A CYP3A4 phenotype-based dosing algorithm for individualized treatment of irinotecan.
OBJECTIVE
Irinotecan, the prodrug of SN-38, is extensively metabolized by cytochrome P450-3A4 (CYP3A4). A randomized trial was done to assess the utility of an algorithm for individualized irinotecan dose calculation based on a priori CYP3A4 activity measurements by the midazolam clearance test.


METHODS
Patients were randomized to receive irinotecan at a conventional dose level of 350 mg/m(2) (group A) or doses based on an equation consisting of midazolam clearance, gamma-glutamyl-transferase, and height (group B). Pharmacokinetics and toxicities were obtained during the first treatment course.


RESULTS
Demographics of 40 evaluable cancer patients were balanced between both groups, including UGT1A1*28 genotype and smoking status. The absolute dose of irinotecan ranged from 480 to 800 mg in group A and 380 to 1,060 mg in group B. The mean absolute dose and area under the curve of irinotecan and SN-38 were not significantly different in either group (P > 0.18). In group B, the interindividual variability in the area under the curve of irinotecan and SN-38 was reduced by 19% and 25%, respectively (P > 0.22). Compared with group A, the incidence of grades 3 to 4 neutropenia was >4-fold lower in group B (45 versus 10%; P = 0.013). The incidence of grades 3 to 4 diarrhea was equal in both groups (10%).


CONCLUSIONS
Incorporation of CYP3A4 phenotyping in dose calculation resulted in an improved predictability of the pharmacokinetic and toxicity profile of irinotecan, thereby lowering the incidence of severe neutropenia. In combination with UGT1A1*28 genotyping, CYP3A4 phenotype determination should be explored further as a strategy for the individualization of irinotecan treatment.
van der Bol
Jessica M
JM
Department of Medical Oncology, Erasmus MC-Daniel den Hoed Cancer Center, University Medical Center, Rotterdam, the Netherlands.
Mathijssen
Ron H J
RH
Creemers
Geert-Jan M
GJ
Planting
André S Th
AS
Loos
Walter J
WJ
Wiemer
Erik A C
EA
Friberg
Lena E
LE
Verweij
Jaap
J
Sparreboom
Alex
A
de Jong
Floris A
FA
D000328:Adult; D000368:Aged; D000465:Algorithms; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D054796:Drug Dosage Calculations; D005260:Female; D006801:Humans; D007206:Individuality; D000077146:Irinotecan; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000493:pharmacokinetics; D008875:Middle Aged; D008954:Models, Biological; D009362:Neoplasm Metastasis; D010641:Phenotype; D057285:Precision Medicine / Q000379:methods; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics
D000972:Antineoplastic Agents, Phytogenic; D011355:Prodrugs; D000077146:Irinotecan; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam; D002166:Camptothecin