AUTHOR=Zhang Luofei , Wu Ruoyun , Li Xingmeng , Feng Weixing , Zhao Zhigang , Mei Shenghui 

TITLE=Combined carbapenem resulted in a 4.48-fold increase in valproic acid clearance: a population pharmacokinetic model in Chinese children and adults with epilepsy or after neurosurgery

JOURNAL=Frontiers in Pharmacology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1423411

DOI=10.3389/fphar.2024.1423411

ISSN=1663-9812

ABSTRACT=<p>Our study aims to explore the pharmacokinetics of valproic acid (VPA) in Chinese patients with epilepsy or after neurosurgery and establish a robust population pharmacokinetics (PPK) model. The PPK model was developed using nonlinear mixed-effects modeling, incorporating a total of 615 VPA plasma concentration data points from 443 Chinese epilepsy or after neurosurgery patients. A one-compartment model with an additive residual model was established. Forward addition and backward elimination strategies were used to assess the impact of covariates on the model parameters. Goodness-of-fit plots, bootstrap, visual predict check and normalized prediction distribution errors were used for model validation. In the final model, the apparent clearance (CL) was estimated using the following formula: <inline-formula id="inf1"><mml:math id="m1" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mtext>CL </mml:mtext><mml:mrow><mml:mfenced open="(" close=")" separators="|"><mml:mrow><mml:mi mathvariant="normal">L</mml:mi><mml:mo>/</mml:mo><mml:mi mathvariant="normal">h</mml:mi></mml:mrow></mml:mfenced></mml:mrow><mml:mo>=</mml:mo><mml:mn>0.430</mml:mn><mml:mo>×</mml:mo><mml:msup><mml:mrow><mml:mfenced open="(" close=")" separators="|"><mml:mrow><mml:mtext>BW</mml:mtext><mml:mo>/</mml:mo><mml:mn>60</mml:mn></mml:mrow></mml:mfenced></mml:mrow><mml:mn>0.787</mml:mn></mml:msup><mml:mo>×</mml:mo><mml:msup><mml:mrow><mml:mfenced open="(" close=")" separators="|"><mml:mrow><mml:mtext>Cr</mml:mtext><mml:mo>/</mml:mo><mml:mn>50.3</mml:mn></mml:mrow></mml:mfenced></mml:mrow><mml:mrow><mml:mo>−</mml:mo><mml:mn>0.253</mml:mn></mml:mrow></mml:msup><mml:mo>×</mml:mo><mml:msup><mml:mrow><mml:mfenced open="(" close=")" separators="|"><mml:mrow><mml:mtext>ALB</mml:mtext><mml:mo>/</mml:mo><mml:mn>39</mml:mn></mml:mrow></mml:mfenced></mml:mrow><mml:mrow><mml:mo>−</mml:mo><mml:mn>0.873</mml:mn></mml:mrow></mml:msup><mml:mo>×</mml:mo><mml:msup><mml:mi mathvariant="normal">e</mml:mi><mml:mtext>gender</mml:mtext></mml:msup><mml:mo>×</mml:mo><mml:msup><mml:mi mathvariant="normal">e</mml:mi><mml:mtext>CBP</mml:mtext></mml:msup><mml:msup><mml:mrow><mml:mo>×</mml:mo><mml:msup><mml:mi mathvariant="normal">e</mml:mi><mml:mrow><mml:mtext>IND</mml:mtext><mml:mn>2</mml:mn><mml:mtext> </mml:mtext></mml:mrow></mml:msup><mml:mo>×</mml:mo><mml:mi mathvariant="normal">e</mml:mi></mml:mrow><mml:msub><mml:mi mathvariant="normal">η</mml:mi><mml:mtext>CL</mml:mtext></mml:msub></mml:msup></mml:mrow></mml:math></inline-formula> (gender = 0.121 when is female, otherwise = 0; CBP = 1.50 when combined with carbapenems, otherwise = 0; IND2 = 0.15 when combined with oxcarbazepine, carbamazepine, phenobarbital, or phenytoin, otherwise = 0). The volume of distribution (V<sub>d</sub>) was estimated using the formula: <inline-formula id="inf2"><mml:math id="m2" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mtext>Vd </mml:mtext><mml:mrow><mml:mfenced open="(" close=")" separators="|"><mml:mrow><mml:mi mathvariant="normal">L</mml:mi></mml:mrow></mml:mfenced></mml:mrow><mml:mo>=</mml:mo><mml:mn>8.66</mml:mn><mml:mo>×</mml:mo><mml:msup><mml:mrow><mml:mfenced open="(" close=")" separators="|"><mml:mrow><mml:mtext>BW</mml:mtext><mml:mo>/</mml:mo><mml:mn>60</mml:mn></mml:mrow></mml:mfenced></mml:mrow><mml:mn>0.751</mml:mn></mml:msup></mml:mrow></mml:math></inline-formula>. Comedication with carbapenems could increase VPA clearance by 4.48 times, and comedication with oxcarbazepine could enhance VPA clearance by 116%. Besides, creatinine and albumin could affect VPA clearance. Goodness-of-fit plots, bootstrap, visual predict check and normalized prediction distribution showed acceptable data fit, stability, and predictability of the model. In our study, a PPK model was utilized to attain a more comprehensive insight into these variables, improving the accuracy and individualization of VPA therapy in Chinese patients with epilepsy or after neurosurgery.</p>