Pharmacokinetic variability of clarithromycin and differences in CYP3A4 activity in patients with cystic fibrosis

TY - JOUR

T1 - Pharmacokinetic variability of clarithromycin and differences in CYP3A4 activity in patients with cystic fibrosis

AU - Dalbøge, C S

AU - Nielsen, X C

AU - Dalhoff, K

AU - Alffenaar, J W

AU - Duno, M

AU - Buchard, A

AU - Uges, D R A

AU - Jensen, A G

AU - Jürgens, G

AU - Pressler, T

AU - Johansen, H K

AU - Høiby, N

N1 - © 2013.

PY - 2014/3

Y1 - 2014/3

N2 - Background: To investigate the correlation between CYP3A4/5 activity and clarithromycin metabolism, and between CYP3A activity and CYP3A genotype. Methods: This is an open-label, prospective pharmacokinetic study evaluating CYP3A activity using The Erythromycin Breath Test. Eight blood samples were collected within 12. h after clarithromycin 500. mg was administered orally. The clarithromycin concentrations were measured by liquid chromatography-tandem mass spectrometry. AUC, Tmax and Cmax were calculated. Selected Single Nucleotide polymorphisms in CYP3A4/5 genes were assessed by PCR and single base extension. Results: Twenty-one chronically infected patients were included. An 8-fold variation in the CYP3A4 activity, 10-fold variation in AUC for clarithromycin (median 881 μg/mL × min), and a 16-fold variation in Cmax for clarithromycin (median 3.4. μg/mL) were found. A linear correlation between the CYP3A4-activity and clarithromycin metabolism was demonstrated (P < 0.05). Conclusion: The large variation in the clarithromycin pharmacokinetics in cystic fibrosis patients may cause treatment failure. The Erythromycin Breath Test could be valuable in identifying cystic fibrosis patients in risk of treatment failure/drug toxicity.

AB - Background: To investigate the correlation between CYP3A4/5 activity and clarithromycin metabolism, and between CYP3A activity and CYP3A genotype. Methods: This is an open-label, prospective pharmacokinetic study evaluating CYP3A activity using The Erythromycin Breath Test. Eight blood samples were collected within 12. h after clarithromycin 500. mg was administered orally. The clarithromycin concentrations were measured by liquid chromatography-tandem mass spectrometry. AUC, Tmax and Cmax were calculated. Selected Single Nucleotide polymorphisms in CYP3A4/5 genes were assessed by PCR and single base extension. Results: Twenty-one chronically infected patients were included. An 8-fold variation in the CYP3A4 activity, 10-fold variation in AUC for clarithromycin (median 881 μg/mL × min), and a 16-fold variation in Cmax for clarithromycin (median 3.4. μg/mL) were found. A linear correlation between the CYP3A4-activity and clarithromycin metabolism was demonstrated (P < 0.05). Conclusion: The large variation in the clarithromycin pharmacokinetics in cystic fibrosis patients may cause treatment failure. The Erythromycin Breath Test could be valuable in identifying cystic fibrosis patients in risk of treatment failure/drug toxicity.

KW - Adult

KW - Anti-Bacterial Agents

KW - Area Under Curve

KW - Biotransformation

KW - Breath Tests

KW - Chromatography, Liquid

KW - Clarithromycin

KW - Cystic Fibrosis

KW - Cytochrome P-450 CYP3A

KW - Drug-Related Side Effects and Adverse Reactions

KW - Erythromycin

KW - Female

KW - Genetic Association Studies

KW - Humans

KW - Male

KW - Polymorphism, Single Nucleotide

KW - Prospective Studies

KW - Risk Assessment

KW - Tandem Mass Spectrometry

KW - Treatment Failure

U2 - 10.1016/j.jcf.2013.08.008

DO - 10.1016/j.jcf.2013.08.008

M3 - Journal article

C2 - 24035278

SN - 1569-1993

VL - 13

SP - 179

EP - 185

JO - Journal of Cystic Fibrosis

JF - Journal of Cystic Fibrosis

IS - 2

ER -