Psicothema · 2022
Cognitive-Behavioral Therapy and Anxiety and Depression Level in Pediatric Obsessive-Compulsive Disorder: A Systematic Review and Meta-Analysis.
СтатьяМетаанализСистематический обзорНазвание и аннотация: Перевод пока не подготовлен
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Kuroda Hiroyuki, Matsunaga Takuya, Terui Takeshi, Tanaka Ikuta, Takimoto Rishu, Fujikawa Koshi, Takayama Tetsuji, Kato Junji, Hirayama Yasuo, Sakamaki Sumio, Kohda Kyuhei, Niitsu Yoshiro
Аннотация
BACKGROUND AND OBJECTIVES: Cytochrome P450 (CYP) 3A4 isoenzyme has been identified in vitro as the key enzyme to metabolize desisobutyryl-ciclesonide (des-CIC), the pharmacologically active metabolite of the inhaled corticosteroid ciclesonide. This pharmacokinetic drug-drug interaction study was conducted to confirm this major metabolic pathway in vivo by using the strong CYP3A4 inhibitor ketoconazole, and to assess the effect of ketoconazole on the pharmacokinetics of ciclesonide and des-CIC.
METHODS: Fourteen healthy adults participated in this open-label, nonrandomized, fixed sequence, two-period, repeated-dose pharmacokinetic study. During the first 7-day treatment period, the subjects orally inhaled ciclesonide 320 microg once daily. During the second 7-day treatment period, the subjects continued with the same dose of orally inhaled ciclesonide and concomitantly received oral ketoconazole 400 mg once daily. Pharmacokinetic profiles for ciclesonide and des-CIC were obtained on day 7 of each study period.
RESULTS: For the parent compound, ciclesonide, no changes in the pharmacokinetic parameter estimates--the area under the serum concentration-time curve during the dosage interval (AUC(tau)), maximum serum concentration (C(max)) and time to reach the C(max)--were observed. In contrast, the AUC(tau) and C(max) of des-CIC increased approximately 3.5-fold and 2-fold under the influence of the CYP3A4 inhibitor ketoconazole.
CONCLUSIONS: The CYP3A4 pathway is the major pathway for biotransformation of the active metabolite of ciclesonide in humans. While elimination of des-CIC was reduced by strong CYP3A4 inhibitor coadministration in vivo, activation of the parent compound ciclesonide to des-CIC was not affected. Dose adjustment is not necessary when ciclesonide needs to be coadministered with ketoconazole, because the potency of an inhaled corticosteroid is mediated by topical concentrations in the lung and because ciclesonide has a very low potential to produce systemic adverse effects.
METHODS: Fourteen healthy adults participated in this open-label, nonrandomized, fixed sequence, two-period, repeated-dose pharmacokinetic study. During the first 7-day treatment period, the subjects orally inhaled ciclesonide 320 microg once daily. During the second 7-day treatment period, the subjects continued with the same dose of orally inhaled ciclesonide and concomitantly received oral ketoconazole 400 mg once daily. Pharmacokinetic profiles for ciclesonide and des-CIC were obtained on day 7 of each study period.
RESULTS: For the parent compound, ciclesonide, no changes in the pharmacokinetic parameter estimates--the area under the serum concentration-time curve during the dosage interval (AUC(tau)), maximum serum concentration (C(max)) and time to reach the C(max)--were observed. In contrast, the AUC(tau) and C(max) of des-CIC increased approximately 3.5-fold and 2-fold under the influence of the CYP3A4 inhibitor ketoconazole.
CONCLUSIONS: The CYP3A4 pathway is the major pathway for biotransformation of the active metabolite of ciclesonide in humans. While elimination of des-CIC was reduced by strong CYP3A4 inhibitor coadministration in vivo, activation of the parent compound ciclesonide to des-CIC was not affected. Dose adjustment is not necessary when ciclesonide needs to be coadministered with ketoconazole, because the potency of an inhaled corticosteroid is mediated by topical concentrations in the lung and because ciclesonide has a very low potential to produce systemic adverse effects.