Pharmacology and Clinical Toxicity of 4'-Iodo-4'-deoxydoxorubicin: An Example of Successful Application of Pharmacokinetics to Dose Escalation in Phase I Trials

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Abstract
In a prospective phase I trial involving 35 patients with metastatic carcinoma, we tested a pharmacokinetic strategy for guiding dose escalation of the anthracycline 4′-iodo-4′-deoxydoxorubicin (I-DOX), a new analogue reported to be more potent and less toxic than doxorubicin. This strategy is potentially a safe and more rapid way of determining the maximum tolerated dose (MTD) of anticancer agents. Retrospective studies have shown that the total plasma durg exposure after a dose lethal to 10% of mice (LD 10 ) is approximately equivalent to the total exposure produced in humans by the MTD. Thus, we intended to aim dose escalation in humans to achieve the area under the curve for I-DOX plasma concentration × time (AUC) equivalent to that produced in mice by an LD 10 . However, differences in I-DOX pharmacokinetics and metabolism in BDF 1 mice and humans at the intitial dose prevented immediate application of this strategy. Therefore, we escalated the dose by the modified Fiboncci scheme while investigating the pharmacology of I-DOX and its major plasma metabolite 4′-iodo-4′-deoxy-13- dihydrodoxorubicin (I-DOXOL). Plasma pharmacokinetics was characterized by rapid elimination and extensive metabolism of I-DOX to I-DOXOL. The ratio of I-DOXOL to I-DOX plasma AUC was 12.8±7.3 SD. The plasma pharmacokinetics of I-DOX and I-DOXOL were linear in the range of tested doses (2–90 mg/m 2 ). The LD 10 in mice was 6.8 mg/kg for I-DOXOL and 6 mg/kg for I-DOX, and the concentration of drug that inhibited by 50% (IC 50 ) the growth of human granulocyte-macrophage colony-forming units (CFU-GM) was 80 n M for I-DOXOL and 50 n M for I-DOX. From these findings, we concluded that the toxic effects of I-DOX and I-DOXOL are equivalent and reset the pharmacokinetic target of escalation to the sum of I-DOX and I-DOXOL AUCs at I-DOX LD 10 . Then we safely applied pharmacokinetically guided escalation to determine the MTD (80 mg/m 2 ). The Plasma AUC of I-DOX and I-DOXOL at the human MTD is 71% of the AUC at mouse LD 10 . The only dose-limiting toxic effect was severe granulocytopenia. [J Natl Cancer Inst 82:469–477, 1990]