Prediction of irinotecan pharmacokinetics by use of cytochrome P450 3A4 phenotyping probes.
BACKGROUND
Irinotecan is a topoisomerase I inhibitor that has been approved for use as a first- and second-line treatment for colorectal cancer. The response to irinotecan is variable, possibly because of interindividual variation in the expression of the enzymes that metabolize irinotecan, including cytochrome P450 3A4 (CYP3A4) and uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). We prospectively explored the relationships between CYP3A phenotype, as assessed by erythromycin metabolism and midazolam clearance, and the metabolism of irinotecan and its active metabolite SN-38.


METHODS
Of the 30 white cancer patients, 27 received at least two treatments with irinotecan administered as one 90-minute infusion (dose, 600 mg) with 3 weeks between treatments, and three received only one treatment. Before the first and second treatments, patients underwent an erythromycin breath test and a midazolam clearance test as phenotyping probes for CYP3A4. Erythromycin metabolism was assessed as the area under the curve for the flux of radioactivity in exhaled CO2 within 40 minutes after administration of [N-methyl-14C]erythromycin. Midazolam and irinotecan were measured by high-performance liquid chromatography. Genomic DNA was isolated from blood and screened for genetic variants in CYP3A4 and UGT1A1. All statistical tests were two-sided.


RESULTS
CYP3A4 activity varied sevenfold (range = 0.223%-1.53% of dose) among patients, whereas midazolam clearance varied fourfold (range = 262-1012 mL/min), although intraindividual variation was small. Erythromycin metabolism was not statistically significantly associated with irinotecan clearance (P = .090), whereas midazolam clearance was highly correlated with irinotecan clearance (r = .745, P<.001). In addition, the presence of a UGT1A1 variant with a (TA)7 repeat in the promoter (UGT1A1*28) was associated with increased exposure to SN-38 (435 ng x h/mL, 95% confidence interval [CI] = 339 to 531 ng x h/mL in patients who are homozygous for wild-type UGT1A1; 631 ng x h/mL, 95% CI = 499 to 762 ng . h/mL in heterozygous patients; and 1343 ng x h/mL, 95% CI = 0 to 4181 ng x h/mL in patients who are homozygous for UGT1A1*28) (P = .006).


CONCLUSIONS
CYP3A4 phenotype, as assessed by midazolam clearance, is statistically significantly associated with irinotecan pharmacokinetics. Evaluation of midazolam clearance combined with UGT1A1*28 genotyping may assist with optimization of irinotecan chemotherapy.
Mathijssen
Ron H J
RH
Department of Medical Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands.
de Jong
Floris A
FA
van Schaik
Ron H N
RH
Lepper
Erin R
ER
Friberg
Lena E
LE
Rietveld
Trinet
T
de Bruijn
Peter
P
Graveland
Wilfried J
WJ
Figg
William D
WD
Verweij
Jaap
J
Sparreboom
Alex
A
D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001944:Breath Tests / Q000379:methods*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D016001:Confidence Intervals; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004917:Erythromycin / Q000493:pharmacokinetics; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008874:Midazolam / Q000378:metabolism / Q000493:pharmacokinetics*; D008875:Middle Aged; D010641:Phenotype; D011237:Predictive Value of Tests; D011446:Prospective Studies; D000099148:UGT1A1 Enzyme
D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D002250:Carbon Radioisotopes; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D004791:Enzyme Inhibitors; D004917:Erythromycin; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D008874:Midazolam; D000099148:UGT1A1 Enzyme; C104464:CYP3A protein, human; C510163:CYP3A4 protein, human