- Email: [email protected]
The efficacy of gabapentin in children of partial seizures and the blood levels
Brain & Development 36 (2014) 194–202 www.elsevier.com/locate/braindev
Original article
The efficacy of gabapentin in children of partial seizures and the blood levels Yutaka Nonoda, Toshiyuki Iwasaki ⇑, Masahiro Ishii Department of Pediatrics, Kitasato University School of Medicine, Kanagawa, Japan Received 17 November 2012; received in revised form 26 March 2013; accepted 6 April 2013
Abstract Aim: To evaluate the long-term efficacy of gabapentin (GBP) and usefulness of measurement of the blood level for the observation of patients that have partial seizures. Methods: Thirty patients (20 effective cases and 10 ineffective cases) treated with GBP for the localization related epilepsy had their peak blood levels of GBP. The levels were measured seven time points, one, 6, 12, 18, 24, 30, and 36 month after the start of medication. The efficacy of GBP was evaluated at one month after the initiation of medication and every year for 3 years, based on the R Ratio and the degree of improvement for the paroxysmal strength and length. Results: GBP levels were higher in the effective cases than the levels in the ineffective cases 6 months after and 1 year after the initiation of medication (p < 0.05). The level 6 months after the start in the effective cases was 5.429 ± 2.384 lg/ml (mean ± SD), and 5.837 ± 3.217 lg/ml after 1 year. The cases that were effective for 1 year maintained approximately the same efficacy for 3 years after the initiation of medication, but there was no correlation between the level and the R Ratio, paroxysmal strength and length. Conclusions: No precise definition of the therapeutic range was recognized because of no correlation between GBP level and the improvement of clinical manifestations. We recommend the GBP optimal range that is established the range within 3–8 lg/ml (mean; 5 lg/ml) as therapeutic target without the side effect. Ó 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. Keywords: Antiepileptic drug; Localization related epilepsy; Paroxysmal strength and length; Response ratio; Optimal range
1. Introduction Gabapentin (GBP) was composed in Germany in 1973. GBP has been administered as an antiepileptic drug (AED) for children with partial seizures in many European countries and America since 1999. It was approved for children in Japan in 2011. It was initially introduced as an AED and was later found to be effective in treating some chronic pain syndromes [1,2]. The
⇑ Corresponding author. Address: Department of Pediatrics, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252–0374, Japan. Tel.: +81 42 778 8111; fax: +81 42 778 8441. E-mail address: [email protected] (T. Iwasaki).
bodyweight gain [3,4] and visual dysfunction [5] observed with the use of GBP seem to be side effects. Moreover, rare cases of overdose-related adverse effects [6] and withdrawal symptoms [7] have been reported. However, neither reference included statements about relationships between blood levels and side effects. No research was found referring to the appearance of side effects with increased blood levels. GBP is a hydrophilic analog of c-aminobutyearic acid (GABA), which is transported across the blood–brain barrier, and is one of the inhibitory neurotransmitters of the mammalian central nervous system [8–17]. Various of published methods for analysis of GBP in human serum have been reported [18–23]. GBP is rapidly absorbed, with a time to peak blood level of 2–3 h and
0387-7604/$ - see front matter Ó 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.braindev.2013.04.006
Y. Nonoda et al. / Brain & Development 36 (2014) 194–202
is not metabolized and the unchanged drug is directly excreted via the kidney with a half-life of 5–8 h. GBP does not influence the blood level of other drugs for combination therapy [24], because it has no mechanism of induction and inhibition of drug metabolizing enzymes in the liver, like other AEDs [11,14,16,17,24]. The efficacy of GBP has been reported in many countries [8–11,13–17,21,22,24]. However the appropriate blood level of GBP has not been established. In addition, no evaluation of the use of GBP for pediatric epilepsy patients has been reported. We therefore thought that effective evaluation and an index to minimize the risk of side effects were required for safe medication with GBP. Thirty patients that experienced partial seizures and were medicated with GBP, were observed in this study. The long-term efficacy of GBP and usefulness of the measurement of the blood level, were evaluated.
195
2. Methods
blood level and electroencephalogram were performed repeatedly every 6 months. The subject included 20 effective cases that were cured with GBP, and 10 cases that discontinued administration. The effective case showed an improvement in the paroxysmal strength and length and/or an approximation of the response ratio (R Ratio) to 1. On the other hand, a discontinued case was defined as a patient that took GBP for more than 1 year with no improvement in their symptoms. These did not include cases that discontinued or tapered GBP therapy due to side effects or other malfunction. Therefore, the subjects were classified as 20 effective cases and 10 ineffective cases (Table 1). The initial dosage of GBP was 10 mg/kg/day and the dosage was increased by 10 mg/kg/day for 2 days. The maintenance dosage was 30 mg/kg/day; otherwise it could increase to 40 mg/kg/day if the effect of treatment was insufficient. However, the adjusted the dosage was limited to 1200 mg/day.
2.1. Patient selection and treatment
2.2. Study design
Thirty patients (16 males and 14 females; ranging from 2.4 to 18 years of age; mean, 9.1 years) that were administered GBP to treat localization related epilepsy in pediatrics of Kitasato University hospital between November 2006 and December 2010, were selected. These patients included 17 cryptogenic cases and 13 symptomatic cases and were randomly selected in a prospective study. Eligible patients were diagnosed to have localization related epilepsy based on their clinical seizure type, electroencephalogram (EEG) and either cranial computed tomography (CT) or magnetic resonance imaging (MRI). Measurement of the GBP
The blood levels of GBP were measured regularly in this study. The patients’ blood was sampled at the pediatric outpatient clinic and measured by high performance liquid chromatography in laboratory (SRL, Inc., Tokyo, Japan). Blood samples to measure the concentration of GBP was obtained after 2–3 h after the administration GBP. The blood level was measured seven times at 1 month after the start of medication and 6, 12, 18, 24, 30, and 36 months after. A minimum sample of 0.2 mL serum was frozen at 20 °C and saved. The efficacy of GBP evaluated four times at 1 month after and 1–3 years after, to determine the R Ratio and the degree of improvement for the paroxysmal strength and length.
Table 1 Patient characteristics. *
Effective cases
Ineffective cases
N (cases) Female Male
20 9 11
10 5 5
Age (year) Body weight (kg) Periods before starting the medication (year) Dosage of GBP
9.22 ± 5.01 30.60 ± 19.08 4.62 ± 3.40
8.76 ± 3.91 26.19 ± 10.64 4.25 ± 3.28
0.982 0.809 0.741
934.50 ± 571.85
753.00 ± 309.91
0.627
2 14 6 1 0 3 10 3 8
3 8 0 0 1 2 6 3 5
Concomitant drugs Carbamazepine Clobazam Clonazepam Lamotrigine Nitrazepam Phenytoin Sodium valproate Topilamate Zonisamide
Distribution data are the mean ± SD. * Mann–Whitney U test.
p
Response ratioðRRatioÞ ¼
T B T þB
B; paroxysmal frequency for 28 days before the evaluation timing. T; paroxysmal frequency for 28 days after the evaluation timing. The paroxysmal strength and length were evaluated with three phases of improvement, aggravation and no change. This study was performed according to the principles of the Declaration of Helsinki. The objective of the study and the therapeutic efficacy and safety were explained to the patients’ parents, and they provided their written informed consent. 2.3. Statistical analysis The correlations between the parameters (GBP blood level, R Ratio, paroxysmal strength and length) were
196
Y. Nonoda et al. / Brain & Development 36 (2014) 194–202
analyzed. The statistical analysis was performed using the nonparametric test or Spearman’s rank correlation coefficient, the Mann–Whitney U test for two different comparisons and the Wilcoxon signed rank test between two groups to determine the significance of the correlation. Excel Statistics 2010 (Social Survey Research Information Co., Ltd., Tokyo, Japan) that added to Microsoft Excel software programs was used for the analyses. 3. Results 3.1. Comparison between the effective cases and the ineffective cases The background of each patient, the dosage of GBP and concomitant AEDs are shown in Table 1.
There were no significant differences in the age and body weight between the effective cases and the ineffective cases. Furthermore, the two groups show consistent age dispersion. Moreover, no differences were recognized in the periods before starting the medication and dosage of GBP. Therefore, no significant differences were observed in the populations of the effective group and the ineffectiveness group. Furthermore, there was almost no difference between two groups in the type and number of concomitant drugs. Fig. 1 shows a comparison of the GBP blood level between the effective cases and the ineffective cases within 1 year. There were significant differences in the blood levels between 6 months and 1 year after the initiation of GBP (p < 0.05).
Fig. 1. Comparisons of the GBP blood level between the effective cases and the ineffective cases (*p < 0.05). The comparison showed significant differences based on the Mann–Whitney U test at 6 months (p = 0.039) and 1 year (p = 0.029). Table 2 Comparison of the results in effective cases. Cases
Age at starting GBP
Periods before starting the medication
Female
Male
*
<6 year old
P6 year old
*
<5 year
P5 year
*
Blood level 1m 6m 1 year 1 year 6 m 2 year 2 year 6 m 3 year
4.394 ± 1.674 5.319 ± 2.440 5.763 ± 2.990 6.674 ± 2.935 6.942 ± 2.324 6.511 ± 2.551 5.880 ± 2.396
5.018 ± 1.450 5.519 ± 2.454 5.896 ± 3.539 5.895 ± 2.087 6.019 ± 3.588 6.657 ± 3.105 6.387 ± 3.695
0.184 0.909 0.970 0.305 0.184 0.909 0.970
3.765 ± 1.614 3.288 ± 1.095 3.438 ± 1.261 4.667 ± 2.455 4.712 ± 1.601 5.402 ± 2.255 4.497 ± 1.815
5.154 ± 1.366 6.346 ± 2.197 6.864 ± 3.275 6.922 ± 2.219 7.167 ± 3.260 7.101 ± 2.922 6.8714 ± 3.323
0.138 0.150 0.138 0.138 0.150 0.138 0.117
4.848 ± 1.689 5.102 ± 2.281 5.164 ± 2.862 6.116 ± 2.690 6.209 ± 2.364 6.588 ± 2.553 6.086 ± 2.465
4.602 ± 1.439 5.829 ± 2.583 6.659 ± 3.600 6.404 ± 2.312 6.701 ± 3.859 6.596 ± 3.228 6.249 ± 3.918
0.620 0.836 0.409 0.804 0.970 0.790 0.621
R Ratio 1m 1 year 2 year 3 year
0.335 ± 0.499 0.372 ± 0.432 0.339 ± 0.423 0.422 ± 0.474
0.377 ± 0.496 0.592 ± 0.456 0.370 ± 0.596 0.443 ± 0.565
0.898 0.284 0.697 0.755
0.024 ± 0.058 0.397 ± 0.397 0.400 ± 0.420 0.400 ± 0.420
0.501 ± 0.518 0.534 ± 0.476 0.337 ± 0.561 0.448 ± 0.562
0.064 0.546 0.800 0.735
0.455 ± 0.522 0.589 ± 0.446 0.565 ± 0.457 0.636 ± 0.461
0.240 ± 0.434 0.375 ± 0.447 0.100 ± 0.478 0.189 ± 0.486
0.138 0.262 0.042 0.150
Distribution data are the mean ± SD * Mann–Whitney U test.
p
p
p
Y. Nonoda et al. / Brain & Development 36 (2014) 194–202
3.2. Details of the effective cases Sex, “age at the introduction of GBP” and “the period before starting the medication” were compared of the GBP blood level and R Ratio (Table 2). There were no significant differences due to sex in the GBP blood level at any time of sampling. The blood level had a tendency to be lower in those that started GBP at a lower age; however it was not significant. Alternatively, the blood level was not affected by the timing of taking other AEDs. The start of AED therapy (especially GBP) was expected to affect the efficacy; however, no significant difference in the R Ratio was recognized. Fig. 2 shows the relationship of the number of combined medicines and the R Ratio. The effective cases in which the efficacy continued for a long term, showed no tendency to decrease the number of concomitant drugs. 3.3. Relationship between the R Ratio, GBP blood level and the time after initiation of medication, strength, length of seizure in effective cases All cases of GBP therapy maintained the efficacy (R Ratio 6 0) for 1 year; however, the results after 2 and 3 years varied (Fig. 3A). All median at each evaluation was less than 0. A comparison of the R Ratio at 1 month after initiation and evaluation times showed no significant difference. Moreover, no significant difference was recognized in either evaluation times. The longitudinal transition of the GBP blood level in effective cases is shown in Fig. 3B. The median of GBP blood levels within 1 year were approximately 5 mg/dl, the lower limit was about 3 mg/dl and the upper limit
197
varied widely. The median level after 1 year and 6 months was approximately 6 mg/dl, the lower limit was about 3 mg/dl and the upper limit was about 8 mg/dl. Furthermore, no significant difference was recognized in either time of sampling. Finally, the R Ratio and GBP blood level showed no correlation (Fig. 3C). The same dispersion was recognized in all of the evaluations from 1 month to 3 years. Fig. 4A shows the relationship between the strength of seizure and the R Ratio; moreover Fig. 4B shows the relationship between the length of seizure and the R Ratio. The R Ratio at 1 month after and 1 year after was related to the strength of seizure. The R Ratio was significantly lower in cases where the strength of seizure were improved or disappeared, in comparison to the cases with no change (Fig. 4A; 1 month after: p < 0.01, 1 year after: p < 0.05). The R Ratio was also correlated with the length of seizure. The R Ratio was significantly lower in cases whose seizures were improved or disappeared in comparison to the cases that showed no change (Fig. 4B; 1 month, 1 and 3 year after: p < 0.01, 2 year after: p < 0.05). Fig. 4C shows the relationship between the strength of seizure and the blood level. There was no significant difference between the improved or disappeared cases and those that showed no change at any time of evaluation. Similarly, the length of seizure and blood level were not related significantly. 4. Discussion Few evaluations of the GBP blood level of pediatric epilepsy patients have been reported, and the appropri-
Fig. 2. Relationship between the number of the combined medications and the R Ratio. The number of combined medicine showed no the significant difference based on the Mann–Whitney U test between cases with an R Ratio < 0 and R Ratio P 0. The number of the combined medicines showed no significant change with the clinical progress according to the Wilcoxon signed rank test.
198
Y. Nonoda et al. / Brain & Development 36 (2014) 194–202
Fig. 3. Relationship of the R Ratio, GBP blood level in the effective cases. (A) Change in the R Ratio. There was not the significant difference according to the Wilcoxon signed rank test. (B) Change in the GBP blood level. There was not the significant difference according to the Wilcoxon signed rank test. (C) Relationship between the R Ratio and GBP blood level at all evaluation points. There was no correlation at any time.
ate range of GBP concentration has not been established. Generally, few studies have described the relationships between blood level and side effects, and
descriptions of increased blood levels causing side effects appear rare. Efficacy, frequency and severity of side effects did not appear related to blood level. On the
Y. Nonoda et al. / Brain & Development 36 (2014) 194–202
199
Fig. 4. Relationship between the R Ratio, GBP blood level and strength/length of seizure in the effective cases (*p < 0.05, **p < 0.01). The significant differences of comparison were evaluated with Mann–Whitney U test. (A) Relationship between the strength of seizure and the R Ratio. There were significant differences at 1 month (p = 0.005) and 1 year (p = 0.012). (B) Relationship between the length of seizure and the R Ratio. The results of comparison showed significant differences at 1 month (p = 0.005), 1 year (p = 0.001), 2 years (p = 0.029) and 3 years (p = 0.002). (C) Relationship between the strength of seizure and the blood level. There were no significant differences.
other hand, the absence of a clear “optimal range” in patient’s dosage does not necessarily mean that the role
of TDM is not useful [17]. It was possible that the optimal plasma level varies between patients. Furthermore,
200
Y. Nonoda et al. / Brain & Development 36 (2014) 194–202
knowledge of the blood level might be useful when the patient presents an unexpected change [6] in their clinical status during follow-up [17]. The current study aimed to identify the “optimal range” of GBP. The study population in the current study showed no significant differences between the effective cases and the ineffectiveness cases in sex, need to start of GBP therapy and type of concomitant drugs (Table 1). Fig. 1 compared the blood level in the effective cases with that in the ineffective cases, and showed that the blood levels were significant different at 6 months and 1 year of treatment (p < 0.05). The GBP blood levels at 1 month showed no significant difference; however the average levels were 4.74 ± 1.55 and 3.44 ± 1.55, respectively and were higher in the effective cases. This suggested that the oral administration of GBP was consistent at the initiation of medication, but the compliance was insufficient 1 month later, because the habitual oral administration had not been established. Consequently, the blood levels of effective cases were higher than the levels of ineffective cases from 6 month after the start of GBP medication. The results of the blood level varied, but the fixed results of statistical analysis were obtained. The mean ± SD at 6 months in the effective cases was 5.429 ± 2.384 lg/ml, and 1 year was 5.837 ± 3.217 lg/ml. The mean ± SD at 6 months in the ineffective cases was 3.513 ± 1.044 lg/ml and 1 year was 3.266 ± 1.467 lg/ml. Side effects such as dizziness [11,17], weight gain [4,11,16,17] and the diplopia [5] have been reported. Previous reports have indicated that side effects are unrelated to blood levels [17], but case reports have described a woman who committed suicide at a GBP blood level of 88 lg/mL [6] and withdrawal symptoms after GBP discontinuation [7]. We therefore could not entirely discount the possibility that increased blood levels cause some side effect. As a result, we thought that there was a need to determine GBP levels in blood. In addition, one study found that blood levels tended to be higher in a patient with intractable pediatric epilepsy compared to a case of benign pediatric epilepsy or adult epilepsy, although no side effects other than weight gain were evident [14]. In our study, there were no cases that had side effects in the effective and or ineffective cases. Therefore, the target GBP blood level was about 5 lg/ ml and was established within 3–8 lg/ml because of the possibility of efficacy and sufficient safety. Gender has little influence on the blood level of antiepileptic drugs and the GBP blood level could unaffected by age [14,15]. No significant difference in the blood level was recognized among males and females at any time point (Table 2). The efficacy also showed no differences due to sex. The “age starting of GBP”, was associated with no significant differences in the blood level and the efficacy in this study. There is no clear trend for the GBP plasma level to be higher and more variable
in young children (6 6 years) in comparison to older children [25]. In addition, “period before starting the GBP” showed no significant differences between the two groups (5 6 years, 5 > years). The study could not determine whether the low tendency of the blood level and the high tendency of their effect of GBP medication were connected with starting GBP at a lower age. The dosage and the efficacy of GBP in children were not affected by the sex or age and there seemed to be no limit to the induction time. Therefore, it was easy to use GBP for pediatric patients with partial seizures. The use of concomitant drugs was expected to decrease in the effective cases of GBP, because GBP does not influence on the blood level of other drugs used in combination therapy [16,17,24]. However, no such decrease was observed. The cases that maintained drug efficacy tended to take fewer concomitant drugs, in comparison to the cases in which the efficacy was not maintained. Unfortunately, there was no significant difference. Furthermore, the extension of GBP treatment was not associated with a decrease in the use of concomitant drugs in either case group. There are few reports of the relationship of the longitudinal transition of the GBP blood level and the effectiveness [26]. There are no reports of the relationship between the GBP blood level and R Ratio. Fig. 3A shows the change in the R Ratio at each assessment point. The R Ratio of each case was usually <0, and the R Ratio showed no significant difference at each assessment point. Therefore, GBP effective cases after one year maintained approximately similar efficacy until 3 years after starting the medication. However, Fig. 3B indicates the importance of maintaining the blood level. There was no significant difference in the GBP blood level at each blood sampling point in the effective case, and the mean blood level ± SD was 5.419 ± 2.715 lg/ ml. Fig. 3C shows the GBP blood level at each assessment point and relationship to the efficacy (R Ratio); however there was no significant correlation. Therefore, no precise definition of the therapeutic range could be recognized in either assessment point; however, the results suggested the possibility of establishing a targeted value in the “optimal range”. The R Ratio is often used for the effective assessment of GBP. This method [27–30] shows that the change in the seizure frequency can be considered, but this method is insufficient to evaluate improvement of comprehensive paroxysmal symptoms. Therefore, the correlation of the R Ratio and paroxysmal conditions was evaluated. Fig. 4A shows the relationship between the paroxysmal strength and the R Ratio, and Fig. 4B shows the relationship of the length and the R Ratio. A decreasing paroxysmal frequency was accompanied by shortening in the paroxysmal time, because the R Ratio within 1 year correlated with the paroxysmal strength. Moreover, the R Ratio correlated with the paroxysmal length at all assessment
Y. Nonoda et al. / Brain & Development 36 (2014) 194–202
points. The R Ratio was significantly lower in cases whose seizures were improved or disappeared than in the cases that showed no change. Therefore, the decrease in the paroxysmal frequency was thought to be due to the improvement in the paroxysmal strength and length. Alternatively, Fig. 4C shows the relationship between paroxysmal strength and GBP blood level at each assessment point and Fig. 4D shows a relationship between the paroxysmal length and the blood level. Antiepileptic activity was recognized in in cases with a sufficient GBP blood level. However, there was no significant difference in the paroxysmal strength, or length as clinical manifestations associated with the GBP blood level. The efficacy of GBP was recognized as unrelated to blood levels [17], but other reports have described the meaning of blood levels for various purposes. These included confirmation of correct dosing with the medicine at home, confirmation of maintained efficacy with decreasing dosage [26] and the safety of breastfeeding after childbirth by a mother taking GBP [31]. The present study could not set the therapeutic range based on TDM, but advocated the optimal range as the index of improvement in seizure frequency, paroxysmal strength, and duration of treatment without side effects. We thought that the constant effect of GBP was provided by maintaining blood levels within this range, and side effects would be minimal. We expect that many clinicians will see GBP as a beneficial option and feel confident in prescribing this agent. In conclusion, the present study demonstrated the long-term efficacy of GBP and of measurement of the blood level. The cases in which GBP was effective for one year maintained approximately the same efficacy for 3 years, because the R Ratio in each case was usually <0 at each assessment point with an improvement in the paroxysmal strength and length. The GBP blood levels in the effective cases were higher than the levels in the ineffective cases at 6 month (mean ± SD: 5.429 ± 2.384 lg/ml) and 1 year (5.837 ± 3.217 lg/ml) and no cases experienced side effects. However, there was no relationship between the GBP blood level and the R Ratio. No precise definition of the therapeutic range could be established and but the study did establish a targeted “optimal range”. Therefore, the target GBP blood level was about 5 lg/ml and was established within 3–8 lg/ml. The evaluation of the GBP blood level simplified the use of GBP for pediatric patients with partial seizures. The optimal range that we advocated was the area in which a balance was achieved between safety and utility. However, in this area, no relationship was found between blood level and efficacy or appearance of side effects. Therefore, determination of blood level is useful to avoid the risk of side effects if GBP dosage is excessively increased to try to achieve greater efficacy or if GBP doses are carelessly skipped.
201
Acknowledgements The abstract of this paper was presented in part at the 41st Congress of The Japan Epilepsy Society in Fukuoka, Japan, November 2007; the 50th Meeting of the Japanese Society of Child Neurology in Tokyo, Japan, May 2008 and the 53rd Annual meeting of the Japanese Society of Child Neurology in Yokohama, Japan, May 2011. We thank Brian Quinn, Japan Medical Communication for editing for the manuscript. References [1] Hauer JM, Wical BS, Charnas L. Gabapentin successfully manages chronic unexplained irritability in children with severe neurologic impairment. Pediatrics 2007;119:e519–22. [2] Low AK, Ward K, Wines AP. Pediatric complex regional pain syndrome. J Pediatr Orthop 2007;27:567–72. [3] Daoud AS, Bataineh H, Otoom S, Abdul-Zahra E. The effect of vigabatrin, lamotrigine and gabapentin of the fertility, weights, sex hormones and biochemical profiles of male rats. Neuro Endocrinol Lett 2004;25:178–83. [4] Jallon P, Picard F. Bodyweight gain and anticonvulsants. A comparative review. Drug safety 2001;24:969–78. [5] Verrotti A, Manco R, Matricardi S, Franzoni E, Chiarelli F. Antiepileptic drugs and visual function. Pediatr Neurol 2007;36:353–60. [6] Middleton O. Suicide by gabapentin overdose. J Forensic Sci 2011;56:1373–5. [7] Hellwig TR, Hammerquist R, Termaat J. Withdrawal symptoms after gabapentin discontinuation. Am J Health Syst Pharm 2010;67:910–2. [8] Chen C, Cowles VE, Hou E. Pharmacokinetics of gabapentin in a novel gastric-retentive extended-release formulation: comparison with an immediate-release formulation and effect of dose escalation and food. J Clin Pharmacol 2011;51:346–58. [9] Lal R, Sukbuntherng J, Luo W, Chen D, Vu A, Tovera J, et al. Pharmacokinetics and tolerability of single escalating doses of gabapentin enacarbil: a randomized-sequence, double-blind, placebo-controlled crossover study in healthy volunteers. Clin Ther 2009;31:1776–86. [10] Governo RJ, Morris PG, Marsden CA, Chapman V. Gabapentin evoked changes in functional activity in nociceptive regions in the brain of the anaesthetized rat: an fMRI study. Br J Pharmacol 2008;153:1558–67. [11] Hwang H, Kim KJ. New antiepileptic drugs in pediatric epilepsy. Brain Dev 2008;30:549–55. [12] Dooley DJ, Taylor CP, Donevan S, Feltner D. Ca2+ channel a2d ligands: novel modulators of neurotransmission. Trends Pharmacol Sci 2007;28:75–82. [13] Sills GJ. The mechanisms of action of gabapentin and pregabalin. Curr Opin Pharmacol 2006;6:108–13. [14] Tallian KB, Nahata MC, Lo W, Tsao CY. Pharmacokinetics of gabapentin in paediatric patients with uncontrolled seizures. J Clin Pharm Ther 2004;29:511–5. [15] Cilio MR, Bolanos AR, Liu Z, Schmid R, Yang Y, Stafstrom CE, et al. Anticonvulsant action and long-term effects of gabapentin in the immature brain. Neuropharmacology 2001;40:139–47. [16] Wallace SJ. Newer antiepileptic drugs: advantages and disadvantages. Brain Dev 2001;23:277–83. [17] Perucca E. Clinical pharmacology and therapeutic use of the new antiepileptic drugs. Fundam Clin Pharmacol 2001;15:405–17. [18] Ebrahimzadeh H, Yamini Y, Firozjaei HA, Kamarei F, Tavassoli N, Rouini MR. Hollow fiber-based liquid phase microextraction
202
[19]
[20]
[21]
[22]
[23]
[24] [25]
Y. Nonoda et al. / Brain & Development 36 (2014) 194–202 combined with high-performance liquid chromatography for the analysis of gabapentin in biological samples. Anal Chim Acta 2010;665:221–6. Kolocouri F, Dotsikas Y, Loukas YL. Dried plasma spots as an alternative sample collection technique for the quantitative LCMS/MS determination of gabapentin. Anal Bioanal Chem 2010;398:1339–47. Wattananat T, Akarawut W. Validated LC-MS-MS method for the determination of gabapentin in human plasma: application to a bioequivalence study. J Chromatogr Sci 2009;47:868–71. Sagirli O, Cetin SM, Onal A. Determination of gabapentin in human plasma and urine by high-performance liquid chromatography with UV-vis detection. J Pharm Biomed Anal 2006;42:618–24. Ji HY, Jeong DW, Kim YH, Kim HH, Yoon YS, Lee KC, et al. Determination of gabapentin in human plasma using hydrophilic interaction liquid chromatography with tandem mass spectrometry. Rapid Commun Mass Spectrom 2006;20:2127–32. Borrey DC, Godderis KO, Engelrelst VI, Bernard DR, Langlois MR. Quantitative determination of vigabatrin and gabapentin in human serum by gas chromatography-mass spectrometry. Clin Chim Acta 2005;354:147–51. Perucca E. Clinically relevant drug interactions with antiepileptic drugs. Br J Clin Pharmacol 2006;61:246–55. Gatti G, Ferrari AR, Guerrini R, Bonanni P, Bonomi I, Perucca E. Plasma gabapentin levels in children with epilepsy: influence of
[26]
[27]
[28]
[29]
[30]
[31]
age, relationship with dosage, and preliminary observations on correlation with clinical response. Ther Drug Monit 2003;25:54–60. Muscas GC, Chiroli S, Luceri F, Mastio MD, Balestrieri F, Arnetoli G. Conversion from thrice daily to twice daily administration of gabapentin (GBP) in partial epilepsy: analysis of clinical efficacy and plasma levels. Seizure 2000;9:47–50. Anhut H, Ashman P, Feuerstein TJ, Sauermann W, Saunders M, Schmidt B. Gabapentin (Neurontin) as add-on therapy in patients with partial seizures: a double-blind, placebo-controlled study. The international gabapentin study group. Epilepsia 1994;35:795–801. Leiderman DB. Gabapentin as add-on therapy for refractory partial epilepsy: results of five placebo-controlled trials. Epilepsia 1994;35:S74–6. Marson AG, Kadir ZA, Hutton JL, Chadwick DW. The new antiepileptic drugs: a systematic review of their efficacy and tolerability. Epilepsia 1997;38:859–80. Appleton R, Fichtner K, LaMoreaux L, Alexander J, Halsall G, Murray G, et al. Gabapentin as add-on therapy in children with refractory partial seizures: a 12-week, multicentre, double-blind, placebo-controlled study. Epilepsia 1999;40:1147–54. ¨ hman I, Vitols S, Tomson T. Pharmacokinetics of gabapentin O during delivery, in the neonatal period, and lactation: does a fetal accumulation occur during pregnancy? Epilepsia 2005;46:1621–4.
Original article
The efficacy of gabapentin in children of partial seizures and the blood levels Yutaka Nonoda, Toshiyuki Iwasaki ⇑, Masahiro Ishii Department of Pediatrics, Kitasato University School of Medicine, Kanagawa, Japan Received 17 November 2012; received in revised form 26 March 2013; accepted 6 April 2013
Abstract Aim: To evaluate the long-term efficacy of gabapentin (GBP) and usefulness of measurement of the blood level for the observation of patients that have partial seizures. Methods: Thirty patients (20 effective cases and 10 ineffective cases) treated with GBP for the localization related epilepsy had their peak blood levels of GBP. The levels were measured seven time points, one, 6, 12, 18, 24, 30, and 36 month after the start of medication. The efficacy of GBP was evaluated at one month after the initiation of medication and every year for 3 years, based on the R Ratio and the degree of improvement for the paroxysmal strength and length. Results: GBP levels were higher in the effective cases than the levels in the ineffective cases 6 months after and 1 year after the initiation of medication (p < 0.05). The level 6 months after the start in the effective cases was 5.429 ± 2.384 lg/ml (mean ± SD), and 5.837 ± 3.217 lg/ml after 1 year. The cases that were effective for 1 year maintained approximately the same efficacy for 3 years after the initiation of medication, but there was no correlation between the level and the R Ratio, paroxysmal strength and length. Conclusions: No precise definition of the therapeutic range was recognized because of no correlation between GBP level and the improvement of clinical manifestations. We recommend the GBP optimal range that is established the range within 3–8 lg/ml (mean; 5 lg/ml) as therapeutic target without the side effect. Ó 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. Keywords: Antiepileptic drug; Localization related epilepsy; Paroxysmal strength and length; Response ratio; Optimal range
1. Introduction Gabapentin (GBP) was composed in Germany in 1973. GBP has been administered as an antiepileptic drug (AED) for children with partial seizures in many European countries and America since 1999. It was approved for children in Japan in 2011. It was initially introduced as an AED and was later found to be effective in treating some chronic pain syndromes [1,2]. The
⇑ Corresponding author. Address: Department of Pediatrics, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252–0374, Japan. Tel.: +81 42 778 8111; fax: +81 42 778 8441. E-mail address: [email protected] (T. Iwasaki).
bodyweight gain [3,4] and visual dysfunction [5] observed with the use of GBP seem to be side effects. Moreover, rare cases of overdose-related adverse effects [6] and withdrawal symptoms [7] have been reported. However, neither reference included statements about relationships between blood levels and side effects. No research was found referring to the appearance of side effects with increased blood levels. GBP is a hydrophilic analog of c-aminobutyearic acid (GABA), which is transported across the blood–brain barrier, and is one of the inhibitory neurotransmitters of the mammalian central nervous system [8–17]. Various of published methods for analysis of GBP in human serum have been reported [18–23]. GBP is rapidly absorbed, with a time to peak blood level of 2–3 h and
0387-7604/$ - see front matter Ó 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.braindev.2013.04.006
Y. Nonoda et al. / Brain & Development 36 (2014) 194–202
is not metabolized and the unchanged drug is directly excreted via the kidney with a half-life of 5–8 h. GBP does not influence the blood level of other drugs for combination therapy [24], because it has no mechanism of induction and inhibition of drug metabolizing enzymes in the liver, like other AEDs [11,14,16,17,24]. The efficacy of GBP has been reported in many countries [8–11,13–17,21,22,24]. However the appropriate blood level of GBP has not been established. In addition, no evaluation of the use of GBP for pediatric epilepsy patients has been reported. We therefore thought that effective evaluation and an index to minimize the risk of side effects were required for safe medication with GBP. Thirty patients that experienced partial seizures and were medicated with GBP, were observed in this study. The long-term efficacy of GBP and usefulness of the measurement of the blood level, were evaluated.
195
2. Methods
blood level and electroencephalogram were performed repeatedly every 6 months. The subject included 20 effective cases that were cured with GBP, and 10 cases that discontinued administration. The effective case showed an improvement in the paroxysmal strength and length and/or an approximation of the response ratio (R Ratio) to 1. On the other hand, a discontinued case was defined as a patient that took GBP for more than 1 year with no improvement in their symptoms. These did not include cases that discontinued or tapered GBP therapy due to side effects or other malfunction. Therefore, the subjects were classified as 20 effective cases and 10 ineffective cases (Table 1). The initial dosage of GBP was 10 mg/kg/day and the dosage was increased by 10 mg/kg/day for 2 days. The maintenance dosage was 30 mg/kg/day; otherwise it could increase to 40 mg/kg/day if the effect of treatment was insufficient. However, the adjusted the dosage was limited to 1200 mg/day.
2.1. Patient selection and treatment
2.2. Study design
Thirty patients (16 males and 14 females; ranging from 2.4 to 18 years of age; mean, 9.1 years) that were administered GBP to treat localization related epilepsy in pediatrics of Kitasato University hospital between November 2006 and December 2010, were selected. These patients included 17 cryptogenic cases and 13 symptomatic cases and were randomly selected in a prospective study. Eligible patients were diagnosed to have localization related epilepsy based on their clinical seizure type, electroencephalogram (EEG) and either cranial computed tomography (CT) or magnetic resonance imaging (MRI). Measurement of the GBP
The blood levels of GBP were measured regularly in this study. The patients’ blood was sampled at the pediatric outpatient clinic and measured by high performance liquid chromatography in laboratory (SRL, Inc., Tokyo, Japan). Blood samples to measure the concentration of GBP was obtained after 2–3 h after the administration GBP. The blood level was measured seven times at 1 month after the start of medication and 6, 12, 18, 24, 30, and 36 months after. A minimum sample of 0.2 mL serum was frozen at 20 °C and saved. The efficacy of GBP evaluated four times at 1 month after and 1–3 years after, to determine the R Ratio and the degree of improvement for the paroxysmal strength and length.
Table 1 Patient characteristics. *
Effective cases
Ineffective cases
N (cases) Female Male
20 9 11
10 5 5
Age (year) Body weight (kg) Periods before starting the medication (year) Dosage of GBP
9.22 ± 5.01 30.60 ± 19.08 4.62 ± 3.40
8.76 ± 3.91 26.19 ± 10.64 4.25 ± 3.28
0.982 0.809 0.741
934.50 ± 571.85
753.00 ± 309.91
0.627
2 14 6 1 0 3 10 3 8
3 8 0 0 1 2 6 3 5
Concomitant drugs Carbamazepine Clobazam Clonazepam Lamotrigine Nitrazepam Phenytoin Sodium valproate Topilamate Zonisamide
Distribution data are the mean ± SD. * Mann–Whitney U test.
p
Response ratioðRRatioÞ ¼
T B T þB
B; paroxysmal frequency for 28 days before the evaluation timing. T; paroxysmal frequency for 28 days after the evaluation timing. The paroxysmal strength and length were evaluated with three phases of improvement, aggravation and no change. This study was performed according to the principles of the Declaration of Helsinki. The objective of the study and the therapeutic efficacy and safety were explained to the patients’ parents, and they provided their written informed consent. 2.3. Statistical analysis The correlations between the parameters (GBP blood level, R Ratio, paroxysmal strength and length) were
196
Y. Nonoda et al. / Brain & Development 36 (2014) 194–202
analyzed. The statistical analysis was performed using the nonparametric test or Spearman’s rank correlation coefficient, the Mann–Whitney U test for two different comparisons and the Wilcoxon signed rank test between two groups to determine the significance of the correlation. Excel Statistics 2010 (Social Survey Research Information Co., Ltd., Tokyo, Japan) that added to Microsoft Excel software programs was used for the analyses. 3. Results 3.1. Comparison between the effective cases and the ineffective cases The background of each patient, the dosage of GBP and concomitant AEDs are shown in Table 1.
There were no significant differences in the age and body weight between the effective cases and the ineffective cases. Furthermore, the two groups show consistent age dispersion. Moreover, no differences were recognized in the periods before starting the medication and dosage of GBP. Therefore, no significant differences were observed in the populations of the effective group and the ineffectiveness group. Furthermore, there was almost no difference between two groups in the type and number of concomitant drugs. Fig. 1 shows a comparison of the GBP blood level between the effective cases and the ineffective cases within 1 year. There were significant differences in the blood levels between 6 months and 1 year after the initiation of GBP (p < 0.05).
Fig. 1. Comparisons of the GBP blood level between the effective cases and the ineffective cases (*p < 0.05). The comparison showed significant differences based on the Mann–Whitney U test at 6 months (p = 0.039) and 1 year (p = 0.029). Table 2 Comparison of the results in effective cases. Cases
Age at starting GBP
Periods before starting the medication
Female
Male
*
<6 year old
P6 year old
*
<5 year
P5 year
*
Blood level 1m 6m 1 year 1 year 6 m 2 year 2 year 6 m 3 year
4.394 ± 1.674 5.319 ± 2.440 5.763 ± 2.990 6.674 ± 2.935 6.942 ± 2.324 6.511 ± 2.551 5.880 ± 2.396
5.018 ± 1.450 5.519 ± 2.454 5.896 ± 3.539 5.895 ± 2.087 6.019 ± 3.588 6.657 ± 3.105 6.387 ± 3.695
0.184 0.909 0.970 0.305 0.184 0.909 0.970
3.765 ± 1.614 3.288 ± 1.095 3.438 ± 1.261 4.667 ± 2.455 4.712 ± 1.601 5.402 ± 2.255 4.497 ± 1.815
5.154 ± 1.366 6.346 ± 2.197 6.864 ± 3.275 6.922 ± 2.219 7.167 ± 3.260 7.101 ± 2.922 6.8714 ± 3.323
0.138 0.150 0.138 0.138 0.150 0.138 0.117
4.848 ± 1.689 5.102 ± 2.281 5.164 ± 2.862 6.116 ± 2.690 6.209 ± 2.364 6.588 ± 2.553 6.086 ± 2.465
4.602 ± 1.439 5.829 ± 2.583 6.659 ± 3.600 6.404 ± 2.312 6.701 ± 3.859 6.596 ± 3.228 6.249 ± 3.918
0.620 0.836 0.409 0.804 0.970 0.790 0.621
R Ratio 1m 1 year 2 year 3 year
0.335 ± 0.499 0.372 ± 0.432 0.339 ± 0.423 0.422 ± 0.474
0.377 ± 0.496 0.592 ± 0.456 0.370 ± 0.596 0.443 ± 0.565
0.898 0.284 0.697 0.755
0.024 ± 0.058 0.397 ± 0.397 0.400 ± 0.420 0.400 ± 0.420
0.501 ± 0.518 0.534 ± 0.476 0.337 ± 0.561 0.448 ± 0.562
0.064 0.546 0.800 0.735
0.455 ± 0.522 0.589 ± 0.446 0.565 ± 0.457 0.636 ± 0.461
0.240 ± 0.434 0.375 ± 0.447 0.100 ± 0.478 0.189 ± 0.486
0.138 0.262 0.042 0.150
Distribution data are the mean ± SD * Mann–Whitney U test.
p
p
p
Y. Nonoda et al. / Brain & Development 36 (2014) 194–202
3.2. Details of the effective cases Sex, “age at the introduction of GBP” and “the period before starting the medication” were compared of the GBP blood level and R Ratio (Table 2). There were no significant differences due to sex in the GBP blood level at any time of sampling. The blood level had a tendency to be lower in those that started GBP at a lower age; however it was not significant. Alternatively, the blood level was not affected by the timing of taking other AEDs. The start of AED therapy (especially GBP) was expected to affect the efficacy; however, no significant difference in the R Ratio was recognized. Fig. 2 shows the relationship of the number of combined medicines and the R Ratio. The effective cases in which the efficacy continued for a long term, showed no tendency to decrease the number of concomitant drugs. 3.3. Relationship between the R Ratio, GBP blood level and the time after initiation of medication, strength, length of seizure in effective cases All cases of GBP therapy maintained the efficacy (R Ratio 6 0) for 1 year; however, the results after 2 and 3 years varied (Fig. 3A). All median at each evaluation was less than 0. A comparison of the R Ratio at 1 month after initiation and evaluation times showed no significant difference. Moreover, no significant difference was recognized in either evaluation times. The longitudinal transition of the GBP blood level in effective cases is shown in Fig. 3B. The median of GBP blood levels within 1 year were approximately 5 mg/dl, the lower limit was about 3 mg/dl and the upper limit
197
varied widely. The median level after 1 year and 6 months was approximately 6 mg/dl, the lower limit was about 3 mg/dl and the upper limit was about 8 mg/dl. Furthermore, no significant difference was recognized in either time of sampling. Finally, the R Ratio and GBP blood level showed no correlation (Fig. 3C). The same dispersion was recognized in all of the evaluations from 1 month to 3 years. Fig. 4A shows the relationship between the strength of seizure and the R Ratio; moreover Fig. 4B shows the relationship between the length of seizure and the R Ratio. The R Ratio at 1 month after and 1 year after was related to the strength of seizure. The R Ratio was significantly lower in cases where the strength of seizure were improved or disappeared, in comparison to the cases with no change (Fig. 4A; 1 month after: p < 0.01, 1 year after: p < 0.05). The R Ratio was also correlated with the length of seizure. The R Ratio was significantly lower in cases whose seizures were improved or disappeared in comparison to the cases that showed no change (Fig. 4B; 1 month, 1 and 3 year after: p < 0.01, 2 year after: p < 0.05). Fig. 4C shows the relationship between the strength of seizure and the blood level. There was no significant difference between the improved or disappeared cases and those that showed no change at any time of evaluation. Similarly, the length of seizure and blood level were not related significantly. 4. Discussion Few evaluations of the GBP blood level of pediatric epilepsy patients have been reported, and the appropri-
Fig. 2. Relationship between the number of the combined medications and the R Ratio. The number of combined medicine showed no the significant difference based on the Mann–Whitney U test between cases with an R Ratio < 0 and R Ratio P 0. The number of the combined medicines showed no significant change with the clinical progress according to the Wilcoxon signed rank test.
198
Y. Nonoda et al. / Brain & Development 36 (2014) 194–202
Fig. 3. Relationship of the R Ratio, GBP blood level in the effective cases. (A) Change in the R Ratio. There was not the significant difference according to the Wilcoxon signed rank test. (B) Change in the GBP blood level. There was not the significant difference according to the Wilcoxon signed rank test. (C) Relationship between the R Ratio and GBP blood level at all evaluation points. There was no correlation at any time.
ate range of GBP concentration has not been established. Generally, few studies have described the relationships between blood level and side effects, and
descriptions of increased blood levels causing side effects appear rare. Efficacy, frequency and severity of side effects did not appear related to blood level. On the
Y. Nonoda et al. / Brain & Development 36 (2014) 194–202
199
Fig. 4. Relationship between the R Ratio, GBP blood level and strength/length of seizure in the effective cases (*p < 0.05, **p < 0.01). The significant differences of comparison were evaluated with Mann–Whitney U test. (A) Relationship between the strength of seizure and the R Ratio. There were significant differences at 1 month (p = 0.005) and 1 year (p = 0.012). (B) Relationship between the length of seizure and the R Ratio. The results of comparison showed significant differences at 1 month (p = 0.005), 1 year (p = 0.001), 2 years (p = 0.029) and 3 years (p = 0.002). (C) Relationship between the strength of seizure and the blood level. There were no significant differences.
other hand, the absence of a clear “optimal range” in patient’s dosage does not necessarily mean that the role
of TDM is not useful [17]. It was possible that the optimal plasma level varies between patients. Furthermore,
200
Y. Nonoda et al. / Brain & Development 36 (2014) 194–202
knowledge of the blood level might be useful when the patient presents an unexpected change [6] in their clinical status during follow-up [17]. The current study aimed to identify the “optimal range” of GBP. The study population in the current study showed no significant differences between the effective cases and the ineffectiveness cases in sex, need to start of GBP therapy and type of concomitant drugs (Table 1). Fig. 1 compared the blood level in the effective cases with that in the ineffective cases, and showed that the blood levels were significant different at 6 months and 1 year of treatment (p < 0.05). The GBP blood levels at 1 month showed no significant difference; however the average levels were 4.74 ± 1.55 and 3.44 ± 1.55, respectively and were higher in the effective cases. This suggested that the oral administration of GBP was consistent at the initiation of medication, but the compliance was insufficient 1 month later, because the habitual oral administration had not been established. Consequently, the blood levels of effective cases were higher than the levels of ineffective cases from 6 month after the start of GBP medication. The results of the blood level varied, but the fixed results of statistical analysis were obtained. The mean ± SD at 6 months in the effective cases was 5.429 ± 2.384 lg/ml, and 1 year was 5.837 ± 3.217 lg/ml. The mean ± SD at 6 months in the ineffective cases was 3.513 ± 1.044 lg/ml and 1 year was 3.266 ± 1.467 lg/ml. Side effects such as dizziness [11,17], weight gain [4,11,16,17] and the diplopia [5] have been reported. Previous reports have indicated that side effects are unrelated to blood levels [17], but case reports have described a woman who committed suicide at a GBP blood level of 88 lg/mL [6] and withdrawal symptoms after GBP discontinuation [7]. We therefore could not entirely discount the possibility that increased blood levels cause some side effect. As a result, we thought that there was a need to determine GBP levels in blood. In addition, one study found that blood levels tended to be higher in a patient with intractable pediatric epilepsy compared to a case of benign pediatric epilepsy or adult epilepsy, although no side effects other than weight gain were evident [14]. In our study, there were no cases that had side effects in the effective and or ineffective cases. Therefore, the target GBP blood level was about 5 lg/ ml and was established within 3–8 lg/ml because of the possibility of efficacy and sufficient safety. Gender has little influence on the blood level of antiepileptic drugs and the GBP blood level could unaffected by age [14,15]. No significant difference in the blood level was recognized among males and females at any time point (Table 2). The efficacy also showed no differences due to sex. The “age starting of GBP”, was associated with no significant differences in the blood level and the efficacy in this study. There is no clear trend for the GBP plasma level to be higher and more variable
in young children (6 6 years) in comparison to older children [25]. In addition, “period before starting the GBP” showed no significant differences between the two groups (5 6 years, 5 > years). The study could not determine whether the low tendency of the blood level and the high tendency of their effect of GBP medication were connected with starting GBP at a lower age. The dosage and the efficacy of GBP in children were not affected by the sex or age and there seemed to be no limit to the induction time. Therefore, it was easy to use GBP for pediatric patients with partial seizures. The use of concomitant drugs was expected to decrease in the effective cases of GBP, because GBP does not influence on the blood level of other drugs used in combination therapy [16,17,24]. However, no such decrease was observed. The cases that maintained drug efficacy tended to take fewer concomitant drugs, in comparison to the cases in which the efficacy was not maintained. Unfortunately, there was no significant difference. Furthermore, the extension of GBP treatment was not associated with a decrease in the use of concomitant drugs in either case group. There are few reports of the relationship of the longitudinal transition of the GBP blood level and the effectiveness [26]. There are no reports of the relationship between the GBP blood level and R Ratio. Fig. 3A shows the change in the R Ratio at each assessment point. The R Ratio of each case was usually <0, and the R Ratio showed no significant difference at each assessment point. Therefore, GBP effective cases after one year maintained approximately similar efficacy until 3 years after starting the medication. However, Fig. 3B indicates the importance of maintaining the blood level. There was no significant difference in the GBP blood level at each blood sampling point in the effective case, and the mean blood level ± SD was 5.419 ± 2.715 lg/ ml. Fig. 3C shows the GBP blood level at each assessment point and relationship to the efficacy (R Ratio); however there was no significant correlation. Therefore, no precise definition of the therapeutic range could be recognized in either assessment point; however, the results suggested the possibility of establishing a targeted value in the “optimal range”. The R Ratio is often used for the effective assessment of GBP. This method [27–30] shows that the change in the seizure frequency can be considered, but this method is insufficient to evaluate improvement of comprehensive paroxysmal symptoms. Therefore, the correlation of the R Ratio and paroxysmal conditions was evaluated. Fig. 4A shows the relationship between the paroxysmal strength and the R Ratio, and Fig. 4B shows the relationship of the length and the R Ratio. A decreasing paroxysmal frequency was accompanied by shortening in the paroxysmal time, because the R Ratio within 1 year correlated with the paroxysmal strength. Moreover, the R Ratio correlated with the paroxysmal length at all assessment
Y. Nonoda et al. / Brain & Development 36 (2014) 194–202
points. The R Ratio was significantly lower in cases whose seizures were improved or disappeared than in the cases that showed no change. Therefore, the decrease in the paroxysmal frequency was thought to be due to the improvement in the paroxysmal strength and length. Alternatively, Fig. 4C shows the relationship between paroxysmal strength and GBP blood level at each assessment point and Fig. 4D shows a relationship between the paroxysmal length and the blood level. Antiepileptic activity was recognized in in cases with a sufficient GBP blood level. However, there was no significant difference in the paroxysmal strength, or length as clinical manifestations associated with the GBP blood level. The efficacy of GBP was recognized as unrelated to blood levels [17], but other reports have described the meaning of blood levels for various purposes. These included confirmation of correct dosing with the medicine at home, confirmation of maintained efficacy with decreasing dosage [26] and the safety of breastfeeding after childbirth by a mother taking GBP [31]. The present study could not set the therapeutic range based on TDM, but advocated the optimal range as the index of improvement in seizure frequency, paroxysmal strength, and duration of treatment without side effects. We thought that the constant effect of GBP was provided by maintaining blood levels within this range, and side effects would be minimal. We expect that many clinicians will see GBP as a beneficial option and feel confident in prescribing this agent. In conclusion, the present study demonstrated the long-term efficacy of GBP and of measurement of the blood level. The cases in which GBP was effective for one year maintained approximately the same efficacy for 3 years, because the R Ratio in each case was usually <0 at each assessment point with an improvement in the paroxysmal strength and length. The GBP blood levels in the effective cases were higher than the levels in the ineffective cases at 6 month (mean ± SD: 5.429 ± 2.384 lg/ml) and 1 year (5.837 ± 3.217 lg/ml) and no cases experienced side effects. However, there was no relationship between the GBP blood level and the R Ratio. No precise definition of the therapeutic range could be established and but the study did establish a targeted “optimal range”. Therefore, the target GBP blood level was about 5 lg/ml and was established within 3–8 lg/ml. The evaluation of the GBP blood level simplified the use of GBP for pediatric patients with partial seizures. The optimal range that we advocated was the area in which a balance was achieved between safety and utility. However, in this area, no relationship was found between blood level and efficacy or appearance of side effects. Therefore, determination of blood level is useful to avoid the risk of side effects if GBP dosage is excessively increased to try to achieve greater efficacy or if GBP doses are carelessly skipped.
201
Acknowledgements The abstract of this paper was presented in part at the 41st Congress of The Japan Epilepsy Society in Fukuoka, Japan, November 2007; the 50th Meeting of the Japanese Society of Child Neurology in Tokyo, Japan, May 2008 and the 53rd Annual meeting of the Japanese Society of Child Neurology in Yokohama, Japan, May 2011. We thank Brian Quinn, Japan Medical Communication for editing for the manuscript. References [1] Hauer JM, Wical BS, Charnas L. Gabapentin successfully manages chronic unexplained irritability in children with severe neurologic impairment. Pediatrics 2007;119:e519–22. [2] Low AK, Ward K, Wines AP. Pediatric complex regional pain syndrome. J Pediatr Orthop 2007;27:567–72. [3] Daoud AS, Bataineh H, Otoom S, Abdul-Zahra E. The effect of vigabatrin, lamotrigine and gabapentin of the fertility, weights, sex hormones and biochemical profiles of male rats. Neuro Endocrinol Lett 2004;25:178–83. [4] Jallon P, Picard F. Bodyweight gain and anticonvulsants. A comparative review. Drug safety 2001;24:969–78. [5] Verrotti A, Manco R, Matricardi S, Franzoni E, Chiarelli F. Antiepileptic drugs and visual function. Pediatr Neurol 2007;36:353–60. [6] Middleton O. Suicide by gabapentin overdose. J Forensic Sci 2011;56:1373–5. [7] Hellwig TR, Hammerquist R, Termaat J. Withdrawal symptoms after gabapentin discontinuation. Am J Health Syst Pharm 2010;67:910–2. [8] Chen C, Cowles VE, Hou E. Pharmacokinetics of gabapentin in a novel gastric-retentive extended-release formulation: comparison with an immediate-release formulation and effect of dose escalation and food. J Clin Pharmacol 2011;51:346–58. [9] Lal R, Sukbuntherng J, Luo W, Chen D, Vu A, Tovera J, et al. Pharmacokinetics and tolerability of single escalating doses of gabapentin enacarbil: a randomized-sequence, double-blind, placebo-controlled crossover study in healthy volunteers. Clin Ther 2009;31:1776–86. [10] Governo RJ, Morris PG, Marsden CA, Chapman V. Gabapentin evoked changes in functional activity in nociceptive regions in the brain of the anaesthetized rat: an fMRI study. Br J Pharmacol 2008;153:1558–67. [11] Hwang H, Kim KJ. New antiepileptic drugs in pediatric epilepsy. Brain Dev 2008;30:549–55. [12] Dooley DJ, Taylor CP, Donevan S, Feltner D. Ca2+ channel a2d ligands: novel modulators of neurotransmission. Trends Pharmacol Sci 2007;28:75–82. [13] Sills GJ. The mechanisms of action of gabapentin and pregabalin. Curr Opin Pharmacol 2006;6:108–13. [14] Tallian KB, Nahata MC, Lo W, Tsao CY. Pharmacokinetics of gabapentin in paediatric patients with uncontrolled seizures. J Clin Pharm Ther 2004;29:511–5. [15] Cilio MR, Bolanos AR, Liu Z, Schmid R, Yang Y, Stafstrom CE, et al. Anticonvulsant action and long-term effects of gabapentin in the immature brain. Neuropharmacology 2001;40:139–47. [16] Wallace SJ. Newer antiepileptic drugs: advantages and disadvantages. Brain Dev 2001;23:277–83. [17] Perucca E. Clinical pharmacology and therapeutic use of the new antiepileptic drugs. Fundam Clin Pharmacol 2001;15:405–17. [18] Ebrahimzadeh H, Yamini Y, Firozjaei HA, Kamarei F, Tavassoli N, Rouini MR. Hollow fiber-based liquid phase microextraction
202
[19]
[20]
[21]
[22]
[23]
[24] [25]
Y. Nonoda et al. / Brain & Development 36 (2014) 194–202 combined with high-performance liquid chromatography for the analysis of gabapentin in biological samples. Anal Chim Acta 2010;665:221–6. Kolocouri F, Dotsikas Y, Loukas YL. Dried plasma spots as an alternative sample collection technique for the quantitative LCMS/MS determination of gabapentin. Anal Bioanal Chem 2010;398:1339–47. Wattananat T, Akarawut W. Validated LC-MS-MS method for the determination of gabapentin in human plasma: application to a bioequivalence study. J Chromatogr Sci 2009;47:868–71. Sagirli O, Cetin SM, Onal A. Determination of gabapentin in human plasma and urine by high-performance liquid chromatography with UV-vis detection. J Pharm Biomed Anal 2006;42:618–24. Ji HY, Jeong DW, Kim YH, Kim HH, Yoon YS, Lee KC, et al. Determination of gabapentin in human plasma using hydrophilic interaction liquid chromatography with tandem mass spectrometry. Rapid Commun Mass Spectrom 2006;20:2127–32. Borrey DC, Godderis KO, Engelrelst VI, Bernard DR, Langlois MR. Quantitative determination of vigabatrin and gabapentin in human serum by gas chromatography-mass spectrometry. Clin Chim Acta 2005;354:147–51. Perucca E. Clinically relevant drug interactions with antiepileptic drugs. Br J Clin Pharmacol 2006;61:246–55. Gatti G, Ferrari AR, Guerrini R, Bonanni P, Bonomi I, Perucca E. Plasma gabapentin levels in children with epilepsy: influence of
[26]
[27]
[28]
[29]
[30]
[31]
age, relationship with dosage, and preliminary observations on correlation with clinical response. Ther Drug Monit 2003;25:54–60. Muscas GC, Chiroli S, Luceri F, Mastio MD, Balestrieri F, Arnetoli G. Conversion from thrice daily to twice daily administration of gabapentin (GBP) in partial epilepsy: analysis of clinical efficacy and plasma levels. Seizure 2000;9:47–50. Anhut H, Ashman P, Feuerstein TJ, Sauermann W, Saunders M, Schmidt B. Gabapentin (Neurontin) as add-on therapy in patients with partial seizures: a double-blind, placebo-controlled study. The international gabapentin study group. Epilepsia 1994;35:795–801. Leiderman DB. Gabapentin as add-on therapy for refractory partial epilepsy: results of five placebo-controlled trials. Epilepsia 1994;35:S74–6. Marson AG, Kadir ZA, Hutton JL, Chadwick DW. The new antiepileptic drugs: a systematic review of their efficacy and tolerability. Epilepsia 1997;38:859–80. Appleton R, Fichtner K, LaMoreaux L, Alexander J, Halsall G, Murray G, et al. Gabapentin as add-on therapy in children with refractory partial seizures: a 12-week, multicentre, double-blind, placebo-controlled study. Epilepsia 1999;40:1147–54. ¨ hman I, Vitols S, Tomson T. Pharmacokinetics of gabapentin O during delivery, in the neonatal period, and lactation: does a fetal accumulation occur during pregnancy? Epilepsia 2005;46:1621–4.