Lucia Angelini, Irene Azzali, Andrea Carlini, Vincenza Andrisano, Serena Montanari, Monia Dall'agata, Giorgia Simonetti, Maria Teresa Bochicchio, Matteo Paganelli, Vanessa Valenti, Paola Cravero, Margherita Currà, Linda Petrini, Costanza Maria Donati, Alessio G Morganti, Andrea Ardizzoni, Oscar Edoardo Corli, Marco Cesare Maltoni, Romina Rossi, Marianna Ricci
In this exploratory cohort, pharmacogenetic variability was not robustly associated with TDF pharmacokinetics, analgesic response, or tolerability after correction for multiple testing. These findings do not support the current clinical implementation of pharmacogenetic-guided TDF therapy, but provide hypothesis-generating signals for future studies.
BACKGROUND/OBJECTIVES: Transdermal fentanyl (TDF) is widely used for moderate-to-severe cancer pain, yet substantial variability in fentanyl exposure, analgesic response, and tolerability remains incompletely explained by clinical factors. We evaluated whether pharmacogenetic variability is associated with pharmacokinetic parameters and clinical outcomes in cancer patients receiving TDF.
METHODS: In this prospective, single-center study, adults with solid or hematological malignancies and chronic cancer pain treated with stable-dose 72 h TDF were enrolled. Blood samples were collected for pharmacokinetic and pharmacogenetic analyses. Serum fentanyl concentrations were quantified using validated gas chromatography-mass spectrometry, and AUC, Cmax, and tmax were calculated using non-compartmental analysis. Genotyping was performed using a predefined pharmacogenetic panel. Analgesic response was defined as a ≥2-point reduction in Numeric Rating Scale score or score = 0 at 72 h. Statistical analyses included correction for multiple testing.
RESULTS: 49 patients were included (median age 65 years; 98% stage IV disease); 38 (77.5%) were responders. No significant differences in AUC, Cmax, or tmax were observed between responders and non-responders. TPMT and UGT2B7 variants showed unadjusted associations with clinical response and pharmacokinetic parameters, respectively; however, none remained statistically significant after correction for multiple testing. No significant associations were observed for CYP3A4/5 or ABCB1 variants, nor between genetic variants and adverse events. Pain reduction correlated with improved functional outcomes.
CONCLUSIONS: In this exploratory cohort, pharmacogenetic variability was not robustly associated with TDF pharmacokinetics, analgesic response, or tolerability after correction for multiple testing. These findings do not support the current clinical implementation of pharmacogenetic-guided TDF therapy, but provide hypothesis-generating signals for future studies.