Findling Robert L, McNamara Nora K, Stansbrey Robert J, Feeny Norah C, Young Christopher M, Peric Franco V, Youngstrom Eric A
Departments of Psychiatry and Pediatrics, University Hospitals of Cleveland/Case Western Reserve University, Cleveland, Ohio 44106, USA.
J Child Adolesc Psychopharmacol. 2006 Feb-Apr;16(1-2):131-45. doi: 10.1089/cap.2006.16.131.
Identifying evidence-based dosing strategies is a key part of new drug development in pediatric populations. Pharmacokinetic (PK) studies can provide important information regarding how best to dose medications in children and adolescents. Utilizing scientifically supported dosing strategies provides the best chance for any given drug to demonstrate both efficacy and acceptable tolerability in definitive, placebo-controlled studies.
Results of both PK studies and randomized, placebo-controlled efficacy trials (RPCTs) in juvenile major depressive disorder (MDD) are reviewed. The degree to which the medication dosing strategies that were employed in the efficacy studies were supported by the extant PK data is considered. Medications that are reviewed include fluoxetine, sertraline, paroxetine, citalopram, escitalopram, venlafaxine, nefazodone, and mirtazapine.
In many instances, the dosing paradigms that were used in the RPCTs differed, sometimes substantially, from the dosing strategies that would have been supported based on the results of PK studies.
Medication dosing regimens may have contributed to the failure of several RPCTs to show drug efficacy in the treatment of pediatric MDD. In addition, the doses of medication used in these RPCTs may also have contributed to the safety and tolerability concerns that have been raised with these drugs. PK and dose-ranging studies should be performed prior to the initiation of definitive efficacy trials so that empirically supported dosing strategies can be incorporated into the design of RPCTs of antidepressants in children and adolescents suffering from MDD.
确定基于证据的给药策略是儿科新药研发的关键部分。药代动力学（PK）研究可为如何最佳地给儿童和青少年用药提供重要信息。采用科学支持的给药策略能为任何一种药物在确定性的安慰剂对照研究中展现疗效和可接受的耐受性提供最佳机会。
回顾了青少年重度抑郁症（MDD）的PK研究以及随机、安慰剂对照疗效试验（RPCT）的结果。考量了疗效研究中所采用的药物给药策略受现有PK数据支持的程度。所回顾的药物包括氟西汀、舍曲林、帕罗西汀、西酞普兰、艾司西酞普兰、文拉法辛、奈法唑酮和米氮平。
在许多情况下，RPCT中使用的给药模式与基于PK研究结果本应支持的给药策略不同，有时差异很大。
药物给药方案可能导致了一些RPCT未能在治疗儿科MDD中显示出药物疗效。此外，这些RPCT中使用的药物剂量也可能导致了对这些药物安全性和耐受性的担忧。在开展确定性疗效试验之前应进行PK和剂量范围研究，以便将经验支持的给药策略纳入患有MDD的儿童和青少年抗抑郁药RPCT的设计中。
