Pharmacology and clinical toxicity of 4'-iodo-4'-deoxydoxorubicin: an example of successful application of pharmacokinetics to dose escalation in phase I trials.
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 drug exposure after a dose lethal to 10% of mice (LD10) 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 x time (AUC) equivalent to that produced in mice by an LD10. However, differences in I-DOX pharmacokinetics and metabolism in BDF1 mice and humans at the initial dose prevented immediate application of this strategy. Therefore, we escalated the dose by the modified Fibonacci 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/m2). The LD10 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% (IC50) the growth of human granulocyte-macrophage colony-forming units (CFU-GM) was 80 nM for I-DOXOL and 50 nM 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 LD10. Then we safely applied pharmacokinetically guided escalation to determine the MTD (80 mg/m2). The plasma AUC of I-DOX and I-DOXOL at the human MTD is 71% of the AUC at mouse LD10. The only dose-limiting toxic effect was severe granulocytopenia.
Gianni
L
L
Laboratory of Clinical Pharmacology, Istituto Nazionale Tumori, Milan, Italy.
Viganò
L
L
Surbone
A
A
Ballinari
D
D
Casali
P
P
Tarella
C
C
Collins
J M
JM
Bonadonna
G
G
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D001711:Biotransformation; D001798:Blood Proteins / Q000378:metabolism; D002277:Carcinoma / Q000188:drug therapy*; D055598:Chemical Phenomena; D002621:Chemistry; D003114:Colony-Forming Units Assay; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D004341:Drug Evaluation; D006410:Hematopoiesis / Q000187:drug effects; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011446:Prospective Studies; D011485:Protein Binding
D000970:Antineoplastic Agents; D001798:Blood Proteins; C053044:4'-deoxy-4'-iododoxorubicin; D004317:Doxorubicin