Limited sampling model for the area under the concentration versus time curve of irinotecan and its application to a multicentric phase II trial.
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.
Yamamoto
N
N
Eastern Japanese Lung Cancer Chemotherapy Group, Japan Clinical Oncology Group, Japan.
Tamura
T
T
Nishiwaki
Y
Y
Kurita
Y
Y
Kawakami
Y
Y
Abe
S
S
Nakabayashi
T
T
Suzuki
S
S
Matsuda
T
T
Hayashi
I
I
Takahashi
T
T
Saijo
N
N
D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D003967:Diarrhea / Q000139:chemically induced; D005047:Etoposide / Q000008:administration & dosage; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use; D006801:Humans; D000077146:Irinotecan; D007970:Leukopenia / Q000139:chemically induced; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D011994:Recombinant Proteins / Q000627:therapeutic use; D015203:Reproducibility of Results; D014839:Vomiting / Q000139:chemically induced
D000972:Antineoplastic Agents, Phytogenic; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D005047:Etoposide; D000077146:Irinotecan; D002166:Camptothecin