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

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: <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mtext>CL </mml:mtext> <mml:mrow> <mml:mfenced><mml:mrow><mml:mi>L</mml:mi> <mml:mo>/</mml:mo> <mml:mi>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><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><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><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>e</mml:mi> <mml:mtext>gender</mml:mtext></mml:msup> <mml:mo>×</mml:mo> <mml:msup><mml:mi>e</mml:mi> <mml:mtext>CBP</mml:mtext></mml:msup> <mml:msup><mml:mrow><mml:mo>×</mml:mo> <mml:msup><mml:mi>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>e</mml:mi></mml:mrow> <mml:msub><mml:mi>η</mml:mi> <mml:mtext>CL</mml:mtext></mml:msub> </mml:msup> </mml:mrow> </mml:math> (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_d) was estimated using the formula: <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mtext>Vd </mml:mtext> <mml:mrow> <mml:mfenced><mml:mrow><mml:mi>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><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> . 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.