Puentes E, Puzantian T, Lum B L
Department of Pharmacy, Veterans Affairs Palo Alto Health Care System, California, USA.
Ther Drug Monit. 1999 Jun;21(3):351-4. doi: 10.1097/00007691-199906000-00019.
Valproate serum concentrations between 45 and 125 microg/mL are associated with 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 healthy volunteers and to test the ability of these PK parameters to estimate concentrations in adult psychiatric patients using a Bayesian program. Population PK parameters for oral valproate were estimated from 18 PK studies in six healthy volunteers (1) using NPEM2. A Bayesian PK program using these population parameters was used to predict valproate concentration-time points 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. Bayesian valproate estimations using these parameters were negatively biased (underestimations) using zero prior concentration and unbiased using 1 or 2 prior concentrations. Mean error values (95% CI) in microg/mL for predictions using 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 error values in microg/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 concentration time points predicted future concentrations that were precise and unbiased, given the wide therapeutic target range.
丙戊酸盐血清浓度在45至125微克/毫升之间与该药在急性躁狂症中的疗效相关。丙戊酸盐的适应性控制给药在精神病学领域尚未得到充分研究。本研究的目的是推导健康志愿者中丙戊酸盐的群体药代动力学（PK）参数，并使用贝叶斯程序测试这些PK参数估计成年精神病患者体内药物浓度的能力。口服丙戊酸盐的群体PK参数是根据对6名健康志愿者进行的18项PK研究（1），使用NPEM2估计得出的。使用这些群体参数的贝叶斯PK程序被用于预测第二组21名成年精神病患者的丙戊酸盐浓度-时间点，这些患者有0个、1个或2个先前的浓度数据。估计的群体参数（平均值±标准差）为：Ka，1.15±1.75/小时；V，0.14±0.042升/千克；CL，0.902±0.133升/小时。使用这些参数进行的贝叶斯丙戊酸盐估计，在先前浓度为零时存在负偏差（低估），而在先前浓度为1个或2个时无偏差。使用0个、1个或2个先前浓度-时间点进行预测时，微克/毫升的平均误差值（95%置信区间）分别为-12.0（-22.5，-1.5）、-9.5（-19.1，0.1）和-2.5（-11.1，6.1），微克/毫升的平均绝对误差值（95%置信区间）分别为19.8（12.6，27.1）、16.3（9.4，23.3）和10.1（4.9，15.2）。从健康成年志愿者得出的群体参数对成年精神病患者体内丙戊酸盐浓度的预测存在偏差。然而，鉴于治疗目标范围较宽，使用1个或2个丙戊酸盐浓度时间点进行的估计能够精确且无偏差地预测未来浓度。
