Abstract
Transdermal fentanyl is widely used to control pain in cancer patients. The high pharmacokinetic variability of fentanyl is assumed to be due to cytochrome P450 3A-mediated (CYP3A) N-dealkylation to norfentanyl in humans. However, recently published clinical studies question the importance of the described metabolic pathway. In this small study in palliative cancer patients under real-life clinical conditions, the influence of CYP3A on fentanyl variability was investigated. In addition to the determination of midazolam plasma concentration to reveal CYP3A activity, plasma concentrations of fentanyl and its metabolite, norfentanyl, were measured in identical blood samples of 20 patients who participated in an ongoing trial and had been on transdermal fentanyl. Fentanyl, norfentanyl, midazolam, and 1′-OH-midazolam were quantified by liquid chromatography/tandem mass spectrometry. Plasma concentrations of fentanyl and norfentanyl exhibited a large variability. Mean estimated total clearance of fentanyl and mean metabolic clearance of midazolam (as a marker of CYP3A activity) were 75.5 and 36.3 L/h. Both clearances showed a weak correlation and hence a minimal influence of CYP3A on fentanyl elimination.
Highlights
Transdermal fentanyl is widely used as a basic therapy in the treatment of pain, which is one of the most common and distressing symptoms of cancer patients near the end of life[1]
As the evaluated subjects had been on individual patch doses ranging from 12.5 to 175 μg/h, all measured plasma concentrations were normalized to a dose of 25 μg/h transdermal fentanyl
This study investigated the variability of exposure of transdermal fentanyl in palliative cancer patients under real-life clinical conditions
Summary
Transdermal fentanyl is widely used as a basic therapy in the treatment of pain, which is one of the most common and distressing symptoms of cancer patients near the end of life[1]. Fentanyl is assumed to be almost exclusively metabolized in the liver by CYP3A-mediated piperidine N-dealkylation to norfentanyl in humans[3,4]. Drug interactions are commonly caused by pharmaceuticals acting as an inducer or inhibitor of the CYP enzymes[5]. As drug interactions are often responsible for the escalation of debilitation symptoms, and responsible for the negative influence of the palliative cancer patients’ quality of life, it is of major significance to be aware of a drug’s CYP-dependent metabolism. As part of a clinical trial investigating the CYP3A activity in palliative cancer patients, this analysis is dealing with the metabolism of fentanyl in a special population under real-life clinical conditions in order to increase knowledge about the influence of CYP3A. The determination of midazolam plasma concentrations as well as plasma concentrations of fentanyl and its metabolite norfentanyl in identical blood samples offers an exceptional opportunity of investigating the interindividual variability
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