Prediction of valproate serum concentrations in adult psychiatric patientsusing Bayesian model estimations with NPEM2 population pharmacokinetic parameters

Valproate serum concentrations between 45 and 125 mu g/mL are associated wi th the drug's efficacy in acute mania. Adaptive control dosing of valproate has not been fully studied in psychiatry. The objective of this study was to derive population pharmacokinetic (PK) parameters for valproate in healt hy volunteers and to test the ability of these PK parameters to estimate co ncentrations in adult psychiatric patients using a Bayesian program. Popula tion PK parameters for oral valproate were estimated from 18 PK studies in six healthy volunteers (1) using NPEM2. A Bayesian PK program using these p opulation parameters was used to predict valproate concentration-time point s in a second cohort of 21 adult psychiatry patients using 0, 1, or 2 prior concentrations. Estimated population parameters (mean +/- SD) were: Ka, 1. 15 +/- 1.75/h; V, 0.14 +/- 0.042 L/Kg; and CL, 0.902 +/- 0.133 L/h. Bayesia n valproate estimations using these parameters were negatively biased (unde restimations) using zero prior concentration and unbiased using 1 or 2 prio r concentrations. Mean error values (95% CI) in mu g/mL for predictions usi ng 0, 1, or 2 prior concentration-time points were -12.0 (-22.5, -1.5), -9. 5 (-19.1, 0.1), and -2.5 (-11.1, 6.1), respectively, and mean absolute erro r values in mu g/mL (95% CI) were 19.8 (12.6, 27.1), 16.3 (9.4, 23.3), and 10.1 (4.9, 15.2), respectively. Population parameters derived from healthy adult volunteers provided biased predictions of valproate concentrations in adult psychiatric patients. However, estimates using 1 or 2 valproate conc entration time points predicted future concentrations that were precise and unbiased, given the wide therapeutic target range.