Teixeira P (1), Laso E (2), Otero MJ (2), GarcÃa Sánchez MJ (1), Santos Buelga D (1).
(1) Department of Pharmaceutical Science, University of Salamanca, Spain. (2) Service of Pharmacy, University Hospital of Salamanca, Spain.
Objectives: The main goal of this study was to evaluate the effect of anthropometric covariates on the clearance (CL) of valproic acid (VLP) in adult patients to develop a population pharmacokinetics (PoPK) model.
Methods: Serum concentrations of VLP were taken from patients aged 15-82 years old, who had been treated with sodium valproate. These patients were included in the TDM program, conducted in the University Hospital of Salamanca over the last 20 years. After applying the inclusion/exclusion criteria previously established, the final database included 512 serum concentrations from 282 patients. Pharmacokinetic analysis was performed with NONMEM V7.3 (FOCEI) considering a one-compartment model, fixing the absorption constant and volume of distribution at 4.1 h-1 and 0.20 L/kg, respectively [1-4]. Proportional error models were assumed to describe interindividual and residual variabilities. The analysed covariates were: total body weight (TBW), body mass index (BMI), height (HGT), body surface area (BSA) and lean body weight (LBW).
Results: All evaluated anthropometric covariates showed the significant influence on CL/FVLP, and its inclusion in the model can explain part of the interindividual variability. Due to correlation of anthropometric covariates, the inclusion of only one of them in the PoPK final model is acceptable. In comparison with the others covariates, the TBW is the easiest to obtain in clinical practice. Moreover, in general, the volume (V) of liposoluble drugs correlates better with the TBW and justifies the difference observed in the CL in overweight patients, for whom when using the TBW measure as body size, the size is one V higher than when the LBW or BSA is used.
The proposed final model for CLVLP/F was as follows:
CL/FVLP (L/h) = 0.57×((TBW/68)0.82)
w2 = 0.037 (shrinkage: 27 %)
s2= 0.058 (shrinkage: 19 %).
The results obtained in the Bootstrap analysis show acceptable performance of the proposed model.
Conclusions: The TBW, the BSA and the LBW are anthropometric covariates that explain the biggest part of interindividual variability on CL/FVLP. However, according to the characteristics of liposolubility of VLP the inclusion of TBW in the model is considered to be suitable; this variable also has the advantage of being more easily obtainable in clinical practice. The final model that includes the TBW on CL/FVLP seems to be appropriate for clinical application in TDM. However, we consider it to be necessary to carry out an external validation of this model to verify its applicability, especially in overweight or obese patients.
References:
[1] Dutta S, Reed RC. Distinct absorption characteristics of oral formulations of valproic acid/divalproex available in the United States. Epilepsy Res. 2007; 73:275-83.
[2] Patsalos PN. Antiepileptic drug interactions. A clinical guide. 2nd ed. Springer; London. 2013.
[3] Serrano BB, Garcia Sanchez MJ, Otero MJ, Buelga DS, Serrano J, Dominguez-Gil A. Valproate population pharmacokinetics in children. J Clin Pharm Ther. 1999; 24:73-80.
[4] Holford N, Anderson B. Mechanism-Based Concepts of Size and Maturity. 2008; Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Presentation/2009/11/WC500009792.pdf. Accessed January/12, 2016.
Reference: PAGE 25 (2016) Abstr 6011 [www.page-meeting.org/?abstract=6011]
Poster: Drug/Disease modeling - CNS