Minor contribution of cytochrome P450 3A activity on fentanyl exposure in palliative care cancer patients

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.

Assessment of Drug–Drug Interaction Risk Between Intravenous Fentanyl and the Glecaprevir/Pibrentasvir Combination Regimen in Hepatitis C Patients Using Physiologically Based Pharmacokinetic Modeling and Simulations

“…Since GLE is a weak CYP3A4 inhibitor which increased the plasma AUC of the CYP3A4 substrate midazolam by only 27%, its interaction with fentanyl was expected to be less pronounced compared with the effect of moderate or strong CYP3A4 inhibitors [ 29 , 30 ]. The metabolism of fentanyl is not fully understood, and a few lines of evidence have suggested that some unknown metabolic pathways may be involved, reducing the metabolic action of CYP3A4 to just 8% [ 27 , 43 ]. One study showed that the strong CYP3A4 inhibitor itraconazole did not affect the PK of IV fentanyl [ 28 ].…”

“…In contrast, midazolam, which is known to be exclusively metabolized by CYP3A4, presents observed exposure increases of 1450% and 250% in the presence of ritonavir and fluconazole [ 25 , 26 ]. This discrepancy in the change in CYP3A4 substrate exposure highlights that fentanyl metabolism is only partially mediated by CYP3A4, an observation supported by studies finding that fentanyl clearance was only 8% mediated by CYP3A4 relative to midazolam, and that itraconazole had no statistically significant effects on the PK of fentanyl [ 27 , 28 ]. The relative contributions of various metabolic and drug transport pathways to the total in vivo elimination of fentanyl are also influenced by the route of administration (oral/transdermal/IV) [ 19 ].…”

Predicting transdermal fentanyl delivery using physics-based simulations for tailored therapy based on the age

“…Transdermal fentanyl therapy shows high inter-individual and intra-individual variability (Lennernäs et al., 2005 ; Kuip et al., 2017 ; Geist et al., 2019 ). Several factors can cause these variabilities (Kuip et al., 2017 ), including a different clearance rate (Grond et al., 2000 ), amongst others.…”

Evaluation of CYP2C19 activity using microdosed oral omeprazole in humans

“…In this study, we investigated whether microdosed oral omeprazole is suitable to determine CYP2C19 activity in vivo in comparison to a therapeutic dose, also under conditions of CYP2C19 inhibition and induction. Since we have previously established midazolam and yohimbine microdosing to determine CYP3A and CYP2D6 activity [14][15][16][17], the additional simultaneous determination of CYP2C19 activity is a logical step to further develop a microdosed cocktail for phenotyping of the most important human CYP isozymes. Furthermore, the use of the hydroxylation index after the omeprazole microdose was evaluated in relation to the CYP2C19 genotype.…”