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Topiramate pharmacokinetics in infants and young children: Contribution of population analysis
Epilepsy Research (2011) 93, 208—211
journal homepage: www.elsevier.com/locate/epilepsyres
SHORT COMMUNICATION
Topiramate pharmacokinetics in infants and young children: Contribution of population analysis Marion Bouillon-Pichault a,b,c,e,∗, Rima Nabbout a,b,d,e, Stephanie Chhun a,b,c,e, Elisabeth Rey a,b,c,e, Catherine Chiron a,b,d,e, Olivier Dulac a,b,d,e, Gerard Pons a,b,c,e, Vincent Jullien a,b,c,e a
Inserm, U663, Paris F-75015, France University Paris Descartes, Faculty of Medicine, Paris F-75005, France c APHP, Groupe Hospitalier Cochin-Saint Vincent de Paul, Paris, France d APHP, Groupe Hospitalier Necker-Enfants Malades, Neurologie Pédiatrique, Paris, France e Université Paris Descartes, Paris, France b
Received 30 June 2010; received in revised form 25 November 2010; accepted 12 December 2010 Available online 21 January 2011
KEYWORDS Epilepsie; Children; Topiramate; Population pharmacokinetics
Summary Purpose: To determine the range of topiramate (TPM) concentrations obtained in children under 4 with the recommended dosage regimen (3—9 mg/kg/day) and to compare them to adult target ranges. Methods: The population pharmacokinetic model developed for TPM, with/without enzyme inducer antiepileptic drugs (EIAEDs) in children was used to determine dosage regimens providing AUC and trough concentrations (Ctrough s) within the adult ranges. Results: TPM pharmacokinetics was described by a one-compartment model. EIAEDs increased the apparent clearance (CL/F) and age and body weight increased the apparent distribution volume (Vd/F). Mean population estimates (% CV interindividual variability) were 0.608/1.15 L/h (13%) for CL/F without/with EIAEDs, 28.6 L (0.2%) for Vd/F and 1.4 h−1 (124%) for the absorption rate constant. Mean AUC0—12 h reached with a 2 mg/kg/day dosing regimen was within described range. A 6—16 mg/kg/day dose depending on age allowed reaching target Ctrough range with the highest probability. Combined EIAEDs led to a 2- and 3-fold decrease in AUC and Ctrough , respectively. Conclusion: TPM dosage of 2/4 mg/kg/day (without/with EIEADs, respectively) provides the AUC reported in adults. In children under 4, alternative dosing regimen should be considered mainly when associated to EIAED to reach Ctrough comparable to adult values. © 2010 Elsevier B.V. All rights reserved.
∗ Corresponding author at: Service de Pharmacologie Clinique, Groupe Hospitalier Cochin-Saint-Vincent de Paul, 74-82 avenue Denfert-Rochereau, 75674 Paris Cedex 14, France. Tel.: +33 1 4048 8209; fax: +33 1 4048 8185. E-mail addresses: [email protected], [email protected] (M. Bouillon-Pichault).
0920-1211/$ — see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.eplepsyres.2010.12.004
Topiramate pharmacokinetics in infants and young children: Contribution of population analysis
Introduction Topiramate (TPM) is a second generation antiepileptic drug (AED) used in monotherapy or adjunctive therapy in adults and children over 2 years with a recommended dosage regimen of 3—6 mg/kg/day in monotherapy and 5—9 mg/kg/day in add-on therapy (Actavis, 2010). The available PK data in children younger than 4 are limited, due to either the small number of patients or the methodology (Glauser et al., 1999; May et al., 2002; Dahlin and Ohman, 2004; Mikaeloff et al., 2004). A 2-fold increase in TPM clearance when combined with enzyme inducers (phenytoin (PHT), carbamazepine (CBZ) or phenobarbitone (PB)) and a lack of effect of valproate (VPA) and lamotrigine (LTG) were described in adults (Bialer et al., 2004) and in children (Dahlin and Ohman, 2004; Mikaeloff et al., 2004). Surprisingly these data were not taken into account neither in dosing recommendations nor in clinical practice as no adaptation of TPM dose is recommended in children with refractory seizures when EIAEDs are associated. To date there is no identified target TPM exposure for infants. However, exposure were reported in adult studies for the recommended dose of 100 mg/day regimen that is to say an AUC0—12 h of 10—40 mg h/L (Sachdeo et al., 1996; Rosenfeld et al., 1997; Doose et al., 2003). Interestingly, a prospective randomized Ctrough controlled study performed in adults evidenced a therapeutic range of 2—10 mg/L for focal epilepsy for which the seizure reduction raised from 39% to 85% (Christensen et al., 2003). Thus, we targeted these two ranges. The aim of our study was to develop a population pharmacokinetic model for TPM in infants and young children aged 6 months to 4 years. This model would allow reconsidering the currently recommended dosage regimen in order to reach targeted exposures and Ctrough .
209
Table 1 Population pharmacokinetic parameters of topiramate in 22 children aged 6 months to 4 years (final model).
Cl/F (L/h) Cl/Finducer (L/h) Vd (L) ka (h−1 ) Tlag (h) covVd—ka (h) 2 ωCl/F 2 ωVd 2 ωKa BW,Vd Age,Vd Multiplicative residual error Additive residual variability
Value
SE
0.608 1.15 28.6 1.04 0.309 0.263 0.0811 0.0557 1.29 0.686 0.305 0.00352 0.122
0.0455 0.12 12 0.31 0.0682 0.11 0.023 0.024 0.44 0.26 0.083 0.0024 0.035
SE: standard error of the estimates; ω2 : interindividual variability; cov: covariance; BW,Vd : influential factor of BW on Cl/F.
Results The model that best fitted the data was a one-compartment model with first order absorption and elimination with a lag time (Tlag). Inter-patient variability was described by an exponential error model, whereas residual variability was described by a combined error model. A covariance term was implemented between the interindividual variabilities of Vd and ka . The covariates kept in the final model were the effect of enzyme inducers on clearance and the effect of BW and age on the distribution volume. The final covariate sub model was then: CL/F (L/h) = 1.15 × EI + 0.608 × (1 − EI)
Methods
V/F (L) = 28.6 ×
The raw data of plasmatic concentrations of TPM of the study published by Mikaeloff et al. (2004) and acquired by our team were used for the present study. This study reported 22 children treated with TPM in association to AEDs. It provides the pharmacokinetic assessment and the method of dosage for plasmatic TPM. Concentration—time data were analyzed using the firstorder conditional estimation with interaction method of the non-linear mixed effects modeling program NONMEM (version VI 2.0) (Beal and Sheiner, 1991). The accuracy and robustness of the final population model were assessed by a visual predictive check. Monte Carlo simulations were used to estimate the Ctrough and the AUC reached with different previously published dosing regimens and for different ages and BW with dosing regimens between 2 and 36 mg/kg/day. Simulated AUC0—12 h and Ctrough obtained from 100 simulations of the database with all dosage regimens described above were compared to targeted Ctrough and AUC ranges. The probability to reach these values for each investigated dosing regimen was obtained by dividing the number of values within the target range by the total number of performed simulations.
ka (h−1 ) = 1.04
BW 70
0.686
×
Age 2.34
0.305
Tlag (h) = 0.309 where EI was equal to 1 if the patients took an enzyme inducer, and to 0 otherwise (Table 1). The absence of bias was observed on the visual predictive check as the TPM observed concentrations were symmetrically distributed around the median and 7.76% of the concentrations were outside the 95% confidence interval (Fig. 1).
Mean AUC0—12 h reached with the currently recommended dosage regimens According to the simulations, the currently recommended TPM dosage regimen of 3—6 mg/kg/day in monotherapy provided an AUC0—12 h between 19.6 ± 3.1 mg/h/L and 39.2 ± 11.7 mg h/L (mean ± standard deviation) for 6month-old children and between 40.8 ± 6.5 mg/h/L and 81.6 ± 24.5 mg/h/L for 4-year-old children. When the combined AED was an EIAED, the currently recommended TPM
M. Bouillon-Pichault et al.
10 8 6 2
4
TPM concentrations – mg/l
6 4 2
TPM concentrations – mg/l
8
12
210
2
4
6
8
10
12
2
Time post dose – hr With EIAED
4
6
8
Time post dose – hr
10
12
Without EIAED
Figure 1 Visual predictive check obtained from 200 simulations of the database with enzyme inducing drug (A) and without enzyme inducing drug (B). Dotted lines indicate the nonparametric 95% confidence interval of the simulations, whereas the points indicate the observed concentrations.
dosage regimen of 5—9 mg/kg/day provided a mean AUC0—12 h between 17.3 ± 15.18 mg/h/L and 31.08 ± 9.33 mg/h/L for 6-month-old children and between 35.9 ± 10.8 mg/h/L and 64.7 ± 19.5 mg/h/L for 4-year-old children. These AUC0—12 h were therefore within or above the range of the 10—40 mg/h/L reported for adults in monotherapy.
Mean Ctrough reached with the currently recommended dosage regimens The currently recommended 3—6 mg/kg/day dosage regimen in monotherapy provided mean Ctrough between 0.88 ± 0.30 mg/L and 1.69 ± 0.95 mg/L for 6-month-old children and between 2.78 ± 0.62 mg/L and 5.55 ± 2.09 mg/L for 4-year-old children whereas the currently recommended 5—9 mg/kg/day dosage regimen in association provided mean Ctrough between 0.55 ± 0.40 mg/L and 0.83 ± 0.63 mg/L for 6-month-old children and between 2.02 ± 0.95 mg/L and 3.62 ± 1.63 mg/L for 4-year-old children when combined with an EIAED. These Ctrough were therefore within or below the range of the described target Ctrough in adults.
Dosage allowing the highest probability to reach the adult AUC0—12 h and Ctrough range When no enzyme inducer is combined to TPM, a dosage regimen between 2 and 3 mg/kg/day would allow reaching the AUC0—12 h described range with a probability higher that 95%. However, to reach Ctrough within the target range with the highest probabilities (higher that 80%), the dosage regimen should be increased until 6—16 mg/kg/day. When enzyme inducers are co-administrated, a dosage regimen of 3—5 mg/kg/day would allow to reach an AUC0—12 h within the described range (p > 95%) whereas this dosage regimen should be increased until 14—36 mg/kg/day to reach Ctrough within the target range with the highest probability (Fig. 2).
Discussion This study provides the first population pharmacokinetic model for TPM. Although the studied population only comprised 22 children, it is the largest population studied in this age range. It confirms the 2-fold increase in weight-normalized clearance compared to adult values (13—26 mL/h/kg for a 70-kg adult without EIAED (Perucca, 2006) vs 47.15 ± 12.85 mL/h/kg in our study). TPM volume of distribution was found to increase with age and bodyweight. The concomitant intake of EIAEDs was found to increase TPM clearance and significantly explains 2 the interindividual variability of TPM clearance (ωCl from 0.178 to 0.0811). Such an effect of the inducers on the clearance is in agreement with previously published data in adults and children (Glauser et al., 1999; Dahlin and Ohman, 2004). However, our simulations allowed to quantify this effect and showed that inducers produce a 2-fold increase in clearance of TPM. TPM dosing should be adjusted when co-administrated to EIAED. Monte Carlo simulations with the currently recommended TPM dosage regimen provide AUC0—12 h which clearly exceeds the superior bound of 40 mg h/L described in adults. It is the opposite for mean Ctrough which is below the superior adult bound of 10 mg h/L and would need a dose up to 36 mg/kg/day to reach the Ctrough adult target for 6month-old children when an enzyme inducer is combined. Therefore, considering AUC would imply to recommend lower doses, whereas considering Ctrough would imply to recommend higher doses. Such a discrepancy in dosing depending on the targeted parameter (AUC0—12 h or Ctrough ) is due to the important decrease in T1/2 in children: from 21 h in adults to 11.19 ± 3.11 h in infants and young children, and even 5.65 ± 3.39 h when an EIAED is combined. Therefore, an increase of the number of daily intakes or the development of an extended release formulation should be considered in this age group instead of increasing the daily dose. Furthermore, as age influenced TPM distribution volume, the younger the child, the lower the concentrations
Topiramate pharmacokinetics in infants and young children: Contribution of population analysis
211
Figure 2 Evolution of probabilities to reach AUC0—12 h (A) and Ctrough (B) within the described range for different ages obtained by Monte Carlo simulations regarding the daily dosing regimen in mg/kg/day (twice a day regimen).
and AUC are. Thus, and according to this study, higher doses should be considered mainly for children below 1 year old. The current recommendations for TPM dosage regimen do not take into account the inducing properties of concomitant AEDs. We confirm the major influence of inducing AEDs on TPM clearance and TPM dosing regimen should be increased to anticipate the effect of the addition of enzyme inducers or decreased to prevent adverse events when enzyme inducers are withdrawn. However, these modifications are based on a pharmacokinetic perspective and it should also rely on type of disease and safety. To date, a Ctrough therapeutic range was established in adults but no relationship between TPM exposure and its efficacy and safety have been demonstrated in children. This relationship would be valuable to optimize the safety and efficacy of the administration of TPM in children. Thus the present model would be a useful tool to establish the optimal dosage regimen in children.
Conflicts of interest 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. None of the authors has any conflict of interest to disclose.
References Actavis, 2010. Product Information TOPIRAMATE ACTAVIS 100 mg cp pellic, Actavis France.
Beal, S.L., Sheiner, L.B., 1991. NONMEM User’s Guide. NONMEM Project Group, University of California at San Francisco, San Francisco. Bialer, M., Doose, D.R., et al., 2004. Pharmacokinetic interactions of topiramate. Clin. Pharmacokinet. 43 (12), 763—780. Christensen, J., Andreasen, F., et al., 2003. Randomized, concentration-controlled trial of topiramate in refractory focal epilepsy. Neurology 61 (9), 1210—1218. Dahlin, M.G., Ohman, I.K., 2004. Age and antiepileptic drugs influence topiramate plasma levels in children. Pediatr. Neurol. 31 (4), 248—253. Doose, D.R., Brodie, M.J., et al., 2003. Topiramate and lamotrigine pharmacokinetics during repetitive monotherapy and combination therapy in epilepsy patients. Epilepsia 44 (7), 917—922. Glauser, T.A., Miles, M.V., et al., 1999. Topiramate pharmacokinetics in infants. Epilepsia 40 (6), 788—791. May, T.W., Rambeck, B., et al., 2002. Serum concentrations of topiramate in patients with epilepsy: influence of dose, age, and comedication. Ther. Drug Monit. 24 (3), 366—374. Mikaeloff, Y., Rey, E., et al., 2004. Topiramate pharmacokinetics in children with epilepsy aged from 6 months to 4 years. Epilepsia 45 (11), 1448—1452. Perucca, E., 2006. Clinical pharmacokinetics of new-generation antiepileptic drugs at the extremes of age. Clin. Pharmacokinet. 45 (4), 351—363. Rosenfeld, W.E., Liao, S., et al., 1997. Comparison of the steadystate pharmacokinetics of topiramate and valproate in patients with epilepsy during monotherapy and concomitant therapy. Epilepsia 38 (3), 324—333. Sachdeo, R.C., Sachdeo, S.K., et al., 1996. Steady-state pharmacokinetics of topiramate and carbamazepine in patients with epilepsy during monotherapy and concomitant therapy. Epilepsia 37 (8), 774—780.
journal homepage: www.elsevier.com/locate/epilepsyres
SHORT COMMUNICATION
Topiramate pharmacokinetics in infants and young children: Contribution of population analysis Marion Bouillon-Pichault a,b,c,e,∗, Rima Nabbout a,b,d,e, Stephanie Chhun a,b,c,e, Elisabeth Rey a,b,c,e, Catherine Chiron a,b,d,e, Olivier Dulac a,b,d,e, Gerard Pons a,b,c,e, Vincent Jullien a,b,c,e a
Inserm, U663, Paris F-75015, France University Paris Descartes, Faculty of Medicine, Paris F-75005, France c APHP, Groupe Hospitalier Cochin-Saint Vincent de Paul, Paris, France d APHP, Groupe Hospitalier Necker-Enfants Malades, Neurologie Pédiatrique, Paris, France e Université Paris Descartes, Paris, France b
Received 30 June 2010; received in revised form 25 November 2010; accepted 12 December 2010 Available online 21 January 2011
KEYWORDS Epilepsie; Children; Topiramate; Population pharmacokinetics
Summary Purpose: To determine the range of topiramate (TPM) concentrations obtained in children under 4 with the recommended dosage regimen (3—9 mg/kg/day) and to compare them to adult target ranges. Methods: The population pharmacokinetic model developed for TPM, with/without enzyme inducer antiepileptic drugs (EIAEDs) in children was used to determine dosage regimens providing AUC and trough concentrations (Ctrough s) within the adult ranges. Results: TPM pharmacokinetics was described by a one-compartment model. EIAEDs increased the apparent clearance (CL/F) and age and body weight increased the apparent distribution volume (Vd/F). Mean population estimates (% CV interindividual variability) were 0.608/1.15 L/h (13%) for CL/F without/with EIAEDs, 28.6 L (0.2%) for Vd/F and 1.4 h−1 (124%) for the absorption rate constant. Mean AUC0—12 h reached with a 2 mg/kg/day dosing regimen was within described range. A 6—16 mg/kg/day dose depending on age allowed reaching target Ctrough range with the highest probability. Combined EIAEDs led to a 2- and 3-fold decrease in AUC and Ctrough , respectively. Conclusion: TPM dosage of 2/4 mg/kg/day (without/with EIEADs, respectively) provides the AUC reported in adults. In children under 4, alternative dosing regimen should be considered mainly when associated to EIAED to reach Ctrough comparable to adult values. © 2010 Elsevier B.V. All rights reserved.
∗ Corresponding author at: Service de Pharmacologie Clinique, Groupe Hospitalier Cochin-Saint-Vincent de Paul, 74-82 avenue Denfert-Rochereau, 75674 Paris Cedex 14, France. Tel.: +33 1 4048 8209; fax: +33 1 4048 8185. E-mail addresses: [email protected], [email protected] (M. Bouillon-Pichault).
0920-1211/$ — see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.eplepsyres.2010.12.004
Topiramate pharmacokinetics in infants and young children: Contribution of population analysis
Introduction Topiramate (TPM) is a second generation antiepileptic drug (AED) used in monotherapy or adjunctive therapy in adults and children over 2 years with a recommended dosage regimen of 3—6 mg/kg/day in monotherapy and 5—9 mg/kg/day in add-on therapy (Actavis, 2010). The available PK data in children younger than 4 are limited, due to either the small number of patients or the methodology (Glauser et al., 1999; May et al., 2002; Dahlin and Ohman, 2004; Mikaeloff et al., 2004). A 2-fold increase in TPM clearance when combined with enzyme inducers (phenytoin (PHT), carbamazepine (CBZ) or phenobarbitone (PB)) and a lack of effect of valproate (VPA) and lamotrigine (LTG) were described in adults (Bialer et al., 2004) and in children (Dahlin and Ohman, 2004; Mikaeloff et al., 2004). Surprisingly these data were not taken into account neither in dosing recommendations nor in clinical practice as no adaptation of TPM dose is recommended in children with refractory seizures when EIAEDs are associated. To date there is no identified target TPM exposure for infants. However, exposure were reported in adult studies for the recommended dose of 100 mg/day regimen that is to say an AUC0—12 h of 10—40 mg h/L (Sachdeo et al., 1996; Rosenfeld et al., 1997; Doose et al., 2003). Interestingly, a prospective randomized Ctrough controlled study performed in adults evidenced a therapeutic range of 2—10 mg/L for focal epilepsy for which the seizure reduction raised from 39% to 85% (Christensen et al., 2003). Thus, we targeted these two ranges. The aim of our study was to develop a population pharmacokinetic model for TPM in infants and young children aged 6 months to 4 years. This model would allow reconsidering the currently recommended dosage regimen in order to reach targeted exposures and Ctrough .
209
Table 1 Population pharmacokinetic parameters of topiramate in 22 children aged 6 months to 4 years (final model).
Cl/F (L/h) Cl/Finducer (L/h) Vd (L) ka (h−1 ) Tlag (h) covVd—ka (h) 2 ωCl/F 2 ωVd 2 ωKa BW,Vd Age,Vd Multiplicative residual error Additive residual variability
Value
SE
0.608 1.15 28.6 1.04 0.309 0.263 0.0811 0.0557 1.29 0.686 0.305 0.00352 0.122
0.0455 0.12 12 0.31 0.0682 0.11 0.023 0.024 0.44 0.26 0.083 0.0024 0.035
SE: standard error of the estimates; ω2 : interindividual variability; cov: covariance; BW,Vd : influential factor of BW on Cl/F.
Results The model that best fitted the data was a one-compartment model with first order absorption and elimination with a lag time (Tlag). Inter-patient variability was described by an exponential error model, whereas residual variability was described by a combined error model. A covariance term was implemented between the interindividual variabilities of Vd and ka . The covariates kept in the final model were the effect of enzyme inducers on clearance and the effect of BW and age on the distribution volume. The final covariate sub model was then: CL/F (L/h) = 1.15 × EI + 0.608 × (1 − EI)
Methods
V/F (L) = 28.6 ×
The raw data of plasmatic concentrations of TPM of the study published by Mikaeloff et al. (2004) and acquired by our team were used for the present study. This study reported 22 children treated with TPM in association to AEDs. It provides the pharmacokinetic assessment and the method of dosage for plasmatic TPM. Concentration—time data were analyzed using the firstorder conditional estimation with interaction method of the non-linear mixed effects modeling program NONMEM (version VI 2.0) (Beal and Sheiner, 1991). The accuracy and robustness of the final population model were assessed by a visual predictive check. Monte Carlo simulations were used to estimate the Ctrough and the AUC reached with different previously published dosing regimens and for different ages and BW with dosing regimens between 2 and 36 mg/kg/day. Simulated AUC0—12 h and Ctrough obtained from 100 simulations of the database with all dosage regimens described above were compared to targeted Ctrough and AUC ranges. The probability to reach these values for each investigated dosing regimen was obtained by dividing the number of values within the target range by the total number of performed simulations.
ka (h−1 ) = 1.04
BW 70
0.686
×
Age 2.34
0.305
Tlag (h) = 0.309 where EI was equal to 1 if the patients took an enzyme inducer, and to 0 otherwise (Table 1). The absence of bias was observed on the visual predictive check as the TPM observed concentrations were symmetrically distributed around the median and 7.76% of the concentrations were outside the 95% confidence interval (Fig. 1).
Mean AUC0—12 h reached with the currently recommended dosage regimens According to the simulations, the currently recommended TPM dosage regimen of 3—6 mg/kg/day in monotherapy provided an AUC0—12 h between 19.6 ± 3.1 mg/h/L and 39.2 ± 11.7 mg h/L (mean ± standard deviation) for 6month-old children and between 40.8 ± 6.5 mg/h/L and 81.6 ± 24.5 mg/h/L for 4-year-old children. When the combined AED was an EIAED, the currently recommended TPM
M. Bouillon-Pichault et al.
10 8 6 2
4
TPM concentrations – mg/l
6 4 2
TPM concentrations – mg/l
8
12
210
2
4
6
8
10
12
2
Time post dose – hr With EIAED
4
6
8
Time post dose – hr
10
12
Without EIAED
Figure 1 Visual predictive check obtained from 200 simulations of the database with enzyme inducing drug (A) and without enzyme inducing drug (B). Dotted lines indicate the nonparametric 95% confidence interval of the simulations, whereas the points indicate the observed concentrations.
dosage regimen of 5—9 mg/kg/day provided a mean AUC0—12 h between 17.3 ± 15.18 mg/h/L and 31.08 ± 9.33 mg/h/L for 6-month-old children and between 35.9 ± 10.8 mg/h/L and 64.7 ± 19.5 mg/h/L for 4-year-old children. These AUC0—12 h were therefore within or above the range of the 10—40 mg/h/L reported for adults in monotherapy.
Mean Ctrough reached with the currently recommended dosage regimens The currently recommended 3—6 mg/kg/day dosage regimen in monotherapy provided mean Ctrough between 0.88 ± 0.30 mg/L and 1.69 ± 0.95 mg/L for 6-month-old children and between 2.78 ± 0.62 mg/L and 5.55 ± 2.09 mg/L for 4-year-old children whereas the currently recommended 5—9 mg/kg/day dosage regimen in association provided mean Ctrough between 0.55 ± 0.40 mg/L and 0.83 ± 0.63 mg/L for 6-month-old children and between 2.02 ± 0.95 mg/L and 3.62 ± 1.63 mg/L for 4-year-old children when combined with an EIAED. These Ctrough were therefore within or below the range of the described target Ctrough in adults.
Dosage allowing the highest probability to reach the adult AUC0—12 h and Ctrough range When no enzyme inducer is combined to TPM, a dosage regimen between 2 and 3 mg/kg/day would allow reaching the AUC0—12 h described range with a probability higher that 95%. However, to reach Ctrough within the target range with the highest probabilities (higher that 80%), the dosage regimen should be increased until 6—16 mg/kg/day. When enzyme inducers are co-administrated, a dosage regimen of 3—5 mg/kg/day would allow to reach an AUC0—12 h within the described range (p > 95%) whereas this dosage regimen should be increased until 14—36 mg/kg/day to reach Ctrough within the target range with the highest probability (Fig. 2).
Discussion This study provides the first population pharmacokinetic model for TPM. Although the studied population only comprised 22 children, it is the largest population studied in this age range. It confirms the 2-fold increase in weight-normalized clearance compared to adult values (13—26 mL/h/kg for a 70-kg adult without EIAED (Perucca, 2006) vs 47.15 ± 12.85 mL/h/kg in our study). TPM volume of distribution was found to increase with age and bodyweight. The concomitant intake of EIAEDs was found to increase TPM clearance and significantly explains 2 the interindividual variability of TPM clearance (ωCl from 0.178 to 0.0811). Such an effect of the inducers on the clearance is in agreement with previously published data in adults and children (Glauser et al., 1999; Dahlin and Ohman, 2004). However, our simulations allowed to quantify this effect and showed that inducers produce a 2-fold increase in clearance of TPM. TPM dosing should be adjusted when co-administrated to EIAED. Monte Carlo simulations with the currently recommended TPM dosage regimen provide AUC0—12 h which clearly exceeds the superior bound of 40 mg h/L described in adults. It is the opposite for mean Ctrough which is below the superior adult bound of 10 mg h/L and would need a dose up to 36 mg/kg/day to reach the Ctrough adult target for 6month-old children when an enzyme inducer is combined. Therefore, considering AUC would imply to recommend lower doses, whereas considering Ctrough would imply to recommend higher doses. Such a discrepancy in dosing depending on the targeted parameter (AUC0—12 h or Ctrough ) is due to the important decrease in T1/2 in children: from 21 h in adults to 11.19 ± 3.11 h in infants and young children, and even 5.65 ± 3.39 h when an EIAED is combined. Therefore, an increase of the number of daily intakes or the development of an extended release formulation should be considered in this age group instead of increasing the daily dose. Furthermore, as age influenced TPM distribution volume, the younger the child, the lower the concentrations
Topiramate pharmacokinetics in infants and young children: Contribution of population analysis
211
Figure 2 Evolution of probabilities to reach AUC0—12 h (A) and Ctrough (B) within the described range for different ages obtained by Monte Carlo simulations regarding the daily dosing regimen in mg/kg/day (twice a day regimen).
and AUC are. Thus, and according to this study, higher doses should be considered mainly for children below 1 year old. The current recommendations for TPM dosage regimen do not take into account the inducing properties of concomitant AEDs. We confirm the major influence of inducing AEDs on TPM clearance and TPM dosing regimen should be increased to anticipate the effect of the addition of enzyme inducers or decreased to prevent adverse events when enzyme inducers are withdrawn. However, these modifications are based on a pharmacokinetic perspective and it should also rely on type of disease and safety. To date, a Ctrough therapeutic range was established in adults but no relationship between TPM exposure and its efficacy and safety have been demonstrated in children. This relationship would be valuable to optimize the safety and efficacy of the administration of TPM in children. Thus the present model would be a useful tool to establish the optimal dosage regimen in children.
Conflicts of interest 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. None of the authors has any conflict of interest to disclose.
References Actavis, 2010. Product Information TOPIRAMATE ACTAVIS 100 mg cp pellic, Actavis France.
Beal, S.L., Sheiner, L.B., 1991. NONMEM User’s Guide. NONMEM Project Group, University of California at San Francisco, San Francisco. Bialer, M., Doose, D.R., et al., 2004. Pharmacokinetic interactions of topiramate. Clin. Pharmacokinet. 43 (12), 763—780. Christensen, J., Andreasen, F., et al., 2003. Randomized, concentration-controlled trial of topiramate in refractory focal epilepsy. Neurology 61 (9), 1210—1218. Dahlin, M.G., Ohman, I.K., 2004. Age and antiepileptic drugs influence topiramate plasma levels in children. Pediatr. Neurol. 31 (4), 248—253. Doose, D.R., Brodie, M.J., et al., 2003. Topiramate and lamotrigine pharmacokinetics during repetitive monotherapy and combination therapy in epilepsy patients. Epilepsia 44 (7), 917—922. Glauser, T.A., Miles, M.V., et al., 1999. Topiramate pharmacokinetics in infants. Epilepsia 40 (6), 788—791. May, T.W., Rambeck, B., et al., 2002. Serum concentrations of topiramate in patients with epilepsy: influence of dose, age, and comedication. Ther. Drug Monit. 24 (3), 366—374. Mikaeloff, Y., Rey, E., et al., 2004. Topiramate pharmacokinetics in children with epilepsy aged from 6 months to 4 years. Epilepsia 45 (11), 1448—1452. Perucca, E., 2006. Clinical pharmacokinetics of new-generation antiepileptic drugs at the extremes of age. Clin. Pharmacokinet. 45 (4), 351—363. Rosenfeld, W.E., Liao, S., et al., 1997. Comparison of the steadystate pharmacokinetics of topiramate and valproate in patients with epilepsy during monotherapy and concomitant therapy. Epilepsia 38 (3), 324—333. Sachdeo, R.C., Sachdeo, S.K., et al., 1996. Steady-state pharmacokinetics of topiramate and carbamazepine in patients with epilepsy during monotherapy and concomitant therapy. Epilepsia 37 (8), 774—780.