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- Population Pharmacokinetic Modeling
Purpose: To develop a population pharmacokinetic model to evaluate the demographic and physiologic determinants of levetiracetam (LEV) pharmacokinetics (PK) and to suggest recommended doses of LEV in children.
Methods: LEV PK were investigated in a prospective open trial of LEV as adjunctive therapy using a population approach performed with NONMEM (Nonlinear Mixed Effects Model) on 170 LEV concentration–time records and covariate information from 44 children between 4 and 16 years of age. Possible associations between pharmacokinetic parameters and age, gender, body weight, creatinine clearance, and concomitant antiepileptic drugs (AEDs) were assessed. The final model was used to perform Monte Carlo simulations in order to identify the dosing regimens that should achieve the same nominal target concentration range as in adults.
Results: LEV PK were well described by a one-compartment model with first-order absorption and elimination. Both LEV apparent clearance and distribution volume were related to body weight, and no pharmacokinetic interaction was observed. Monte Carlo simulations showed that a 10mg/kg twice daily (b.i.d.) regimen provides a plasma concentration similar to that obtained in adults for the recommended 500 mg b.i.d. starting dose, and that a 20 mg/kg b.i.d. regimen would achieve the previously described 6–20 mg/L target range for the trough concentration.
Discussion: Our results support the use of a weight-based LEV dosing regimen and provide a basis for a recommended pediatric dosage regimen. The relationship between LEV plasma concentrations and clinical effect has not been evaluated fully and could differ between adults and children. Clinical studies should be able to validate these dosing recommendations.
Levetiracetam (LEV) is a newly developed antiepileptic drug (AED) that has been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency for clinical use in adults since the year 2000. It has a unique mechanism of action different from that of classical AEDs, as it acts via the involvement of a novel binding site, the synaptic vesicle protein 2A (Lynch et al., 2004). In adults, adjunctive therapy with LEV was shown to be well tolerated and effective in controlling partial seizures (Cereghino et al., 2000; Shorvon et al., 2000). Similar results were shown in children between 4 and 16 years of age, as nearly half of the subjects on LEV had a more than 50% reduction in seizure frequency and 7% became seizure free with a LEV target dose of 60 mg/kg daily (Glauser et al., 2006).
After oral administration, LEV is completely absorbed and it is not bound to plasma proteins. Unlike other AEDs that are metabolized, LEV is primarily excreted unchanged by the kidney. Only one-third of LEV is metabolized into an inactive compound via a metabolic pathway involving enzymatic hydrolysis. LEV is not metabolized by the hepatic cytochrome P450 system (Patsalos, 2000).
The pharmacokinetics (PK) of LEV are well characterized in adults (Patsalos, 2000; Radtke, 2001; Pigeolet et al., 2007), but information in children is limited (Pellock et al., 2001; Fountain et al., 2007; Glauser et al., 2007; Snoeck et al., 2007), with some discrepancies among studies. On the one hand, three different LEV pharmacokinetic studies performed in either infants (ages ranging from 2.3 to 46.2 months) or children (ages ranging from 4 to 12 years) found similar weight-normalized clearances (approximately 1–1.5 ml/min/kg) and elimination half-lives (4–6 h) (Pellock et al., 2001; Fountain et al., 2007; Glauser et al., 2007). These results strongly suggested that both apparent clearance and distribution volume of LEV are directly proportional to body weight during childhood and that the pediatric LEV dosing regimen should be expressed in mg per kg and should furthermore be constant throughout a wide age range in order to provide similar plasma concentrations in pediatric patients of different ages, from a 2-month-old infant to a 12-year old child.
However, on the other hand, a population pharmacokinetic analysis performed in children from 3 months to 18 years revealed conflicting results, as the apparent clearance of LEV increased less rapidly than body weight, suggesting that the weight-normalized dose should decrease with increasing body weights (Snoeck et al., 2007).
Considering all the results currently available, the relationship between the PK parameters of LEV and age and/or body weight, and, therefore, the need for adjusting the LEV dosing regimen with respect to age or body weight still appear to be under debate in some instances.
Population PK is the optimal methodology for investigating the relationships between the pharmacokinetic parameters of a given drug and the possibly relevant covariates. Furthermore, because a population pharmacokinetic model also takes into account the interindividual and intraindividual variabilities of pharmacokinetic parameters, a population approach makes possible the determination of the dosing regimen to achieve plasma concentrations within a given target range. Because of the lack of knowledge regarding the specific pharmacokinetic–pharmacodynamic relationship of LEV in children as a function of the epilepsy syndrome under investigation, an acceptable endpoint would be the achievement of the same LEV steady-state area under the curve (AUC) as in adults for the recommended adult doses. Another possibility could be the achievement of the same target range of trough concentrations (i.e., 6–20 mg/L) that was previously suggested in adults (Johannessen et al., 2003).
The purpose of the present study was to assess LEV PK in a pediatric population using a population approach to identify demographic and physiologic determinants of LEV concentration, including the effects of concomitant AEDs. The optimal pediatric dosing regimens were also defined to achieve plasma concentrations within a given target range.
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- Population Pharmacokinetic Modeling
In the present study, we developed a one-compartment model with first-order absorption and elimination that characterized the pharmacokinetic profile of LEV oral administration in children. The model we developed describes the data adequately, except for a few (i.e., 8 of 49) concentrations determined <1.5 h after the first LEV dose. This alteration in the fit is probably not clinically significant because it does not involve steady-state data. The predictive ability of our model is furthermore evidenced by the close agreement between our results and the results of previous studies that are displayed in Table 4 (Pellock et al., 2001; Fountain et al., 2007). Moreover, our mean CL/F and V/F (2.47 L/h and 21.9 L) are also similar to the values found in the previous population pharmacokinetic analysis performed in children (2.17 L/h and 21.5 L) (Snoeck et al., 2007).
Table 4. Levetiracetam pharmacokinetic parameters from literature and from our study
|Dose||Parameters||Fountain et al., 2007 N = 21||Pellock et al., 2001 N = 24||Our study N = 44|
|10 mg/kg b.i.d.||AUC0–12 (mg h/L)||145 ± 44||/||142 ± 33|
|C12 h (mg/L)||8.4 ± 3.8||/||6.4 ± 2.7|
|T1/2 (h)||4.9 ± 0.6||/||6.8 ± 1.5|
|CL/F (ml/min/kg)||1.14 ± 0.18||/||1.24 ± 0.29|
|20 mg/kg b.i.d.||AUC0–12 (mg h/L)||322 ± 71||241 ± 76||283 ± 65|
|C12 h (mg/L)||15.6 ± 5.3||/||12.7 ± 4.7|
|T1/2 (h)||4.9 ± 0.4||6.0 ± 1.1||6.8 ± 1.5|
|CL/F (ml/min/kg)||1.10 ± 0.16||1.43 ± 0.36||1.24 ± 0.29|
|V/F (L/kg)||/||0.72 ± 0.12||0.72 ± 0.21|
|30 mg/kg b.i.d.||AUC0–12 (mg h/L)||433 ± 94||/||425 ± 98|
|C12 h (mg/L)||20.6 ± 5.8||/||19.1 ± 7.2|
|T1/2 (h)||4.9 ± 0.7||/||6.8 ± 1.5|
|CL/F (ml/min/kg)||1.12 ± 0.119||/||1.24 ± 0.29|
Although the interindividual variability of the absorption lag-time could not be estimated, the absorption profile defined by our model is in agreement with the data found in adults. For instance, a dosing regimen of 500 mg b.i.d. in adults leads to a mean Cmax of 17 mg/L (Patsalos, 2004). Considering the mean population parameters of our model, and the median BW in our population (33 kg), the pediatric dose of 10 mg/kg b.i.d., which is equivalent to the 500-mg b.i.d. adult dose, would provide a very consistent mean Cmax of 13.5 mg/L.
Body weight was identified as the sole covariate that explained interindividual variability on both LEV apparent plasma clearance and distribution volume. Although LEV is eliminated mainly unchanged via renal excretion, creatinine clearance was not found to be a significant covariate. This can probably be explained by the natural maturation of the renal function during childhood, so that creatinine clearance evolves in parallel with age and, therefore, with body weight. The fact that creatinine production increases with the muscular mass, which is reflected by body weight, is a supplemental argument explaining that all the information on the interindividual variability of LEV PK provided by creatinine clearance is included in the relationship between LEV pharmacokinetic parameters and body weight. Finally, the predictive ability of calculated creatinine clearance is probably hampered by this confusion between production and clearance. Indeed, when standard equations, which assume a normal creatinine production, are used for children with low creatinine value, nonphysiologic creatinine clearance was sometimes estimated, probably because the low creatinine concentration resulted from a low creatinine production rather than a high clearance. Furthermore, no child with impaired renal function was included in the study, which also explains the lack of relationship between apparent clearance and creatinine clearance in our model. Therefore, our model is not relevant for children with renal failure, and the dosing recommendations we defined cannot be applied to them.
In the allometric model, an exponent value close to 1 suggests that CL/F and V/F are directly proportional to body weight. For instance, considering CL/F, the relationship CL/F = 2.47x(BW/33)0.87 is close to 2.47x(BW/33), which means that CL/F is directly proportional to BW as it is close to 0.074xBW. This is also consistent with previously published studies (Pellock et al., 2001; Fountain et al., 2007; Glauser et al., 2007). Therefore, our results support the use of a weight-based LEV dosing regimen in children between 4.6 and 16.6 years of age and weighing between 16 and 65 kg. According to the results of the Monte Carlo simulations, two different therapeutic dosing strategies can be used in children with epilepsy. The first one confirmed the current recommendations that consist of starting LEV therapy at a 10 mg/kg b.i.d. dosing regimen, followed by further dose adjustment according to the clinical outcome. Indeed, from a pharmacokinetic point of view, a 10 mg/kg b.i.d. pediatric dose provides the same plasma steady-state AUC as the 500 mg b.i.d. dose in adults, which is the starting recommended dose of LEV for adults. Furthermore, our study provides evidence that children weighing up to 65 kg need a higher dose if a 500-mg dose is considered for a 70-kg adult. So, for an equivalent body weight of 60 kg, adolescents need higher LEV doses than adults in order to achieve the same plasma concentration. This result is also consistent with those of previous studies (Pellock et al., 2001; Fountain et al., 2007; Glauser et al., 2007). The second strategy would be to give an LEV starting dose at a 20 mg/kg b.i.d. dose in order to have the highest probability (90%) of reaching the 6–20 mg/L target range of trough concentrations that was defined in adults. However, clinically some patients would not tolerate this starting dose and would become excessively sleepy. But because trough concentrations comprised a minority of our data (i.e., 25%), our dosing proposal based on target trough concentrations should be validated on a larger population. Furthermore, the relationship between LEV plasma concentrations and clinical effect has not been evaluated and could differ between adults and children. This assumption also emphasizes the need for clinical studies to validate these dosing recommendations.