Hennig Stefanie, Waterhouse Timothy H, Bell Scott C, France Megan, Wainwright Claire E, Miller Hugh, Charles Bruce G, Duffull Stephen B
School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australia.
Br J Clin Pharmacol. 2007 Apr;63(4):438-50. doi: 10.1111/j.1365-2125.2006.02778.x. Epub 2006 Oct 30.
The primary objective of the study was to estimate the population pharmacokinetic parameters for itraconazole and hydroxy-itraconazole, in particular, the relative oral bioavailability of the capsule compared with solution in adult cystic fibrosis patients, in order to develop new dosing guidelines. A secondary objective was to evaluate the performance of a population optimal design.
The blood sampling times for the population study were optimized previously using POPT v.2.0. The design was based on the administration of solution and capsules to 30 patients in a cross-over study. Prior information suggested that itraconazole is generally well described by a two-compartment disposition model with either linear or saturable elimination. The pharmacokinetics of itraconazole and the metabolite were modelled simultaneously using NONMEM. Dosing schedules were simulated to assess their ability to achieve a trough target concentration of 0.5 mg ml(-1).
Out of 241 blood samples, 94% were taken within the defined optimal sampling windows. A two-compartment model with first order absorption and elimination best described itraconazole kinetics, with first order metabolism to the hydroxy-metabolite. For itraconazole the absorption rate constants (between-subject variability) for capsule and solution were 0.0315 h(-1) (91.9%) and 0.125 h(-1) (106.3%), respectively, and the relative bioavailability of the capsule was 0.82 (62.3%) (confidence interval 0.36, 1.97), compared with the solution. There was no evidence of nonlinearity. Simulations from the final model showed that a dosing schedule of 500 mg twice daily for both formulations provided the highest chance of target success.
The optimal design performed well and the pharmacokinetics of itraconazole and hydroxy-itraconazole were described adequately by the model. The relative bioavailability for itraconazole capsules was 82% compared with the solution.
本研究的主要目的是估算伊曲康唑和羟基伊曲康唑的群体药代动力学参数，尤其是在成年囊性纤维化患者中，比较胶囊与溶液剂的相对口服生物利用度，以便制定新的给药指南。次要目的是评估群体优化设计的性能。
群体研究的采血时间先前已使用POPT v.2.0进行了优化。该设计基于在一项交叉研究中对30名患者给予溶液剂和胶囊剂。先前的信息表明，伊曲康唑通常可用具有线性或饱和消除的二室处置模型很好地描述。使用NONMEM同时对伊曲康唑及其代谢物的药代动力学进行建模。模拟给药方案以评估其达到0.5 mg/ml谷浓度目标的能力。
在241份血样中，94%是在规定的最佳采样窗口内采集的。具有一级吸收和消除的二室模型最能描述伊曲康唑的动力学，其代谢为羟基代谢物的过程为一级代谢。对于伊曲康唑，胶囊剂和溶液剂的吸收速率常数（个体间变异性）分别为0.0315 h⁻¹（91.9%）和0.125 h⁻¹（106.3%），与溶液剂相比，胶囊剂的相对生物利用度为0.82（62.3%）（置信区间0.36, 1.97）。没有非线性的证据。最终模型的模拟表明，两种制剂均每日两次服用500 mg的给药方案达到目标成功的机会最高。
优化设计表现良好，模型充分描述了伊曲康唑和羟基伊曲康唑的药代动力学。与溶液剂相比，伊曲康唑胶囊的相对生物利用度为82%。
