BRIEF COMMUNICATION
Vigabatrin pediatric dosing information for refractory complex partial seizures: Results from a population dose– response analysis *Jace C. Nielsen, †Dwain Tolbert, †Mahlaqa Patel, *Kenneth G. Kowalski, and †David L. Wesche Epilepsia, 55(12):e134–e138, 2014 doi: 10.1111/epi.12825
SUMMARY
Jace Nielsen is a pharmacometrician for the Ann Arbor Pharmacometrics Group in Ann Arbor, Michigan.
We predicted vigabatrin dosages for adjunctive therapy for pediatric patients with refractory complex partial seizures (rCPS) that would produce efficacy comparable to that observed for approved adult dosages. A dose–response model related seizurecount data to vigabatrin dosage to identify dosages for pediatric rCPS patients. Seizure-count data were obtained from three pediatric and two adult rCPS clinical trials. Dosages were predicted for oral solution and tablet formulations. Predicted oral solution dosages to achieve efficacy comparable to that of a 1 g/day adult dosage were 350 and 450 mg/day for patients with body weight ranges 10–15 and >15–20 kg, respectively. Predicted oral solution dosages for efficacy comparable to a 3 g/day adult dosage were 1,050 and 1,300 mg/day for weight ranges 10–15 and >15–20 kg, respectively. Predicted tablet dosage for efficacy comparable to a 1 g/day adult dosage was 500 mg/ day for weight ranges 25–60 kg. Predicted tablet dosage for efficacy comparable to a 3 g/day adult dosage was 2,000 mg for weight ranges 25–60 kg. Vigabatrin dosages were identified for pediatric rCPS patients with body weights ≥10 kg. KEY WORDS: Vigabatrin, Dosage prediction, Epilepsy, Infantile spasm, Refractory complex partial seizures.
Vigabatrin tablets (500 mg) are approved by the U.S. Food and Drug Administration (FDA) as adjunctive therapy for adult patients with refractory complex partial seizures (rCPS) who have responded inadequately to several alternative treatments and for whom the potential benefits outweigh the potential risk of vision loss.1 Vigabatrin is used worldwide as adjunctive therapy to treat rCPS in children, but is not approved for children with rCPS 15–20, and >20–25 kg, respectively. For the tablet, dosages were predicted for one body weight group ranging from 25–60 kg. In addition, Table 2 includes the predicted percentage reductions in seizure rate for a typical 70-kg adult receiving either 1 or 3 g/day dosages; the predicted percentage reductions in seizure rate for the minimum and maximum body weight values within a specific body weight category for a proposed dosage (i.e., the drug effect range for a specific weight category); and the ratio of the drug Epilepsia, 55(12):e134–e138, 2014 doi: 10.1111/epi.12825
e136 J. C. Nielsen et al. Table 1. Summary of study designs Study no. Patients
Study design
Treatmenta,b
Patient no.
Key inclusion/exclusion criteria I: 3–16 years of age (inclusive) I: Diagnosis of complex partial epilepsy with or without secondary generalization I: At least 6 rCPS during last 8 weeks of baseline phase I: Stable regimen of AEDs E Generalized epilepsy E: Progressive neurologic disorders E: Treatable causes of seizures (e.g., infection) E: Nonepileptic seizures (e.g., febrile seizures) I: 3–16 years of age (inclusive) I: Diagnosis of partial epilepsy with rCPS or PSSG I: At least 4 rCPS or PSSG during the baseline phase I: Stable regimen of AEDs E: Generalized epilepsy E: Progressive neurologic disorders E: Treatable causes of seizures (e.g., infection) E: Nonepileptic seizures (e.g., febrile seizures) I: 3–16 years of age (inclusive) I: Diagnosis of complex partial epilepsy with or without secondary generalization I: At least 4 rCPS or PSSG during the baseline phase E: Generalized epilepsy E: Progressive neurologic disorders E: Treatable causes of seizures (e.g., infection) E: Nonepileptic seizures (e.g., febrile seizures) I: 18–60 years of age (inclusive) I: Documented rCPS or PSSG I: At least 6 rCPS during last 8 weeks of baseline phase I: Stable regimen of AEDs E: Progressive neurologic disorders E: Treatable causes of seizures (e.g., infection) I: 18–60 years of age (inclusive) I: Documented rCPS or PSSG I: At least 6 rCPS during last 8 weeks of baseline phase I: Stable regimen of AEDs E: Progressive neurologic disorders E: Treatable causes of seizures (e.g., infection)
118
Pediatric Randomized, double-blind, placebocontrolled (10-week baseline, 6week titration, 8-week maintenance)
Placebo or vigabatrin at 20 mg/kg/day 60 mg/kg/day 100 mg/kg/day
125
192
Pediatric Randomized, double-blind, placebocontrolled (6-week baseline, 10week titration, 7-week maintenance)
Placebo or vigabatrin at 0.5–1.5 g/day for 10–15 kg 0.5–2.0 g/day for 16–30 kg 1.0–3.0 g/day for 31–50 kg 1.0–4.0 g/day for >50 kg
55
221
Pediatric Randomized, double-blind, placebocontrolled (6-week baseline, 10week titration, 7-week maintenance)
Placebo or vigabatrin at 0.5–1.5 g/day for 10–15 kg 0.5–2.0 g/day for 16–30 kg 1.0–3.0 g/day for 31–50 kg 1.0–4.0 g/day for >50 kg
85
24
Adult
Randomized, double-blind, placeboPlacebo or vigabatrin controlled (8-week baseline, 4-week 3 g/day titration, 12-week maintenance)
25
Adults
Randomized, double-blind, placeboPlacebo or vigabatrin 1 g/day 174 controlled (8-week baseline, 6-week vigabatrin 3 g/day titration, 12-week maintenance) vigabatrin 6 g/day
182
AED, antiepileptic drug; rCPS, refractory complex partial seizure; E, exclusion criteria; I, inclusion criteria; PSSG, partial seizures with secondary generalization. Reproduced with permission from Nielsen et al.18 a Vigabatrin dosage titrated in all studies. b Dosage regimen was twice daily in all studies.
effect for the minimum and maximum body weight values for a particular body weight category and proposed dosage relative to the approved dosage in a 70-kg adult. As an example, one can consider the proposed maintenance dosage Epilepsia, 55(12):e134–e138, 2014 doi: 10.1111/epi.12825
of 1,500 mg/day for pediatric patients in the >20–25 kg body weight category. The model predicted percentage reductions in seizure rate owing to vigabatrin treatment for a 1,500 mg/day dosage to be 45.1% for a typical 20-kg
e137 Vigabatrin Dosages for Children with rCPS Table 2. Dosing information for pediatric patients with refractory complex partial seizures
Formulation
Target Adult dosage (mg/day)
Oral solution Oral solution Oral solution Tablet Tablet Oral solution Oral solution Oral solution Tablet Tablet
1,000b 1,000b 1,000b 1,000b 1,000b 3,000 3,000 3,000 3,000 3,000
Body weight (kg)
Predicted dosage (mg/day)
Drug effect in 70-kg adult at target dosage (percentage reduction in seizure rate)
Drug-effect rangea (percentage reduction in seizure rate)
Ratio of drug effect (range) relative to drug effect in a 70-kg adult
10–15 >15–20 >20–25 >25–60 70 10–15 >15–20 >20–25 >25–60 70
350 450 500 500 1,000 1,050 1,300 1,500 2,000 3,000
21.6 21.6 21.6 21.6 21.6 43.8 43.8 43.8 43.8 43.8
19.7–24.0 21.0–24.0 20.5–22.8 13.1–20.5 21.6 41.6–46.3 42.3–45.7 42.5–45.1 37.3–47.7 43.8
0.912–1.110 0.972–1.110 0.949–1.060 0.606–0.949 1.000–1.000 0.950–1.060 0.966–1.040 0.970–1.030 0.852–1.090 1.000–1.000
a
Based on the minimum and maximum body weights for each of the corresponding body weight intervals. 1,000 mg/day is considered a starting dosage of vigabatrin for treatment initiation.
b
patient and 42.5% for a typical 25-kg patient (i.e., a drug effect range of 42.5–45.1). These percentage seizure reductions are similar to the 43.8% reduction predicted for a 70kg adult patient and result in ratios of pediatric drug effect relative to adult drug effect close to one (0.970–1.03). The predicted vigabatrin dosages for each weight category and for both formulations were mostly within 15% of the therapeutic drug effect in a 70-kg adult patient. The one exception was for the tablet dosage form in the >25–60 kg weight category for the treatment initiation dosage (i.e., 1,000 mg/ day in adults). The inability to achieve a pediatric dosage for this body weight interval that resulted in a seizure reduction within 15% of adult effect is related to the tablet strength (500 mg) in the context of the total daily dosage. Because the tablet strength is 500 mg, only 500 and 1,000 mg/day dosages could be considered. The 500 mg/ day dosage was selected as a more conservative starting dosage, which could be titrated at the physician’s discretion to the recommended maintenance dosage. It is important to note that all the recommended maintenance dosages resulted in predicted drug effects for pediatric patients that were within 15% of predicted adult effects.
Discussion Many older AEDs have inadequate information on use in pediatric populations, a consequence of the lack of randomized controlled trials conducted in children.5,6 Three randomized controlled trials were conducted with vigabatrin in children with rCPS.16,17 However, these trials were suspended prior to completion of planned enrollment for administrative reasons. Thus, the individual studies were inadequately powered to characterize the vigabatrin dose– response curve. In the current study, clinical outcome data available from both adult and pediatric populations were used to develop a dose–response model to predict seizure frequency reductions. Appropriate dosing regimens were
determined by comparing exposure–response relationships between adults and children via pharmacometrics analysis. In the present study, vigabatrin dosage predictions were provided for children ≥10 kg and are intended to help clinicians find the optimal vigabatrin dosage for seizure control. The dosage predictions were for both the oral solution and tablet formulations. Because of the flexibility of the oral solution dosage formulation, dosages were predicted for body weights in 5-kg increments. The tablet size was less flexible, since the smallest dosage unit was 500 mg. Therefore, tablet dosages were predicted for wider body weight ranges (25–60 kg). Nevertheless, the predicted efficacy was within 15% of the response predicted at the approved dosages for adults for the maintenance dosage. The dose–response model leading to the pediatric dosage predictions was developed for patients with rCPS who did not have clinically significant renal impairment. Therefore, the pediatric dosage predictions should not be extrapolated to other indications (e.g., infantile spasms) and do not address dosage modifications for patients with renal impairment. Dosage instructions for patients with infantile spasms and renal impairment are provided in the vigabatrin prescribing information.1 In addition, no pharmacometrics analyses were conducted for adverse events. Vigabatrin is an effective treatment for rCPS and is associated with benefits as well as risks, the most notable being retinopathy with the development of peripheral visual field deficits.22 Treatment decisions should be made in consideration of the efficacy as well as the documented safety risks.1,23,24 In summary, the present analysis provides for the first time a prediction of vigabatrin dosages for children supported by a pharmacometrics dose–response analysis.
Acknowledgments The authors acknowledge Susan K. Paulson, Ph.D., of Pharma-Start, LLC, of Northbrook, Ill., and Michael A. Nissen, ELS, of Lundbeck Epilepsia, 55(12):e134–e138, 2014 doi: 10.1111/epi.12825
e138 J. C. Nielsen et al. (Deerfield, IL) for their assistance in the preparation and revision of this manuscript. This assistance was fully funded by Lundbeck.
Conflict of interest These analyses were funded by Lundbeck LLC. Dwain Tolbert is a fulltime employees of Lundbeck, LLC. David Wesche and Mahlaqa Patel were full-time employees of Lundbeck LLC at the time this study was conducted. Jace C. Nielsen and Kenneth G. Kowalski, of Ann Arbor Pharmacometrics Group, Inc. (Ann Arbor, Michigan), are paid consultants of Lundbeck LLC. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
References 1. Lundbeck. Sabril (vigabatrin) prescribing information. Deerfield, IL: Lundbeck; 2013. 2. Ben-Menachem E. Mechanism of action of vigabatrin: correcting misperceptions. Acta Neurol Scand 2011;124 (Suppl. 192):5–15. 3. Grant SM, Heel RC. Vigabatrin: a review of its pharmacodynamics and pharmacokinetic properties, and therapeutic potential in epilepsy and disorders of motor control. Drugs 1991;41:889–926. 4. Willmore LJ, Abelson MB, Ben-Manachem E, et al. Vigabatrin: 2008 update. Epilepsia 2009;50:163–173. 5. Garofalo E. Obtaining pediatric indications for new anti-epileptic drugs: how and when. Epilepsy Res 2006;68:38–42. 6. Chiron C, Dulac O, Pons G. Antiepileptic drug development in children considerations for a revisited strategy. Drugs 2008;68:17–25. 7. Rheims S, Cucherat M, Arzimanoglou A, et al. Greater response to placebo in children than in adults: a systematic review and metaanalysis in drug resistant partial epilepsy. PLoS Med 2008;5:e166, 1223–1237. 8. Ryvlin P, Cucherat M, Rheims S. Risk of sudden unexpected death in epilepsy in patients given adjunctive antiepileptic treatment for refractory seizures: a meta-analysis of placebo-controlled randomized trials. Lancet Neurol 2011;10:961–968. 9. Bhattaram VA, Booth BP, Ramchandani RP, et al. Impact of pharmacometrics on drug approval and labeling decisions: a survey of 42 new drug applications. AAPS J 2005;7:E503–E512.
Epilepsia, 55(12):e134–e138, 2014 doi: 10.1111/epi.12825
10. Lee JY, Garnett CE, Gobburu JVS, et al. Impact of pharmacometric analyses on new drug approval and labelling decisions. Clin Pharmacokinet 2011;50:627–635. 11. Troconiz IF, Plan EL, Miller R, et al. Modeling overdispersion and Markovian features in count data. J Pharmacokinet Pharmacodyn 2009;36:461–477. 12. Ahn JE, Plan EL, Karlsson MO, et al. Modeling longitudinal daily seizure frequency data from pregabalin add-on treatment. J Clin Pharmacol 2012;52:880–892. 13. Snodgrass SR, Parks BR. Anticonvulsant blood levels: historical review with a pediatric focus. J Child Neurol 2000;15:734–746. 14. Girgis IG, Nandy P, Nye JS, et al. Pharmacokinetic–pharmacodynamic assessment of topiramate dosing regimens for children with epilepsy 2 to < 10 years of age. Epilepsia 2010;51:1954–1962. 15. Nedelman JR, Rubin DB, Sheiner LB. Diagnostics for confounding in PK/PD models for oxcarbazepine. Stat Med 2007;26:290–308. 16. Ben-Menachem E, Sander JW. Vigabatrin therapy for refractory complex partial seizures: review of major European trials. Acta Neurol Scand 2011;124 (Suppl. 192):16–28. 17. Sabrilâ (vigabatrin). Center for drug evaluation and research, United States food and drug administration, (NDA) 020427. Available at: www.fda.gov/Drugs/default.htm. Accessed January 21, 2014. 18. Nielsen JC, Hutmacher M, Wesche D, et al. Population dosageresponse analysis of daily seizure count following vigabatrin therapy in adult and pediatric patients with refractory complex partial seizures. J Clin Pharmacol 2014 Aug 12 [Epub ahead of print]. 19. Boxenbaum H. Interspecies scaling, allometry, physiological time and the ground plan of pharmacokinetics. J Pharmacokinet Biopharm 1982;10:201–227. 20. Dean C, Mosier M, Penry K. Dose–response study of vigabatrin as add-on therapy in patients with uncontrolled complex partial seizures. Epilepsia 1999;40:74–82. 21. French JA, Mosier M, Walker S, et al. A double-blind, placebocontrolled study of vigabatrin three g/day in patients with uncontrolled complex partial seizures. Neurology 1996;46:54–61. 22. Pellock JM. Balancing clinical benefits of vigabatrin with its associated risk of vision loss. Acta Neurol Scand 2011;124 (Suppl. 192):83–91. 23. Plant GT, Sergott RC. Understanding and interpreting vision safety issues with vigabatrin. Acta Neurol Scand 2011;124 (Suppl. 192):57–71. 24. Walker SD, K€alvi€ainen R. Non-vision adverse events with vigabatrin therapy. Acta Neurol Scand 2011;124 (Suppl. 192):72–82.
This document is a scanned copy of a printed document. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material.
Vigabatrin pediatric dosing information for refractory complex partial seizures: Results from a population dose– response analysis *Jace C. Nielsen, †Dwain Tolbert, †Mahlaqa Patel, *Kenneth G. Kowalski, and †David L. Wesche Epilepsia, 55(12):e134–e138, 2014 doi: 10.1111/epi.12825
SUMMARY
Jace Nielsen is a pharmacometrician for the Ann Arbor Pharmacometrics Group in Ann Arbor, Michigan.
We predicted vigabatrin dosages for adjunctive therapy for pediatric patients with refractory complex partial seizures (rCPS) that would produce efficacy comparable to that observed for approved adult dosages. A dose–response model related seizurecount data to vigabatrin dosage to identify dosages for pediatric rCPS patients. Seizure-count data were obtained from three pediatric and two adult rCPS clinical trials. Dosages were predicted for oral solution and tablet formulations. Predicted oral solution dosages to achieve efficacy comparable to that of a 1 g/day adult dosage were 350 and 450 mg/day for patients with body weight ranges 10–15 and >15–20 kg, respectively. Predicted oral solution dosages for efficacy comparable to a 3 g/day adult dosage were 1,050 and 1,300 mg/day for weight ranges 10–15 and >15–20 kg, respectively. Predicted tablet dosage for efficacy comparable to a 1 g/day adult dosage was 500 mg/ day for weight ranges 25–60 kg. Predicted tablet dosage for efficacy comparable to a 3 g/day adult dosage was 2,000 mg for weight ranges 25–60 kg. Vigabatrin dosages were identified for pediatric rCPS patients with body weights ≥10 kg. KEY WORDS: Vigabatrin, Dosage prediction, Epilepsy, Infantile spasm, Refractory complex partial seizures.
Vigabatrin tablets (500 mg) are approved by the U.S. Food and Drug Administration (FDA) as adjunctive therapy for adult patients with refractory complex partial seizures (rCPS) who have responded inadequately to several alternative treatments and for whom the potential benefits outweigh the potential risk of vision loss.1 Vigabatrin is used worldwide as adjunctive therapy to treat rCPS in children, but is not approved for children with rCPS 15–20, and >20–25 kg, respectively. For the tablet, dosages were predicted for one body weight group ranging from 25–60 kg. In addition, Table 2 includes the predicted percentage reductions in seizure rate for a typical 70-kg adult receiving either 1 or 3 g/day dosages; the predicted percentage reductions in seizure rate for the minimum and maximum body weight values within a specific body weight category for a proposed dosage (i.e., the drug effect range for a specific weight category); and the ratio of the drug Epilepsia, 55(12):e134–e138, 2014 doi: 10.1111/epi.12825
e136 J. C. Nielsen et al. Table 1. Summary of study designs Study no. Patients
Study design
Treatmenta,b
Patient no.
Key inclusion/exclusion criteria I: 3–16 years of age (inclusive) I: Diagnosis of complex partial epilepsy with or without secondary generalization I: At least 6 rCPS during last 8 weeks of baseline phase I: Stable regimen of AEDs E Generalized epilepsy E: Progressive neurologic disorders E: Treatable causes of seizures (e.g., infection) E: Nonepileptic seizures (e.g., febrile seizures) I: 3–16 years of age (inclusive) I: Diagnosis of partial epilepsy with rCPS or PSSG I: At least 4 rCPS or PSSG during the baseline phase I: Stable regimen of AEDs E: Generalized epilepsy E: Progressive neurologic disorders E: Treatable causes of seizures (e.g., infection) E: Nonepileptic seizures (e.g., febrile seizures) I: 3–16 years of age (inclusive) I: Diagnosis of complex partial epilepsy with or without secondary generalization I: At least 4 rCPS or PSSG during the baseline phase E: Generalized epilepsy E: Progressive neurologic disorders E: Treatable causes of seizures (e.g., infection) E: Nonepileptic seizures (e.g., febrile seizures) I: 18–60 years of age (inclusive) I: Documented rCPS or PSSG I: At least 6 rCPS during last 8 weeks of baseline phase I: Stable regimen of AEDs E: Progressive neurologic disorders E: Treatable causes of seizures (e.g., infection) I: 18–60 years of age (inclusive) I: Documented rCPS or PSSG I: At least 6 rCPS during last 8 weeks of baseline phase I: Stable regimen of AEDs E: Progressive neurologic disorders E: Treatable causes of seizures (e.g., infection)
118
Pediatric Randomized, double-blind, placebocontrolled (10-week baseline, 6week titration, 8-week maintenance)
Placebo or vigabatrin at 20 mg/kg/day 60 mg/kg/day 100 mg/kg/day
125
192
Pediatric Randomized, double-blind, placebocontrolled (6-week baseline, 10week titration, 7-week maintenance)
Placebo or vigabatrin at 0.5–1.5 g/day for 10–15 kg 0.5–2.0 g/day for 16–30 kg 1.0–3.0 g/day for 31–50 kg 1.0–4.0 g/day for >50 kg
55
221
Pediatric Randomized, double-blind, placebocontrolled (6-week baseline, 10week titration, 7-week maintenance)
Placebo or vigabatrin at 0.5–1.5 g/day for 10–15 kg 0.5–2.0 g/day for 16–30 kg 1.0–3.0 g/day for 31–50 kg 1.0–4.0 g/day for >50 kg
85
24
Adult
Randomized, double-blind, placeboPlacebo or vigabatrin controlled (8-week baseline, 4-week 3 g/day titration, 12-week maintenance)
25
Adults
Randomized, double-blind, placeboPlacebo or vigabatrin 1 g/day 174 controlled (8-week baseline, 6-week vigabatrin 3 g/day titration, 12-week maintenance) vigabatrin 6 g/day
182
AED, antiepileptic drug; rCPS, refractory complex partial seizure; E, exclusion criteria; I, inclusion criteria; PSSG, partial seizures with secondary generalization. Reproduced with permission from Nielsen et al.18 a Vigabatrin dosage titrated in all studies. b Dosage regimen was twice daily in all studies.
effect for the minimum and maximum body weight values for a particular body weight category and proposed dosage relative to the approved dosage in a 70-kg adult. As an example, one can consider the proposed maintenance dosage Epilepsia, 55(12):e134–e138, 2014 doi: 10.1111/epi.12825
of 1,500 mg/day for pediatric patients in the >20–25 kg body weight category. The model predicted percentage reductions in seizure rate owing to vigabatrin treatment for a 1,500 mg/day dosage to be 45.1% for a typical 20-kg
e137 Vigabatrin Dosages for Children with rCPS Table 2. Dosing information for pediatric patients with refractory complex partial seizures
Formulation
Target Adult dosage (mg/day)
Oral solution Oral solution Oral solution Tablet Tablet Oral solution Oral solution Oral solution Tablet Tablet
1,000b 1,000b 1,000b 1,000b 1,000b 3,000 3,000 3,000 3,000 3,000
Body weight (kg)
Predicted dosage (mg/day)
Drug effect in 70-kg adult at target dosage (percentage reduction in seizure rate)
Drug-effect rangea (percentage reduction in seizure rate)
Ratio of drug effect (range) relative to drug effect in a 70-kg adult
10–15 >15–20 >20–25 >25–60 70 10–15 >15–20 >20–25 >25–60 70
350 450 500 500 1,000 1,050 1,300 1,500 2,000 3,000
21.6 21.6 21.6 21.6 21.6 43.8 43.8 43.8 43.8 43.8
19.7–24.0 21.0–24.0 20.5–22.8 13.1–20.5 21.6 41.6–46.3 42.3–45.7 42.5–45.1 37.3–47.7 43.8
0.912–1.110 0.972–1.110 0.949–1.060 0.606–0.949 1.000–1.000 0.950–1.060 0.966–1.040 0.970–1.030 0.852–1.090 1.000–1.000
a
Based on the minimum and maximum body weights for each of the corresponding body weight intervals. 1,000 mg/day is considered a starting dosage of vigabatrin for treatment initiation.
b
patient and 42.5% for a typical 25-kg patient (i.e., a drug effect range of 42.5–45.1). These percentage seizure reductions are similar to the 43.8% reduction predicted for a 70kg adult patient and result in ratios of pediatric drug effect relative to adult drug effect close to one (0.970–1.03). The predicted vigabatrin dosages for each weight category and for both formulations were mostly within 15% of the therapeutic drug effect in a 70-kg adult patient. The one exception was for the tablet dosage form in the >25–60 kg weight category for the treatment initiation dosage (i.e., 1,000 mg/ day in adults). The inability to achieve a pediatric dosage for this body weight interval that resulted in a seizure reduction within 15% of adult effect is related to the tablet strength (500 mg) in the context of the total daily dosage. Because the tablet strength is 500 mg, only 500 and 1,000 mg/day dosages could be considered. The 500 mg/ day dosage was selected as a more conservative starting dosage, which could be titrated at the physician’s discretion to the recommended maintenance dosage. It is important to note that all the recommended maintenance dosages resulted in predicted drug effects for pediatric patients that were within 15% of predicted adult effects.
Discussion Many older AEDs have inadequate information on use in pediatric populations, a consequence of the lack of randomized controlled trials conducted in children.5,6 Three randomized controlled trials were conducted with vigabatrin in children with rCPS.16,17 However, these trials were suspended prior to completion of planned enrollment for administrative reasons. Thus, the individual studies were inadequately powered to characterize the vigabatrin dose– response curve. In the current study, clinical outcome data available from both adult and pediatric populations were used to develop a dose–response model to predict seizure frequency reductions. Appropriate dosing regimens were
determined by comparing exposure–response relationships between adults and children via pharmacometrics analysis. In the present study, vigabatrin dosage predictions were provided for children ≥10 kg and are intended to help clinicians find the optimal vigabatrin dosage for seizure control. The dosage predictions were for both the oral solution and tablet formulations. Because of the flexibility of the oral solution dosage formulation, dosages were predicted for body weights in 5-kg increments. The tablet size was less flexible, since the smallest dosage unit was 500 mg. Therefore, tablet dosages were predicted for wider body weight ranges (25–60 kg). Nevertheless, the predicted efficacy was within 15% of the response predicted at the approved dosages for adults for the maintenance dosage. The dose–response model leading to the pediatric dosage predictions was developed for patients with rCPS who did not have clinically significant renal impairment. Therefore, the pediatric dosage predictions should not be extrapolated to other indications (e.g., infantile spasms) and do not address dosage modifications for patients with renal impairment. Dosage instructions for patients with infantile spasms and renal impairment are provided in the vigabatrin prescribing information.1 In addition, no pharmacometrics analyses were conducted for adverse events. Vigabatrin is an effective treatment for rCPS and is associated with benefits as well as risks, the most notable being retinopathy with the development of peripheral visual field deficits.22 Treatment decisions should be made in consideration of the efficacy as well as the documented safety risks.1,23,24 In summary, the present analysis provides for the first time a prediction of vigabatrin dosages for children supported by a pharmacometrics dose–response analysis.
Acknowledgments The authors acknowledge Susan K. Paulson, Ph.D., of Pharma-Start, LLC, of Northbrook, Ill., and Michael A. Nissen, ELS, of Lundbeck Epilepsia, 55(12):e134–e138, 2014 doi: 10.1111/epi.12825
e138 J. C. Nielsen et al. (Deerfield, IL) for their assistance in the preparation and revision of this manuscript. This assistance was fully funded by Lundbeck.
Conflict of interest These analyses were funded by Lundbeck LLC. Dwain Tolbert is a fulltime employees of Lundbeck, LLC. David Wesche and Mahlaqa Patel were full-time employees of Lundbeck LLC at the time this study was conducted. Jace C. Nielsen and Kenneth G. Kowalski, of Ann Arbor Pharmacometrics Group, Inc. (Ann Arbor, Michigan), are paid consultants of Lundbeck LLC. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
References 1. Lundbeck. Sabril (vigabatrin) prescribing information. Deerfield, IL: Lundbeck; 2013. 2. Ben-Menachem E. Mechanism of action of vigabatrin: correcting misperceptions. Acta Neurol Scand 2011;124 (Suppl. 192):5–15. 3. Grant SM, Heel RC. Vigabatrin: a review of its pharmacodynamics and pharmacokinetic properties, and therapeutic potential in epilepsy and disorders of motor control. Drugs 1991;41:889–926. 4. Willmore LJ, Abelson MB, Ben-Manachem E, et al. Vigabatrin: 2008 update. Epilepsia 2009;50:163–173. 5. Garofalo E. Obtaining pediatric indications for new anti-epileptic drugs: how and when. Epilepsy Res 2006;68:38–42. 6. Chiron C, Dulac O, Pons G. Antiepileptic drug development in children considerations for a revisited strategy. Drugs 2008;68:17–25. 7. Rheims S, Cucherat M, Arzimanoglou A, et al. Greater response to placebo in children than in adults: a systematic review and metaanalysis in drug resistant partial epilepsy. PLoS Med 2008;5:e166, 1223–1237. 8. Ryvlin P, Cucherat M, Rheims S. Risk of sudden unexpected death in epilepsy in patients given adjunctive antiepileptic treatment for refractory seizures: a meta-analysis of placebo-controlled randomized trials. Lancet Neurol 2011;10:961–968. 9. Bhattaram VA, Booth BP, Ramchandani RP, et al. Impact of pharmacometrics on drug approval and labeling decisions: a survey of 42 new drug applications. AAPS J 2005;7:E503–E512.
Epilepsia, 55(12):e134–e138, 2014 doi: 10.1111/epi.12825
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