Rodrigues Christelle (1), Chhun Stéphanie (2), Chiron Catherine (1), Dulac Olivier (1), Rey Elisabeth (1), Pons Gérard (1), Jullien Vincent (1, 3)
(1) INSERM U1129, Paris, France; Paris Descartes University; CEA, Gif-sur-Yvette, France (2) Assistance Publique – Hôpitaux de Paris, Hôpital Necker-Enfants Malades – Enfants Malades, Inserm U1151, INEM, Laboratoire d’immunologie biologique, Paris, France (3) Service de Pharmacologie, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75015 Paris, France
Objectives: Valproic acid (VPA) is an antiepileptic drug widely used in the pediatric population. A sustained-release (SR) granule formulation facilitating oral drug intake by children is available at a recommended mean daily dose between 20 and 30 mg/kg [1]. No pediatric PK data are available to date for this SR granule formulation. So, the present work primarily aimed to develop a population PK model for this form in children with epilepsy. Afterwards, the final model was used to evaluate if dosage recommendations are adequate to obtain a trough concentration (Ctrough) within the reference range of 50-100 mg/L [2] and, if not, which doses would be more suitable. A secondary objective was to take into account the non-linearity due to the saturable protein binding in order to investigate the relationships between the doses and the total and free concentrations of VPA.
Methods: Ninety-eight children (1 – 17.6 years, 325 plasma samples) were included in the study. The model was built with NONMEM 7.3. One and two compartment models with zero or first order absorption and elimination were tested. Flip-flop was handled by adding a constant C to the model and by parameterizing ka to be equal to the sum of ke and C [3]. Three models were tested to describe the protein binding properties of VPA: 1) the addition of total daily dose (TDD) as a covariate on VPA clearance ; 2) a maximum effect (Emax) model where the TDD is also used as a covariate on CL [4]; and 3) a physiological protein-binding model [5] where unbound clearance and volume are estimated, and in which the total concentration is predicted from the apparent maximum concentration of the binding site for VPA (Bmax) and the apparent dissociation constant of VPA from plasma proteins (Kd). Since no unbound data was available in the present study, Bmax and Kd were fixed to their previously determined values of 130 and 7.8 mg/L, respectively [6]. Body weight (BW), age, sex, height, body surface area, creatinine, SGOT, SGPT and concomitant antiepileptic drugs were tested as potential covariates. Covariates were included in the model using a power function. Using the final model, Monte Carlo simulations were performed for doses of 20, 30, 40 and 60 mg/kg/day and BW between 10 and 70 kg, in order to predict steady-state Ctrough, maximum concentration (Cmax) and area under the curve (AUC) for the total and free drug. The probability to obtain total Ctrough between 50 and 100 mg/L was calculated and the associated free VPA range was determined.
Results: A one compartment model, with first-order absorption and flip-flop parameterization and linear elimination was used to describe the data. The saturable protein binding of VPA was best described with model 3). It allowed lower values of OFV and BIC in addition to be more physiological and mechanistic. Typical values for unbound VPA clearance and distribution volume were 6.24 L/h/70kg and 130 L/70kg respectively, corresponding to total values of 0.624 L/h/70kg and 1.3 L/70kg. Both parameters were related to body weight via allometric models. VPA total and unbound Ctrough, Cmax and AUC increased with the total daily dose and with BW. The range of unbound Ctrough corresponding to the total Ctrough within the therapeutic range was 4.2 – 14.8 mg/L. The highest probability to obtain a Ctrough within the target range for 10 kg children was obtained with a 40 mg/kg daily, whereas daily doses of 30 mg/kg and 20 mg/kg were found appropriate for 20 – 30 kg and ≥ 40 kg children respectively. However, for these same doses, the exposure to unbound VPA could differ by 40 %.
Conclusions: The first pharmacokinetic model for a pediatric VPA formulation, sustained release granules, was developed, evidencing the occurrence of flip-flop due to its modified rate of absorption. This model took into account the nonlinear relationship between dose and clearance secondary to the saturable protein binding. The model also shows that VPA pharmacokinetic parameters are related to BW by allometric functions. If the present study supports the current dose recommendations of 20-30mg/kg/day, except for children under 20 kg who may need higher doses, it also highlights the need for further research on the pharmacokinetics/pharmacodynamic profile of unbound VPA.
References:
[1] Résumé des caractéristiques du produit (2013) Micropakine L.P.
[2] Patsalos PN, Berry DJ, Bourgeois BFD, Cloyd JC, Glauser TA, Johannessen SI, Leppik IE, Tomson T, Perucca E (2008) Antiepileptic drugs – best practice guidelines for therapeutic drug monitoring : A position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia 49:1239–1276.
[3] Yáñez JA, Remsberg CM, Sayre CL, Forrest ML, Davies NM (2012) Flip-flop pharmacokinetics – delivering a reversal of disposition: challenges and opportunities during drug development. Ther Deliv 2:643–672.
[4] Ding J, Wang Y, Lin W, Wang C, Zhao L, Li X, Zhao Z, Miao L, Jiao Z (2015) A Population Pharmacokinetic Model of Valproic Acid in Pediatric Patients with Epilepsy : A Non-Linear Pharmacokinetic Model Based on Protein-Binding Saturation. Clin Pharmacokinet 54:305–317.
[5] Holford N (2011) Protein binding model.http://www.cognigencorp.com/nonmem/current/2011-May/2497.html. Accessed 20 Jun 2017.
[6] Ueshima S, Aiba T, Makita T, Nishihara S, Kitamura Y, Kurosaki Y, Kawasaki H, Sendo T, Ohtsuka Y, Gomita Y (2008) Characterization of non-linear relationship between total and unbound serum concentrations of valproic acid in epileptic children. J Clin Pharm Ther 33:31–38.
Reference: PAGE 27 (2018) Abstr 8479 [www.page-meeting.org/?abstract=8479]
Poster: Drug/Disease Modelling - Paediatrics