted in Caucasian populations [7,19]. The overall clinical significance of LTG serum concentrations has been demonstrated recently, with LTG tolerability highly correlated with LTG serum concentration [20]. In the present study, adverse effects requiring a dose reduction or discontinuation were uncommon in patients with the upper level of LTG (N14 mg/l). Moreover, in three patients with high levels of LTG, a further increase of LTG dose or addon of other AED was done without significant side effects. This finding suggests that although the generally accepted target range is 3 to 14 mg/l, higher levels above 14 mg/l are often tolerated and can lead to additional efficacy in patients with refractory epilepsy. The present study was a retrospective cohort study, and thus the day of assessment of serum LTG levels varied from patient to patient and the cumulative effect of LTG dosing may have affected the results. This study was also limited in the lack of detailed information about oral contraceptive use although the rate of contraceptive pill use is very low in Korean epilepsy patients. The effect of oral contraceptives on LTG clearance has been demonstrated, with LTG serum levels decreased by greater than 50% in patients comedicated with oral contraceptives [21]. Despite these limitations, the authors believe that the findings presented here have meaningful implications for the clinical interpretation of LTG serum levels. The present study identified the effect of AED comedication on LTG clearance and created a pharmacokinetic profile of LTG in Korean adult epilepsy patients. The findings of our study suggest that VPA or EIAED comedication significantly influences LTG clearance, and therefore should be considered when determining LTG dosage.
14
0.053 ± 0.034 9
0.038 ± 0.019
94
0.050 ± 0.036 52
0.021 ± 0.008
0.808 2 or more
VPA
EIAED = enzyme inducing antiepileptic drug; VPA = valproate; CL = clearance; PB = phenobarbital; CBZ = carbamazepine; PH = phenytoin. ⁎ Comparison between one EIAED coadministration and multiple EIAED coadministration.
. 0.029 ± 0.013 0.047 0.040 ± 0.022 0.022 ± 0.008 0.018 ± 0.010
0.022 ± 0.006
0.048 0 0.094 ± 0.046 2 0.049 ± 0.031 1 0.047 ± 0.022 38 0.054 ± 0.038 9
0.061 ± 0.068 5
0.031 ± 0.015 6
1 2 9 2 17 70 7
Number of patients CL, l/Kg/h Number of patients CL, l/Kg/h No VPA
Number of coadministered EIAEDs
1 PB + CBZ + PH
Fig. 2. Correlation between dose and concentration of lamotrigine. LTG, lamotrigine; VPA, valproate; EIAED, enzyme inducing anti-epileptic drugs.
CBZ + PH PB + PH PB + CBZ PH CBZ PB
Comedication
Table 3 Summary of lamotrigine clearance for each EIAED coadministration.
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Abbreviations AED antiepileptic-drug CBZ carbamazepine CL clearance Css concentration at steady state EIAED enzyme-inducing antiepileptic-drug LTG lamotrigine PH phenytoin PH phenytoin VPA valproate Acknowledgment This study was supported by a grant from Samsung Biomedical Research Institute (GL1B22111). References [1] French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs, II: treatment of refractory epilepsy: report of the TTA and QSS Subcommittees of the American Academy of Neurology and the American Epilepsy Society. Epilepsia 2004;45:410–23. [2] French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs, I: treatment of new-onset epilepsy: report of the TTA and QSS Subcommittees of the American Academy of Neurology and the American Epilepsy Society. Epilepsia 2004;45:401–9. [3] Charles L. Drug information handbook. 17th ed. American Pharmaceutical Association: Washington, D.C.; 2008. [4] Hurley SC. Lamotrigine update and its use in mood disorders. Ann Pharmacother 2002;36:860–73. [5] Magdalou J, Herber R, Bidault R, Siest G. In vitro N-glucuronidation of a novel antiepileptic drug, lamotrigine, by human liver microsomes. J Pharmacol Exp Ther 1992;260: 1166–73. [6] Weintraub D, Buchsbaum R, Resor Jr SR, Hirsch LJ. Effect of antiepileptic drug comedication on lamotrigine clearance. Arch Neurol 2005;62:1432–6. [7] Almeida AM, Falcao AC, Sales F, Baldeiras I, Rocha MJ, Caramona MM. Lamotrigine pharmacokinetic evaluation in epileptic patients submitted to VEEG monitoring. Eur J Clin Pharmacol 2006;62:737–42. [8] Kanner AM, Frey M. Adding valproate to lamotrigine: a study of their pharmacokinetic interaction. Neurology 2000;55:588–91. [9] Fitton A, Goa KL. Lamotrigine. An update of its pharmacology and therapeutic use in epilepsy. Drugs 1995;50:691–713. [10] Sander JW, Trevisol-Bittencourt PC, Hart YM, Patsalos PN, Shorvon SD. The efficacy and long-term tolerability of lamotrigine in the treatment of severe epilepsy. Epilepsy Res 1990;7:226–9. [11] Kilpatrick ES, Forrest G, Brodie MJ. Concentration–effect and concentration–toxicity relations with lamotrigine: a prospective study. Epilepsia 1996;37:534–8. [12] Brodie MJ. Lamotrigine. Lancet 1992;339:1397–400. [13] Morris RG, Lee MY, Cleanthous X, Black AB. Long-term follow-up using a higher target range for lamotrigine monitoring. Ther Drug Monit 2004;26:626–32. [14] Morris RG, Black AB, Harris AL, Batty AB, Sallustio BC. Lamotrigine and therapeutic drug monitoring: retrospective survey following the introduction of a routine service. Br J Clin Pharmacol 1998;46:547–51. [15] Yamamoto Y, Inoue Y, Matsuda K, Takahashi Y, Kagawa Y. Influence of concomitant antiepileptic drugs on plasma lamotrigine concentration in adult Japanese epilepsy patients. Biol Pharm Bull 2012;35:487–93.
H.-J. Kim et al. / Clinica Chimica Acta 438 (2015) 269–273 [16] Gidal BE, Anderson GD, Rutecki PR, Shaw R, Lanning A. Lack of an effect of valproate concentration on lamotrigine pharmacokinetics in developmentally disabled patients with epilepsy. Epilepsy Res 2000;42:23–31. [17] Armijo JA, Bravo J, Cuadrado A, Herranz JL. Lamotrigine serum concentration-to-dose ratio: influence of age and concomitant antiepileptic drugs and dosage implications. Ther Drug Monit 1999;21:182–90. [18] Hussein Z, Posner J. Population pharmacokinetics of lamotrigine monotherapy in patients with epilepsy: retrospective analysis of routine monitoring data. Br J Clin Pharmacol 1997;43:457–65.
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[19] Bootsma HP, Vos AM, Hulsman J, et al. Lamotrigine in clinical practice: long-term experience in patients with refractory epilepsy referred to a tertiary epilepsy center. Epilepsy Behav 2008;12:262–8. [20] Hirsch LJ, Weintraub D, Du Y, et al. Correlating lamotrigine serum concentrations with tolerability in patients with epilepsy. Neurology 2004;63:1022–6. [21] Sabers A, Ohman I, Christensen J, Tomson T. Oral contraceptives reduce lamotrigine plasma levels. Neurology 2003;61:570–1.
Contents lists available at ScienceDirect
Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim
Effect of comedication on lamotrigine clearance in Korean epilepsy patients Hee-Jung Kim a,1, Tae-Eun Kim b,d,1, Eun Yeon Joo c, Dae-Won Seo c,⁎, Soo-Youn Lee a,b,⁎⁎, Seung Bong Hong c a
Department of Laboratory Medicine & Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea Department of Clinical Pharmacology & Therapeutics, Samsung Medical Center, Seoul, Republic of Korea Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Seoul, Republic of Korea d Department of Clinical Pharmacology, Konkuk University Medical Center, Seoul, Republic of Korea b c
a r t i c l e
i n f o
Article history: Received 23 June 2014 Received in revised form 2 September 2014 Accepted 2 September 2014 Available online 8 September 2014 Keywords: Epilepsy Comedication Korean Lamotrigine Pharmacokinetics Clearance
a b s t r a c t Background: Lamotrigine (LTG) is a widely used antiepileptic-drug (AED) for the treatment of epilepsy. We investigated the effect of AED comedication on LTG clearance in Korean patients with epilepsy. Methods: The authors reviewed the medical charts for all patients ≥ 18 years who have received LTG as monotherapy or adjunctive therapy. Data collected included LTG levels, dosage, treatment duration, concomitant AEDs and specific side effects. LTG clearance was estimated according to comedication. Results: A total of 580 blood samples from 548 patients were analyzed. LTG clearance in the enzyme-inducing AED (EIAED) coadministration group was the highest (0.050 l/kg/h), followed by the LTG monotherapy group (0.028 l/kg/h), the coadministration group of both valproate (VPA) and EIAED (0.024 l/kg/h) and the VPA coadministration group (0.018 l/kg/h). When LTG was administered with both VPA and EIAED, the multiple EIAED group had higher LTG clearance than the single EIAED group. Conclusions: Concomitant administration of valproate reduced LTG clearance by approximately 35%, while EIAEDs increased LTG clearance by 80%. These relationships indicate the importance of considering the effects of comedication on LTG clearance when determining LTG dosage. © 2014 Published by Elsevier B.V.
1. Introduction Lamotrigine (LTG) is a widely used antiepileptic drug (AED) for the treatment of new-onset as well as refractory epilepsy [1,2]. LTG was introduced as adjunctive treatment for partial seizures in Europe in 1991 and in the United States in 1994. At the present time, it is indicated as adjunctive therapy in the treatment of Lennox–Gastaut syndrome, generalized seizures, and partial seizures in adults and children 2 years and older, and as monotherapy in adults with partial seizures [3]. Furthermore, there is an increasing interest in its properties for treating bipolar disorders [4]. LTG is metabolized mainly in the liver by glucuronidation and excreted renally as a glucuronide conjugate [5]. The coadministration of hepatic enzyme-inducing AED (EIAED), such as phenytoin, carbamazepine, phenobarbital or primidone, significantly increases the systemic clearance of LTG [6,7], while valproate (VPA), a known inhibitor of glucuronidation, significantly reduces the elimination of LTG [6–8]. LTG is rapidly absorbed and reaches peak serum concentrations 1 to 5 h after administration [3]. The mean half-life of LTG ranges from ⁎ Corresponding author. ⁎⁎ Correspondence to: S.-Y. Lee, Department of Laboratory Medicine & Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 135-710, Republic of Korea. Tel: +82 2 3410 2702; fax: +82 2 3410 2719. E-mail address: [email protected] (S.-Y. Lee). 1 These authors contributed equally to this work.
http://dx.doi.org/10.1016/j.cca.2014.09.004 0009-8981/© 2014 Published by Elsevier B.V.
25 to 33 h in healthy volunteers taking only LTG, 59 to 70 h in healthy volunteers comedicated with VPA, and 13 to 14 h in patients comedicated with an EIAED [3]. Although plasma LTG levels are described in many publications, a therapeutic range for LTG is not well established. Therapeutic serum concentrations range from 1–3 mg/l or 1–4 mg/l were originally proposed based on preclinical data [9–11]. However, later studies suggested that these concentrations may have been too low, and showed that some patients tolerated concentrations above 10 mg/l with greater efficacy and without clinical toxicity [12]. Morris et al. advised a plasma LTG level of 3–14 mg/l [13,14]. 2. Materials and methods 2.1. Patients This study was approved by the medical ethics committee for Samsung Medical Center. The authors reviewed the medical charts for all patients ≥ 18 years seen at the Epilepsy Center in the Samsung Medical Center, who received LTG as monotherapy or adjunctive therapy and had their weight and LTG serum concentrations levels recorded. Patients who were being titrated or who were noncompliant were excluded from the study, as were patients with levels below the quantification limit, as it suggested potential noncompliance. The patients with hepatic or renal dysfunction were also excluded.
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H.-J. Kim et al. / Clinica Chimica Acta 438 (2015) 269–273
2.2. Serum LTG concentrations
3.2. Effect of comedication on the pharmacokinetics of lamotrigine
AED blood levels were obtained for every patient at least 10 h after dose administration. Patients were treated with stable doses for a period of at least 3 weeks before blood levels were obtained. When N 1 LTG level was observed in a patient while taking the same drug combination and LTG dosage, the levels were averaged. Serum LTG concentrations were measured by high-performance liquid chromatography (Agilent 1200 Series, Agilent) and with a Chromsystems kit. The linear assay range was 0.5–50 mg/l (r2 N 0.99). The intra- and inter-assay imprecisions were coefficients of variation less than 10%. The weight-corrected hourly rate of clearance was calculated as follows:
3. Results
All patients were divided into subgroups based on comedication. LTG monotherapy group, LTG plus VPA group, LTG plus both EIAED and VPA group and LTG plus EIAED group included 248, 131, 61 and 108 patients, respectively. LTG doses were not significantly different among 4 subgroups except for between LTG plus VPA group and LTG plus EIAED group (p = 0.016) (Table 2). LTG clearance was significantly different between the groups; LTG clearance in the EIAED coadministration group was the highest, followed by the LTG monotherapy group and the combination group of VPA and EIAED. The LTG clearance was the lowest in the LTG and VPA combination group (Table 2). The mean LTG clearance of the VPA coadministration group (0.018 l/kg/h) was significantly lower than the LTG monotherapy group (0.028 l/kg/h), while the EIAED coadministration group (0.050 l/kg/h) showed significantly higher LTG clearance than the LTG monotherapy group. However, the mean LTG clearance of the VPA and EIAED coadministration group (0.024 l/kg/h) was not significantly different from that of the LTG monotherapy group. In addition, although the mean LTG clearance of the VPA and EIAED coadministration group was higher than the VPA coadministration group (0.018 l/kg/h), this difference was not significant (Table 2, Fig. 1). For EIAED coadministration groups with or without VPA, LTG clearances were analyzed according to each EIAED and compared according to the number of coadministered EIAEDs (Table 3). When a single EIAED was coadministered, phenytoin exhibited the highest increase of LTG clearance followed by carbamazepine and phenobarbital. However, the effects of phenytoin were not distinguishable from other EIAEDs when multiple EIAEDs were coadministered. When comparing LTG clearance according to the number of EIAEDs, different results were observed depending on whether or not VPA was administered concurrently. When EIAED was coadministered without VPA, there was no significant difference in LTG clearance between the single EIAED group and the multiple EIAED group. However, when both EIAEDs and VPA were administered with LTG, the LTG clearance of the multiple EIAED group was significantly higher than that of the single EIAED group.
3.1. Patient demographics and pharmacokinetic parameters
3.3. Predictive model of LTG serum concentrations
A total of 580 blood samples from 548 patients were obtained, yielding 548 LTG levels for analysis. The patient group consisted of 251 males and 297 females with a mean age of 34.9 ± 12.8 years (range 18.0–83.2) and mean weight of 63.6 ± 12.5 kg (range 35.8–117.4) (Table 1). The average LTG dose and treatment period were 2.98 mg/kg/day and 627 days, respectively. All patients were treated for N 21 days to ensure steady-state. The mean concentration at steady state (Css) was 5.57 ± 3.91 mg/l and the mean clearance was 0.030 ± 0.029 l/kg/h (Table 1).
LTG daily dose, body weight and comedication of VPA and EIAED were predictors of LTG serum concentration. Age and sex did not appear to impact LTG levels. LTG daily dose was the most significant predictor of LTG serum concentration (β = 0.570, Fig. 2), followed by comedication of VPA (β = 0.428), EIAED (β = −0.289) and body weight (β = 0.021). The final model is shown below, with an r2 = 0.541: LTG serum concentration = 4.397–0.049 ∗ body weight + 0.021 ∗ daily LTG dose + 3.6 ∗ CMVPA − 2.516 ∗ CMEIAED
CL ðl=kg=hÞ ¼ weight−adjusted daily dose ðmg=kgÞ= ðsteady state serum concentration Þðmg=lÞ 24 ðhÞÞ: 2.3. Statistical analysis Four treatment groups were established to investigate each AED comedication effect: LTG monotherapy group, LTG plus VPA group, LTG plus both EIAED and VPA group and LTG plus EIAED group. LTG daily doses, steady-state concentrations and clearances were analyzed according to treatment group, and LTG clearances were compared between treatment groups using an ANOVA test and adjusting for multiplicity with the Tukey method. The Mann–Whitney U test was used to compare LTG clearance between the group with one EIAED coadministration and the group with multiple EIAED coadministration. A predictive model for LTG serum concentration was created using multiple regression analysis, with daily dose of LTG, age, weight, and comedication of VPA or EIAED as independent variables. The model estimation proceeded backwards. IBM SPSS Statistics™ 21 (Datasolution Inc., ver 21) was used for statistical analysis with a 2-sided level of statistical significance set at 0.05.
Table 1 Summary of patient characteristics.
3.4. Toxic effects of high levels of LTG
Number of patients
548
Female/male Age (year)⁎ Body weight (kg)⁎ LTG Dose (mg/kg/day)⁎ LTG treatment period (days)⁎
297/251 34.9 ± 12.8 63.6 ± 12.5 2.98 ± 1.86 627 ± 653
Number of patients according to type of epilepsy Localization-related Generalized Undetermined whether focal or generalized
391 123 34
LTG = Lamotrigine. ⁎ Mean ± SD.
- CMVPA: 1 if VPA was coadministered and 0 if VPA was not coadministered - CMEIAED: 1 if any EIAED was coadministered and 0 if no EIAEDs were coadministered.
Of the 548 patients in this study, 22 patients had LTG levels N 14 mg/l (range, 14.1–27.9 mg/l) (data not shown). Among these patients, 2 patients experienced side effects of LTG. One patient with an LTG level of 15.0 mg/l developed tremors, thus the LTG dose was reduced. Another patient with 16.9 mg/l developed mild tremors, which did not lead to a dosage change or discontinuation of LTG. On the other hand, three patients with LTG levels of 15.7, 20.0 and 27.9 mg/l did not have any side effects, but their seizures were not well-controlled. Thus, their dosage of LTG was increased or another antiepileptic drug was added to their treatment. Meanwhile, four out of 526 patients with lower LTG levels also experienced side effects of headache, nausea, vomiting and tremor.
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Table 2 Summary of lamotrigine pharmacokinetic parameters. Parameters
All data
Number of patients Dose LTG, mg/kg/day⁎ Css, mg/l⁎ CL, l/Kg/h⁎
548 2.98 ± 1.86 5.57 ± 3.91 0.030 ± 0.029
Treatment group LTG
LTG + VPA
LTG + VPA + EIAED
LTG + EIAED
248 2.95 ± 1.99 4.99 ± 3.19 0.028 ± 0.019
131 2.71 ± 1.56 8.46 ± 4.73 0.018 ± 0.034
61 2.85 ± 1.50 5.65 ± 3.39 0.024 ± 0.012
108 3.43 ± 2.04 3.36 ± 2.23 0.050 ± 0.035
0.025 b0.001 b0.001
LTG = lamotrigine; Css = concentration at steady state; CL = clearance; VPA = valproate; EIAED = enzyme-inducing anti-epileptic drugs. ⁎ Mean ± SD.
4. Discussion The present study found that the combination of LTG and VPA decreased LTG clearance by 36% compared to LTG monotherapy. When one or more of EIAEDs were combined with LTG, LTG clearance increased by approximately 80%. The clearance of LTG in combination with EIAED(s) but without VPA was therefore approximately 3 times higher than the LTG clearance with VPA but without an EIAED. When both EIAED and VPA are combined with LTG simultaneously, their effects appear to cancel each other out, resulting in an LTG clearance similar to monotherapy. The synergistic enzyme-inducing effect of multiple EIAEDs was observed only when VPA was administered concurrently. Though several previous studies had classified comedication of EIAED by the number of inducers or by the combinations of different inducers [15–18], the effect of VPA coadministration had not yet been
Fig. 1. Distribution of lamotrigine serum concentrations according to comedication group. LTG, lamotrigine; VPA, valproate; EIAED, enzyme inducing anti-epileptic drugs; NS, not significant.
identified. One possible explanation for this is that without VPA, the inducing effect of multiple EIAEDs reached a plateau; however, with coadministration of VPA, enzyme activity which had been inhibited by VPA could be further induced by multiple EIAEDs, leading to higher LTG clearance than a single EIAED. As expected, among all the patient-related variables, LTG daily dose had the most significant influence on LTG serum concentrations. Comedication of VPA or EIAED also changed LTG serum concentrations, with VPA having a greater effect than EIAED (β = 0.428 vs. − 0.289). The predictive model in this study was mostly in line with a previous research [6], although the previous model found that age was a contributing factor, while our study showed that gender and age were not related to serum LTG levels. In addition, EIAEDs were not differentiated in this study, while the previous study evaluated each EIAED separately. The model fit in this study was better than the previous study in that it had a higher r2 (0.541 vs. 0.38). LTG clearance observed in Korean epilepsy patients in our study was generally lower than LTG clearance in Caucasians [6–8], which is similar to a previous study that found that LTG clearance in Japanese subjects was lower than Caucasians [15]. In the present study, concomitant administration of VPA reduced LTG clearance by approximately 36%. Compared to our study, previous studies conducted mostly in Caucasian populations reported higher LTG clearance in monotherapy and a 50 to 60% reduction in LTG clearance after coadministration of LTG and VPA [6–8,19]. On the other hand, EIAEDs increased LTG clearance by approximately 80%, which is similar to the aforementioned studies conducted in Caucasian populations [7,19]. The overall clinical significance of LTG serum concentrations has been demonstrated recently, with LTG tolerability highly correlated with LTG serum concentration [20]. In the present study, adverse effects requiring a dose reduction or discontinuation were uncommon in patients with the upper level of LTG (N14 mg/l). Moreover, in three patients with high levels of LTG, a further increase of LTG dose or addon of other AED was done without significant side effects. This finding suggests that although the generally accepted target range is 3 to 14 mg/l, higher levels above 14 mg/l are often tolerated and can lead to additional efficacy in patients with refractory epilepsy. The present study was a retrospective cohort study, and thus the day of assessment of serum LTG levels varied from patient to patient and the cumulative effect of LTG dosing may have affected the results. This study was also limited in the lack of detailed information about oral contraceptive use although the rate of contraceptive pill use is very low in Korean epilepsy patients. The effect of oral contraceptives on LTG clearance has been demonstrated, with LTG serum levels decreased by greater than 50% in patients comedicated with oral contraceptives [21]. Despite these limitations, the authors believe that the findings presented here have meaningful implications for the clinical interpretation of LTG serum levels. The present study identified the effect of AED comedication on LTG clearance and created a pharmacokinetic profile of LTG in Korean adult epilepsy patients. The findings of our study suggest that VPA or EIAED comedication significantly influences LTG clearance, and therefore should be considered when determining LTG dosage.
14
0.053 ± 0.034 9
0.038 ± 0.019
94
0.050 ± 0.036 52
0.021 ± 0.008
0.808 2 or more
VPA
EIAED = enzyme inducing antiepileptic drug; VPA = valproate; CL = clearance; PB = phenobarbital; CBZ = carbamazepine; PH = phenytoin. ⁎ Comparison between one EIAED coadministration and multiple EIAED coadministration.
. 0.029 ± 0.013 0.047 0.040 ± 0.022 0.022 ± 0.008 0.018 ± 0.010
0.022 ± 0.006
0.048 0 0.094 ± 0.046 2 0.049 ± 0.031 1 0.047 ± 0.022 38 0.054 ± 0.038 9
0.061 ± 0.068 5
0.031 ± 0.015 6
1 2 9 2 17 70 7
Number of patients CL, l/Kg/h Number of patients CL, l/Kg/h No VPA
Number of coadministered EIAEDs
1 PB + CBZ + PH
Fig. 2. Correlation between dose and concentration of lamotrigine. LTG, lamotrigine; VPA, valproate; EIAED, enzyme inducing anti-epileptic drugs.
CBZ + PH PB + PH PB + CBZ PH CBZ PB
Comedication
Table 3 Summary of lamotrigine clearance for each EIAED coadministration.
0.004
H.-J. Kim et al. / Clinica Chimica Acta 438 (2015) 269–273 p-Value⁎
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Abbreviations AED antiepileptic-drug CBZ carbamazepine CL clearance Css concentration at steady state EIAED enzyme-inducing antiepileptic-drug LTG lamotrigine PH phenytoin PH phenytoin VPA valproate Acknowledgment This study was supported by a grant from Samsung Biomedical Research Institute (GL1B22111). References [1] French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs, II: treatment of refractory epilepsy: report of the TTA and QSS Subcommittees of the American Academy of Neurology and the American Epilepsy Society. Epilepsia 2004;45:410–23. [2] French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs, I: treatment of new-onset epilepsy: report of the TTA and QSS Subcommittees of the American Academy of Neurology and the American Epilepsy Society. Epilepsia 2004;45:401–9. [3] Charles L. Drug information handbook. 17th ed. American Pharmaceutical Association: Washington, D.C.; 2008. [4] Hurley SC. Lamotrigine update and its use in mood disorders. Ann Pharmacother 2002;36:860–73. [5] Magdalou J, Herber R, Bidault R, Siest G. In vitro N-glucuronidation of a novel antiepileptic drug, lamotrigine, by human liver microsomes. J Pharmacol Exp Ther 1992;260: 1166–73. [6] Weintraub D, Buchsbaum R, Resor Jr SR, Hirsch LJ. Effect of antiepileptic drug comedication on lamotrigine clearance. Arch Neurol 2005;62:1432–6. [7] Almeida AM, Falcao AC, Sales F, Baldeiras I, Rocha MJ, Caramona MM. Lamotrigine pharmacokinetic evaluation in epileptic patients submitted to VEEG monitoring. Eur J Clin Pharmacol 2006;62:737–42. [8] Kanner AM, Frey M. Adding valproate to lamotrigine: a study of their pharmacokinetic interaction. Neurology 2000;55:588–91. [9] Fitton A, Goa KL. Lamotrigine. An update of its pharmacology and therapeutic use in epilepsy. Drugs 1995;50:691–713. [10] Sander JW, Trevisol-Bittencourt PC, Hart YM, Patsalos PN, Shorvon SD. The efficacy and long-term tolerability of lamotrigine in the treatment of severe epilepsy. Epilepsy Res 1990;7:226–9. [11] Kilpatrick ES, Forrest G, Brodie MJ. Concentration–effect and concentration–toxicity relations with lamotrigine: a prospective study. Epilepsia 1996;37:534–8. [12] Brodie MJ. Lamotrigine. Lancet 1992;339:1397–400. [13] Morris RG, Lee MY, Cleanthous X, Black AB. Long-term follow-up using a higher target range for lamotrigine monitoring. Ther Drug Monit 2004;26:626–32. [14] Morris RG, Black AB, Harris AL, Batty AB, Sallustio BC. Lamotrigine and therapeutic drug monitoring: retrospective survey following the introduction of a routine service. Br J Clin Pharmacol 1998;46:547–51. [15] Yamamoto Y, Inoue Y, Matsuda K, Takahashi Y, Kagawa Y. Influence of concomitant antiepileptic drugs on plasma lamotrigine concentration in adult Japanese epilepsy patients. Biol Pharm Bull 2012;35:487–93.
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