Pharmacokinetics and pharmacodynamics of irinotecan and its metabolites from plasma and saliva data in patients with metastatic digestive cancer receiving Folfiri regimen.
OBJECTIVE
Irinotecan is extensively metabolized into at least four compounds and previous pharmacokinetic-pharmacodynamic studies have given varying results. We hypothesized that saliva, a noninvasive, safe and painless biological sampling process, could be a good predictor of the behavior of irinotecan and its metabolites.


METHODS
Thirty-five patients with metastatic digestive cancer were treated with a Folfiri regimen every 2 weeks. The irinotecan-administered dose was 180 mg/m(2); 17 patients participated in a dose-escalating study. Irinotecan and its metabolites (SN-38, SN-38G, APC, NPC) were quantified in plasma and saliva by high-performance liquid chromatography with fluorescence detection.


RESULTS
The mean irinotecan systemic clearance and steady-state volume of distribution values were 14.3 l/h/m(2) and 211 l/m(2), respectively. The intrapatient variability (22-28%) was far lower than the interindividual variability (33-88%). Age and weight were the two physiological parameters that influenced drug disposition. For irinotecan, SN-38, APC and NPC, similar pharmacokinetic profiles were observed from plasma and saliva data. The saliva/plasma AUC ratios averaged 1 for irinotecan, 0.3 for SN-38, 0.17 for APC and 0.27 for NPC. Neutropenia, diarrhea and nausea were the main toxicities encountered. From both plasma and saliva data, the percentage decrease in neutrophil count appeared to be related to irinotecan and SN-38 AUCs.


CONCLUSIONS
All these findings provide a rationale for an individual adaptation of irinotecan dosing. In case of difficult venous access, the titration of irinotecan and of its active metabolite SN-38 in saliva may prove relevant.
Poujol
Sylvain
S
Oncopharmacology Department, Pharmacy service, Val d'Aurelle Anticancer Centre, parc Euromédecine, Montpellier, France.
Bressolle
Françoise
F
Duffour
Jacqueline
J
Abderrahim
Anissa Gauthey
AG
Astre
Cécile
C
Ychou
Marc
M
Pinguet
Frédéric
F
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D019540:Area Under Curve; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D004067:Digestive System Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D012463:Saliva / Q000378:metabolism*; D014018:Tissue Distribution
D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin