Use of Pharmacokinetics and Pharmacodynamics in Preclinical Studies to Guide Dosage Escalation Schemes in Phase I Studies of Anticancer Drugs

  • Jerry M. Collins

Abstract

For the concept of pharmacologically-guided clinical trials with new anticancer drugs, the principal focus has been development of links between preclinical testing and Phase I clinical trials. Recent experiences with very lengthy Phase I trials for at least 8 drugs have provided particular impetus for the project. The specific concept was that dose-limiting toxicity is predicted by drug concentrations in plasma, and that the quantitative relationship between drug exposure (as measured by plasma drug concentration times time, or CxT) and toxicity holds across species. As a consequence, dose escalations in man could safely be based on measurements of drug levels in plasma, rather than on empirical escalation schemes. Although the concept is still relatively new, practical results have already been achieved. Examples will be given of Phase I trials which were completed with a savings of 12–24 months. Overall, there is now a substantial collection of data which demonstrates that coordination with preclinical pharmacology and toxicology studies can save both time and resources in early clinical trials without a loss of safety.

Keywords

Anticancer Drug Preclinical Testing Lengthy Phase Entry Dose Escalation Scheme 
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References

  1. Collins, J M., D. S. Zaharko, R. L. Dedrick, and B. A. Chabner (1986). Potential risks for preclinical pharmacology Phase I clinical trials. Cancer Treat. Rep.,70, 73–80.PubMedGoogle Scholar
  2. Collins, J. M., B. Leyland-Jones, and C. K. Grieshaber (1987). Role of preclinical pharmacology in Phase I clinical trials: considerations of schedule-dependence. In F. M. Muggia (Ed.), Concepts in Cancer Chemotherapy Martinus Nijhoff, Boston. pp. 129–140.Google Scholar
  3. Collins, J. M., C. K. Grieshaber, and B. A. Chabner (1990). Pharmacologically guided Phase I clinical trials based upon preclinical drug development. J. Nat. Cancer Inst.,82, 1321–1326.PubMedCrossRefGoogle Scholar
  4. EORTC Pharmacokinetics and Metabolism Group (1987). Pharmacokinetically guided dose escalation in Phase I clinical trials. Commentary and proposed guidelines. Eur. J. Cancer Clin. Oncol., 23, 1083–1087.Google Scholar
  5. Foster, B.J., M. A. Graham, D. R. Newell, L. A. Gumbrell, and A. H. Calvert (1988). Clinical pharmacokinetics of antrapyrazole CL-941 factors compromising the implementation of a pharmacokinetically guided dose escalation scheme. Proc. Amer. Soc. Clin. Oncol.,7, 64.Google Scholar
  6. Gianni, L., L. Vigano, A. Surbone, D. Ballinari, P. Casali, C. Tarella, J. M. Collins, and G. Bonadonna (1990). Pharmacology and clinical toxicity of 4’-iodo-4’ deoxydoxorubicin: an example of a successful application of pharmacokinetics to dose escalation in Phase I trials. J. Natl. Cancer Inst.,82, 469–477.PubMedCrossRefGoogle Scholar
  7. Graham, M. A., D. R. Newell, B. J. Foster, and A. H. Calvert (1989). The pharmacokinetics and toxicity of the anthrapyrazole anti-cancer drug C1–941 in the mouse: a guide for rational dose escalation in patients. Cancer Chemother. Pharmacol.,23, 8–14.PubMedCrossRefGoogle Scholar
  8. Newell, D. R. (1990). Phase I clinical studies with cytotoxic drugs: pharmacokinetic and pharmacodynamic considerations. Brit. J. Cancer,61, 189–191.PubMedCrossRefGoogle Scholar
  9. van Hennik, M.B., W. J. F. van der Vijgh, I. Klein, F. Elferink, J. B. Vermorken, B. Winograd, and H. M. Pinedo (1987). Comparative pharmacokinetics of cisplatin and three analogues in mice and humans. Cancer Res. 47, 6297–6301.Google Scholar

Copyright information

© Springer Science+Business Media New York 1993

Authors and Affiliations

  • Jerry M. Collins
    • 1
  1. 1.Division of Clinical PharmacologyFood and Drug AdministrationRockvilleUSA

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