The relevance of pharmacokinetic studies in designing efficacy trials in juvenile major depression.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Departments of Psychiatry and Pediatrics, University Hospitals of Cleveland/Case Western Reserve University, Cleveland, Ohio 44106, USA. Robert.Findling@uhhs.com
Robert L
RL
Findling
Nora K
NK
McNamara
Robert J
RJ
Stansbrey
Norah C
NC
Feeny
Christopher M
CM
Young
Franco V
FV
Peric
Eric A
EA
Youngstrom
D000293:Adolescent; D000928:Antidepressive Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D002648:Child; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000453:epidemiology / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D012107:Research Design
D000928:Antidepressive Agents