Pharmacokinetics of carboplatin administered with lobradimil to pediatric patients with brain tumors.
OBJECTIVE
To determine the pharmacokinetics of adaptively dosed carboplatin when administered in combination with the bradykinin agonist, lobradimil (RMP-7, Cereport), to pediatric patients with brain tumors.


METHODS
Carboplatin pharmacokinetic studies were performed on 21 of 25 children with primary brain tumors who received carboplatin and lobradimil on two consecutive days every 28 days in a phase I dose-escalation trial of lobradimil. Carboplatin was adaptively dosed, based on the radioisotopic glomerular filtration rate (GFR) to achieve a target plasma area under the concentration vs time curve (AUC) of 3.5 mg.min/ml per dose x2 (2.5 mg.min/ml per dose x2 in patients with prior craniospinal radiation or myeloablative chemotherapy). The adaptive dosing formula was: carboplatin dose (mg/m2)=target AUC (mg.min/ml) x [0.93 x GFR (ml/min/m2)+15]. Carboplatin was infused over 60 min (n=15) or 15 min (n=6). The 10-min lobradimil infusion (100-600 ng/kg ideal body weight) began 5 min before the end of the carboplatin infusion. Frequent blood samples were drawn over 24 h after the first dose of carboplatin/lobradimil. Ultrafilterable platinum was measured by atomic absorption spectroscopy, and the AUC of ultrafilterable platinum was derived using the linear trapezoidal rule and extrapolated to infinity.


RESULTS
The median GFR was 65 ml/min/m2 (range 38-95 ml/min/m2) and the median carboplatin doses for the 2.5 and 3.5 mg min/ml target AUCs were 154 and 276 mg/m2/day (124-235 and 179-360 mg/m2/day), respectively. The measured carboplatin AUC exceeded the target AUC in all 21 patients by a median of 35% (range 0.2-131%). The median carboplatin AUCs at the 2.5 and 3.5 mg.min/ml target AUCs were 3.4 and 4.8 mg.min/ml (2.51-5.8 and 3.9-7.7 mg.min/ml), respectively. Carboplatin clearance was lower than values previously reported in children and correlated poorly with GFR (r2=0.14).


CONCLUSIONS
Adaptive dosing of carboplatin based on GFR overestimated the dose required to achieve the target carboplatin AUC in pediatric patients with brain tumors treated with concurrent lobradimil. The degree to which the measured carboplatin AUC exceeded the target AUC appeared to be greater at higher doses of lobradimil, suggesting that the failure of the adaptive dosing method was related to an unexpected pharmacokinetic drug interaction.
Warren
Katherine
K
Neuro-Oncology Branch and Pediatric Oncology Branch, National Cancer Institute, Bloch Building, #82, 9030 Old Georgetown Road, Bethesda, MD 20892-8200, USA. warrenk@mail.nih.gov
Gervais
Anne
A
Aikin
Alberta
A
Egorin
Merrill
M
Balis
Frank M
FM
D000293:Adolescent; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001812:Blood-Brain Barrier; D001920:Bradykinin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy*; D016190:Carboplatin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male
D000970:Antineoplastic Agents; C089876:RMP 7; D016190:Carboplatin; D001920:Bradykinin