Genetic, pathological and physiological determinants of transdermal fentanyl pharmacokinetics in 620 cancer patients of the EPOS study.
OBJECTIVE
This study aimed to investigate whether CYP3A4/5 genetic variants, together with clinical and patient factors, influence serum fentanyl and norfentanyl concentrations and their ratio in cancer pain patients receiving transdermal fentanyl.


METHODS
CYP3A4*22 and CYP3A5*3 polymorphisms were analysed in 620 cancer pain patients receiving transdermal fentanyl (12.5-700 μg/h) from the European Pharmacogenetic Opioid Study. Using stepwise linear regression, CYP3A4/5 genetic variability was examined in combination with patient factors relating to organ drug elimination function and ABCB1 genetics for their association with serum fentanyl and norfentanyl concentrations and metabolic ratio (MR) (norfentanyl : fentanyl).


RESULTS
Delivery rate-adjusted serum fentanyl concentrations (0.0012-1.1 nmol/l/μg.h) and MRs (0.08-499) varied widely. Only 43% of variability in serum fentanyl concentrations was accounted for by delivery rate and less than 50% by CYP3A4/5 genotypes and clinical variables (delivery rate, sex, comedications, kidney disease, BMI, serum albumin). CYP3A4*22 and CYP3A5*3 variants, CYP3A inhibitors and variables relating to liver and kidney function (serum albumin, glomerular filtration rate, kidney disease, BMI) were associated with MR, but accounted for only 14% of variability.


CONCLUSIONS
Serum fentanyl concentrations and MR vary considerably between cancer pain patients on transdermal fentanyl patches. CYP3A4*22 and CYP3A5*3 genotypes, and multiple clinical factors, combine to influence transdermal fentanyl pharmacokinetics, but accounted for only a small proportion of variability in this study. Identification of the remaining factors determining serum fentanyl concentrations, and their relationship to efficacy and adverse effects may aid in improving the safety and effectiveness of transdermal fentanyl.
aDiscipline of Pharmacology, School of Medical Sciences bSchool of Mathematical Sciences, University of Adelaide cDepartment of Clinical Pharmacology, Royal Adelaide Hospital, Adelaide, Australia dDepartment of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark eDepartment of Circulation and Medical Imaging, Norwegian University of Science and Technology fDepartment of Cancer Research and Molecular Medicine, European Palliative Care Research Centre, Trondheim, Norway.
Daniel T
DT
Barratt
Benedikte
B
Bandak
Pål
P
Klepstad
Ola
O
Dale
Stein
S
Kaasa
Lona L
LL
Christrup
Jonathan
J
Tuke
Andrew A
AA
Somogyi
D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000701:Analgesics, Opioid / Q000494:pharmacology* / Q000627:therapeutic use; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D005283:Fentanyl / Q000494:pharmacology* / Q000627:therapeutic use; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000150:complications* / Q000188:drug therapy / Q000473:pathology; D010146:Pain / Q000150:complications / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D057968:Transdermal Patch; D055815:Young Adult
C115572:ABCD1 protein, human; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters; D000701:Analgesics, Opioid; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D005283:Fentanyl