Several new biologic agents designed to stimulate platelet growth and development are now in clinical trials. The need for a pre-clinical treatment model was the impetus for this study. Carboplatin is a frequently used chemotherapeutic agent which produces thrombocytopenia in a high percentage of human patients. A dose-response study was performed to determine the optimum dose required to produce thrombocytopenia with acceptable toxicity. Carboplatin dose can be determined using an area under the curve (AUC) formula which is applicable to nonhuman primates. In humans, AUC dosing can reproducibly predict toxicities. Three dose ranges were planned (AUC of 7, 8 & 9) using 3 groups of 3 rhesus monkeys (Macaca mulatta). Two dosing groups (AUC 7 & 8) have been completed. The dose of carboplatin was administered by IV infusion. Supportive therapy was instituted as necessary and consisted of antiemetic and fluid therapy with administration of granulocyte colony stimulating factor (G-CSF) as needed. All animals were followed during the study by monitoring physical exams, CBC's, and serum chemistries. One of 3 animals in Group 1 (AUC 7) demonstrated adverse reactions after dosing. The 2 unaffected animals never developed thrombocytopenia. The 1 animal with adverse reactions demonstrated anemia, thrombocytopenia, leukopenia, elevated serum ALT and AST. These abnormal findings resolved completely within 30 days of dosing. All 3 animals in Group 2 (AUC of 8) demonstrated at least 1 abnormal finding on clinical laboratory testing or physical examination. Two of the animals resolved these abnormalities by 30 days post dosing with carboplatin. The third animal died during week 2 post infusion of ulcerative enteritis. All 3 animals had mild to moderate leukopenia during the study period. The terminal animal was the only subject demonstrating thrombo-cytopenia, elevated serum ALT and AST. Plans are in place to begin the third dosing group (AUC of 9) after determining glomerular filtration rate of each individual animal. In addition, G-CSF will be administered beginning on the day of carboplatin dosing to decrease the rate of leukopenia.
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