Limited sampling model for the area under the concentration versus time curve of irinotecan and its application to a multicentric phase II trial

• Published in: Clinical cancer research 1997-07, Vol.3 (7), p.1087-1092
• Main Authors: YAMAMOTO, N, TAMURA, T, TAKAHASHI, T, SAIJO, N, NISHIWAKI, Y, KURITA, Y, KAWAKAMI, Y, ABE, S, NAKABAYASHI, T, SUZUKI, S, MATSUDA, T, HAYASHI, I
• Format: Article
• Language: English
• Subjects: Aged; Antineoplastic agents; Antineoplastic Agents, Phytogenic - adverse effects; Antineoplastic Agents, Phytogenic - pharmacokinetics; Antineoplastic Agents, Phytogenic - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Camptothecin - adverse effects; Camptothecin - analogs & derivatives; Camptothecin - pharmacokinetics; Camptothecin - therapeutic use; Carcinoma, Non-Small-Cell Lung - blood; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - pathology; Chemotherapy; Diarrhea - chemically induced; Etoposide - administration & dosage; Granulocyte Colony-Stimulating Factor - therapeutic use; Humans; Leukopenia - chemically induced; Lung Neoplasms - blood; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Medical sciences; Metabolic Clearance Rate; Middle Aged; Nausea - chemically induced; Pharmacology. Drug treatments; Recombinant Proteins - therapeutic use; Reproducibility of Results; Vomiting - chemically induced
• ISSN: 1078-0432; 1557-3265

We previously established a limited sampling model (LSM) for the area under the concentration versus time curve (AUC) of irinotecan (CPT-11). Using this LSM, we performed a pharmacokinetic-pharmacodynamic analysis of CPT-11 in a multicentric Phase II study for non-small cell lung cancer. Ten institutes participated in this study, 36 patients were registered, and 30 patients were evaluable for the pharmacokinetic-pharmacodynamic analysis. CPT-11 and etoposide were administered daily for three consecutive days, both at a dose of 60 mg/m2. Blood samples were obtained 4 and 8 h after infusion on days 1 and 3. When using the LSM, there is a significant possible source of error in the timing of these selected points. In this study, however, the sample timing error was small. Mean timing errors were 1.0-4.0 min at each point. The estimated CPT-11 AUCs were: Day 1 Day 2 Day 1 + 3 Mean +/- SD (mg.h/liter) 3.76+/-0.68 4.10+/-0.86 7.86+/-1.43 Range 2.01-5.03 2. 29-5.72 4.30-10.68 Max/min 2.50 2.45 2.48 High interpatient variability was observed in the AUC. The CPT-11 AUC correlated positively with the grade of emesis (P = 0.003) and the percent decreases in WBC count (P = 0.001) and absolute neutrophil count (P =0.0006), but it did not correlate with the grade of diarrhea or response. We concluded that the LSM was useful in estimating individual pharmacokinetic parameters in multicentric trials.