British journal of clinical pharmacology · 2024
Single-dose and steady-state pharmacokinetics of clomipramine, yohimbine and clomipramine/yohimbine combination: A clinical drug-drug interaction study.
СтатьяКлиническое исследованиеНазвание и аннотация: Перевод в очереди
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Leutzendorff Amelie, Al Jalali Valentin, Bauer Martin, Minichmayr Iris K, Reiter Birgit, Duchek Michael Wölfl-, Nussbaumer-Pröll Alina, Weber Maria, Eberl Sabine, Spies Marie, Sarhan Maysa, Geilen Johannes, Walther Alexander, Drai Daniel, Zeitlinger Markus
Аннотация
AIMS: Clomipramine (CLOMI) has shown effectiveness in treating premature ejaculation but is linked to erectile dysfunction and reduced libido. Yohimbine (YOH), by contrast, is effective in treating erectile dysfunction and may improve libido. Combining CLOMI and YOH could potentially leverage the benefits of both drugs. This study aimed to investigate the interactions between these drugs and to evaluate their safety profile.
METHODS: A prospective, open-labelled, single-centre, pharmacokinetic (PK) drug-drug interaction study was performed in 15 healthy male subjects. Single-dose and steady-state PK were investigated using noncompartmental analysis after mono- and combination therapy of the 2 orally applied drugs. Plasma sampling was performed at baseline, 0.5 (YOH), 1, 1.5 (YOH), 2, 3, 4, 5, 6, 8, 12 and 24 h (CLOMI). Differences in the area under the curve after multiple dosing (MD) were determined using an equivalence boundary of 80-125%.
RESULTS: The geometric mean ratio of the area under the curve up to 12 h for MD CLOMI (combination vs. monotherapy) was 112% (90% confidence interval: 104-120%), whereas for MD YOH this ratio was 137% (90% confidence interval: 112-168%). The study drugs were safe and well tolerated as mono- and combination therapy, with no major adverse events reported.
CONCLUSION: A PK assessment of clomipramine and yohimbine indicated a clinically significant drug-drug interaction for MD YOH in combination with CLOMI. This might be explained by competitive, CLOMI-related inhibition of YOH metabolism, probably mediated by cytochrome P450 2D6. However, according to European Medicines Agency guidelines, the effect can be classified as interaction absent (<1,25 fold) or minor (>1.25-<2-fold). Given the complimentary mechanisms of action and the favourable safety profiles, the findings pave the way for future efficacy studies.
METHODS: A prospective, open-labelled, single-centre, pharmacokinetic (PK) drug-drug interaction study was performed in 15 healthy male subjects. Single-dose and steady-state PK were investigated using noncompartmental analysis after mono- and combination therapy of the 2 orally applied drugs. Plasma sampling was performed at baseline, 0.5 (YOH), 1, 1.5 (YOH), 2, 3, 4, 5, 6, 8, 12 and 24 h (CLOMI). Differences in the area under the curve after multiple dosing (MD) were determined using an equivalence boundary of 80-125%.
RESULTS: The geometric mean ratio of the area under the curve up to 12 h for MD CLOMI (combination vs. monotherapy) was 112% (90% confidence interval: 104-120%), whereas for MD YOH this ratio was 137% (90% confidence interval: 112-168%). The study drugs were safe and well tolerated as mono- and combination therapy, with no major adverse events reported.
CONCLUSION: A PK assessment of clomipramine and yohimbine indicated a clinically significant drug-drug interaction for MD YOH in combination with CLOMI. This might be explained by competitive, CLOMI-related inhibition of YOH metabolism, probably mediated by cytochrome P450 2D6. However, according to European Medicines Agency guidelines, the effect can be classified as interaction absent (<1,25 fold) or minor (>1.25-<2-fold). Given the complimentary mechanisms of action and the favourable safety profiles, the findings pave the way for future efficacy studies.