Nefazodone Pharmacokinetics in Depressed Children and Adolescents

Findling, Robert L.; Preskorn, Sheldon; Marcus, Ronald N.; Magnus, Ryan D.; D'amico, Frances; Marathe, Punit; Reed, Michael D.

doi:10.1097/00004583-200008000-00016

Cited by 32 publications

(4 citation statements)

References 10 publications

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“…Many studies were published that were given a negative labeling change or not granted a labeling change. 16,[25][26][27][28] The peer-reviewed journals that accepted the publications were high quality. The mean impact factor for journals that accepted publications, was 6.…”

Section: Resultsmentioning

confidence: 99%

Peer-Reviewed Publication of Clinical Trials Completed for Pediatric Exclusivity

Benjamin¹,

Smith²,

Murphy³

et al. 2006

JAMA

140

117

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Section: Resultsmentioning

confidence: 99%

Peer-Reviewed Publication of Clinical Trials Completed for Pediatric Exclusivity

Benjamin¹,

Smith²,

Murphy³

et al. 2006

JAMA

140

117

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show abstract

“…After single and repeated nefazodone doses (200 mg twice daily) mean exposure to mClPP was substantially greater and the elimination t 1/2 longer in PM than EM of the CYP2D6 probes debrisoquine and dextrometorphan [57,73]. After single and repeated nefazodone doses (200 mg twice daily) mean exposure to mClPP was substantially greater and the elimination t 1/2 longer in PM than EM of the CYP2D6 probes debrisoquine and dextrometorphan [57,73].…”

Section: Elimination Of 1-aryl-piperazinesmentioning

confidence: 99%

N-Dealkylation of Arylpiperazine Derivatives: Disposition and Metabolism of the 1-Aryl-Piperazines Formed

Caccia

2007

CDM

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In recent years several arylpiperazine derivatives have reached the stage of clinical application, mainly for the treatment of depression, psychosis or anxiety. Examples are the pyrimidinylpiperazine buspirone, the chlorophenylpiperazine derivatives nefazodone and trazodone, the dichlorophenylpiperazine aripiprazole and the benzisothiazolyl derivatives perospirone and ziprasidone. Most of them undergo extensive pre-systemic and systemic metabolism including CYP3A4-dependent N-dealkylation to 1-aryl-piperazines. These metabolites are best known for the variety of serotonin receptor-related effects they cause in man and animals, although some have affinity for other neurotransmitter receptors; others, however, are still largely unexplored despite uncontrolled use as amphetamine-like designer drugs. Once formed they distribute extensively in tissues, including brain which is the target site of most arylpiperazine derivatives, and are then primarily biotransformed by CYP2D6-dependent oxidation to hydroxylates which are excreted as conjugates; only 1-(2-benzisothiazolyl)-piperazine is more susceptible to sulfur oxidation than to aromatic hydroxylation. In studies analysing animal brain and human blood, 1-aryl-piperazine concentrations were either higher or lower than the parent compound(s), although information is available only for some derivatives. At steady state, the metabolite-to-parent drug ratios varied widely among individuals taking the same dosage of the same arylpiperazine derivative. This is consistent with the known individual variability in the expression and activity of CYP3A4 and CYP2D6. This review also surveys current published information on physiological and pathological factors affecting the 1-aryl-piperazine-to-parent drug ratios and examines the potential role of 1-aryl-piperazine formation in the pharmacological actions of the arylpiperazine derivatives that are already or will shortly be available in major markets.

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“…A PK study was conducted in which 28 depressed children and adolescents (ages 7-17 years) were treated with nefazodone (Findling et al 2000). Blood sampling for PK analysis was done at three separate time points during the first 2 weeks of treatment-after the first 50-mg dose, after 1 week of treatment at 50 mg twice-daily, and after 1 subsequent week of treatment at 100 mg twice-daily.…”

Section: Nefazodonementioning

confidence: 99%

The Relevance of Pharmacokinetic Studies in Designing Efficacy Trials in Juvenile Major Depression

Findling

McNamara

Stansbrey

et al. 2006

Journal of Child and Adolescent Psychopharmacology

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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.

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Nefazodone Pharmacokinetics in Depressed Children and Adolescents

Cited by 32 publications

References 10 publications

Peer-Reviewed Publication of Clinical Trials Completed for Pediatric Exclusivity

Peer-Reviewed Publication of Clinical Trials Completed for Pediatric Exclusivity

N-Dealkylation of Arylpiperazine Derivatives: Disposition and Metabolism of the 1-Aryl-Piperazines Formed

The Relevance of Pharmacokinetic Studies in Designing Efficacy Trials in Juvenile Major Depression

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