Pharmacokinetics and pharmacodynamics of irinotecan during a phase II clinical trial in colorectal cancer. Pharmacology and Molecular Mechanisms Group of the European Organization for Research and Treatment of Cancer.

PURPOSE: A pharmacokinetic study was performed during a phase II clinical trial of irinotecan (CPT-11) to confirm the pharmacokinetic profile of this drug and its metabolite and to investigate interpatient and intrapatient pharmacokinetic variations and pharmacokinetic-pharmacodynamic relationships. PATIENTS AND METHODS: Twenty-six men and 21 women (mean age, 61 years) with metastatic colorectal cancer, performance status less than 3 (World Health Organization [WHO] scale), and normal renal and hepatic function were administered CPT-11 (350 mg/m2) by 30-minute intravenous (IV) infusion every 21 days. CPT-11 and its metabolites SN-38 and SN-38 glucuronide (SN-38G) were determined by high-performance liquid chromatography (HPLC) using fluorimetric detection. RESULTS: The mean CPT-11 clearance and area under the concentration-time curve (AUC) were 15.2 L/h. m2 and 24,769ng. h/mL, respectively. The large difference in SN-38 and SN-38G AUCs (559 v 2,283 ng. h/mL) was suggestive of extensive glucuronidation of SN-38. Interindividual variation in the metabolic ratio ([AUCSN-38 + AUCSN-38Gl/AUCCPT-11) was marked (coefficient of variation [CV] = 51.6%] compared with intrapatient variation in this variable (CV = 32.6%). A significant relationship existed between percentage reduction in neutrophil count and the AUC of CPT-11 (r = .597, P < .001) and SN-38 (r = .559, P < .001). No relationship was identified between any pharmacokinetic parameter and delayed diarrhea or therapeutic outcome. CONCLUSION: Interindividual variations in the metabolic ratio suggest interpatient variation in carboxylesterase activity. Furthermore, glucuronidation of SN-38 may also be in part responsible for the large interpatient variability in the total SN-38 AUC. Conversely, low intrapatient variation of this parameter was observed in this study, which indicates a lack of autoinduction of the carboxylesterase system. The relationship between neutropenia and both CPT-11 and SN-38 pharmacokinetic parameters confirms the results of previous studies.

Population pharmacokinetics of carboplatin in children.

OBJECTIVES: In pediatric patients, administration of carboplatin according to body surface area results in a large variation in the area under the plasma ultrafilterable carboplatin concentration versus time curve. A population pharmacokinetic study using the NONMEM program was undertaken to determine the effects of a variety of covariates on the clearance of ultrafilterable carboplatin. PATIENTS: Plasma carboplatin pharmacokinetics were determined in 57 children (2 months to 18 years old, with serum creatinine levels ranging from 27 to 268 mumol/L) treated for various tumor types. RESULTS: The best fit corresponded to the formula: clearance (ml/min) = 2.85.weight.(1-0.00357.serum creatinine).(1-0.372.Np) + 8.7 (with serum creatinine in micromoles per liter, weight in kilograms, and Np = 1 or 0 for unilateral nephrectomy or not, respectively). The interindividual variability in clearance, as expressed by the coefficient of variation, decreased from 74% (no covariates) to 49% by taking account of weight, and to 29% under the final regression formula. CONCLUSION: The ability of this formula to predict carboplatin clearance in children should be evaluated prospectively and compared to a method based on the determination of the glomerular filtration rate.

[Prediction of carboplatin clearance from morphological and biological patient characteristics]. / Prédiction de la clairance du carboplatine à partir des caractéristiques morphologiques et biologiques du patient.

Hematologic toxicity of carboplatin is largely dependent on its pharmacokinetics. Its seems likely that therapeutic efficacy is also related to plasma drug exposure. Dosage adjustments based on isotopic determination of glomerular filtration rate have been proposed but their ambulatory use is not conceivable. A population pharmacokinetic study was undertaken to determine a relationship between patient characteristics and carboplatin clearance. Plasma carboplatin pharmacokinetics were determined as ultrafilterable platinum in 70 patients (23 to 84 years old) treated with different combination regimens including carboplatin at doses ranging from 184 to 950 mg (1-hr i.v. infusion) for various tumor types. Data were analysed using Nonlinear Mixed Effects Model (NONMEM). The data from 34 patients (46 cycles) were used to obtain the most predictive formula for the carboplatin clearance (ml/min): [formula: see text] The obtained formula was prospectively evaluated with the data from 36 other patients (43 cycles) and compared to other methods available to predict carboplatin clearance. Prospectively this formula predicted the clearance with a good precision (median absolute percent error of 10% range 0-30%) and minimal bias (median percent error: 2% range--25-30%). This method of prediction was as accurate as the one which requires the glomerular filtration rate to be measured by 51Cr-EDTA injection. This formula should allow to individualize very easily the carboplatin dosage in adults by multiplying the calculated carboplatin clearance by the area under the curve desired for administration.

Escalating dose of mitoxantrone with high-dose cyclophosphamide, carmustine, and etoposide in patients with refractory lymphoma undergoing autologous bone marrow transplantation.

PURPOSE: We conducted a dose-finding study of mitoxantrone (MITO) in combination with high-dose cyclophosphamide, carmustine (BCNU), and etoposide (CBV) in refractory lymphoma undergoing autologous bone marrow transplantation (ABMT). The objective were to determine the following: (1) the maximum-tolerated dose of MITO, (2) the extramedullary toxicity of this regimen, (3) its antitumor activity, and (4) the pharmacokinetic characteristics of MITO at each dose level. PATIENTS AND METHODS: Escalating doses of MITO (15 to 90 mg/m2, single bolus infusion on day -8) followed by CBV were administered to 20 patients (mean age, 38.5 years) with refractory lymphoma. MITO concentrations were determined by high-performance liquid chromatography (HPLC). RESULTS: No toxic death occurred. The maximum-tolerated dose appears to be 75 mg/m2. Two of five patients treated with 90 mg/m2 developed severe organ toxicity, versus zero of 15 treated with doses up to 75 mg/m2. Duration of neutropenia was longer for patients treated with 90 mg/m2 (31.7 days) than for patients treated with doses up to 75 mg/m2 (22.1 days) (P < .05). A linear relationship was observed between administered dose of MITO and (1) plasma peak value, (2) area under the curve (AUC), and (3) plasma concentration on the day of marrow infusion (day 0). Hematologic toxicity was related to the terminal half-life (T1/2) of MITO, and day-0 plasma concentration. A high complete response (CR) rate was observed (60%), and eight of 11 (73%) patients treated with MITO > or = 60 mg/m2 achieved a CR. CONCLUSION: MITO (up to 75 mg/m2) and CBV can be administered with acceptable toxicity and a promising CR rate in this poor-risk population, justifying further phase II studies.