The Usefulness of Pharmacokinetics in the Development of Antineoplastic and Anti-Aids Agents

  • Julie L. Eiseman
Part of the NATO ASI Series book series (NSSA, volume 221)


There are many difficulties to be faced, both ethical and scientific, in the introduction of a new agent into clinical practice. In the development of cytotoxic agents such as antineoplastic drugs and antiviral agents directed against HIV (human immunodeficiency virus) the path is similar. Clinicians deliver and patients take experimental treatments with the hope of therapeutic benefit in the face of a life threatening illness. In most cases, the chance of therapeutic benefit from the experimental treatment is low; in 187 clinical trials on 54 experimental agents the response rate was only 4% [Estey et al., 1986]. Since the likelihood of toxicity is much greater, investigators involved in the development of these cytotoxic agents must plan their experiments well and gain the most amount of information regarding the efficacy and toxicity of the agent with the fewest number of patients. It is the goal of this chapter to illustrate the successful use of pharmacokinetics in the development of two such therapeutic agents which have recently been introduced to the clinic as approved therapies: Carboplatin as an antineoplastic agent and Zidovudine as an anti-AIDS agent. Through these examples, the importance of pharmacokinetics during the Phase I testing of cytotoxic agents will be established and the use of pharmacokinetics in the development of these two agents will provide guidelines for future phase I testing strategies.


Human Immunodeficiency Virus Antineoplastic Agent Total Body Clearance Antineoplastic Drug Total Platinum 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Balis, F.M., Pizzo, P.A., Eddy, J., Wilfert, C., McKinney, R., Scott, G., Murphy, R.F., Jarosinski, P.F., Falloon, J., and Poplack, D.G., 1989. Pharmacokinetics of Zidovudine Administered Intravenously and Orally in Children with Humna Immunodeficiency Virus Infection. J. Pediatrics 114: 880.CrossRefGoogle Scholar
  2. Balis, F.M., McCully, C., Gough, L., Pizzo, P.A., and Poplack,D.G., 1989. Pharmacokinetics of Subcutaneous Azidothymidine in Rhesus Monkeys. Antimicrob. Agts. Chemother. 33: 810.Google Scholar
  3. Belani, C.P., Egorin, M.J., Abrams, J.S., Hiponia, D., Eisenberger, M., Aisner, J., and Van Echo, D.A., 1990. A Novel Phartnacodynamically Based Approach to Dose Optimization of Carboplatin when Used in Combination with Etoposide. In: Carboplatin (JM 8) Current Perspectives and Future Directions ( P.A. Bunn, Jr., R.F. Canetta, R.F. Ozols, and M. Rozencweig, ed.), page 39. W.B. Saunders Co., Philadelphia.Google Scholar
  4. Bilello, J.A., Eiseman, J.L., MacAuley, C., Bell, M.M., and Yetter, R.A., 1988. 3Azidothymidine Prevents the Dissemination of Retrovirus in LP-BM5 MuLV-Infected Mice. Int. Conf. AIDS Res., Stockholm, p. 170.Google Scholar
  5. Blum, M.R., Liao, S.H.T., Good, S.S., and deMiranda, P., 1988. Pharmacokinetics and Bioavailability of Zidovudine in Humans. Am. J. Med. 85: Suppl. 2A, p. 189.Google Scholar
  6. Bozzette, S.A. and Richman D.D., 1990 Salvage Therapy for Zidovudine Intolerant HIVImInfected Patients with Alternating and Intermittent Regimens of Zidovudine and Dideoxycytidine. Am. J. Med. 88:Suppl. 5B, p. 24S.Google Scholar
  7. Collins, J.M., Zaharko, D.S., Dedrick, R.I., and Chabner, B.A., 1986. Potential Roles for Preclinical Pharmacology in Phase I Clinical Trials. Cancer Treat. Rep. 70: 73.PubMedGoogle Scholar
  8. Collins, J.M. and Unadkat, J.D., 1989. Clinical Pharmacokinetics of Zidovudine, An Overview of Current Data. Clin. Pharmacolcinet 17: 1.CrossRefGoogle Scholar
  9. Collins, J.M., Grieshabar, C.K., and Chabner, B., 1990. Pharmacologically Guided Phase I Clinical Trials Based Upon Preclinical Drug Development. J. Natl. Cancer Institute. 82: 1321.CrossRefGoogle Scholar
  10. Miranda, P., Good, S.S., Yarchaon, R., Thomas, R.V., Blum, M.R., Myers C.E., and Broder, S., 1989. Alteration of Zidovudine Pharmacokinetics in Patients with AIDS or AIDS Related Complex. Clin. Phartn. Then 46: 494CrossRefGoogle Scholar
  11. Doshi, K.J., Gallo, J.M., Boudinot, F.D., Schinazi, R.F., and Chu, C.K., 1989. Comparative Pharmacokinetics of 3 Azido 3Deoxythymidine (AZT) and 3 Azido 2,3 dideoxyuridine (AZddU) in Mice. Drug Met. Disp. 17: 590.Google Scholar
  12. Egorin, Mi., Van Echo, D.A., Tipping, S.J., Olman, E.A., Whitacre, M., Thompson, B.W., and Aisner, J., 1984. Pharmacokinetics and Dosage Reduction of cis Diammine(1,1Tmcyclobutanecarboxylato)platinum in Patients with hnpaired Renal Function. Cancer Res. 44: 5432.PubMedGoogle Scholar
  13. Egorin, M.J., Van Echo, D.A., Olman, E.A., Whitacre, M.Y., Forrest, A., and Aisner J., 1985. Prospective validation of a pharmacologically based dosing scheme for the cis-Diamminedichloroplatinum (II) analog diamminecyclobutanedicarboxylatoplatinum, Cancer Res. 45: 6502.PubMedGoogle Scholar
  14. Eiseman, J.L., Bell, M.M., Bilello, J.A., Wetherall, D.L., MacAuley, C., and Yetter, R.A., 1988. Pharmacokinetics of 3Azidothymidine (AZT) in Retrovirus Infected Mice. Fed. Proc. 2: 3596.Google Scholar
  15. Estey, E., Hoth, D., Simon, R., Marsoni, S., Leyland Jones, B., and Wittes, R., 1986. Therapeutic Response in Phase I Trials of Antineoplastic Agents. Cancer Treat. Rep. 70: 1105.Google Scholar
  16. Freireich, E.J., Gehan, E.A., Rall, D.P., Schmidt, L.H., and Skipper, H.E., 1966. Quantitative Comparison of Toxicity of Anticancer Agents in Mouse, Rat, Hamster, Dog, Monkey and Man. Cancer Chemother. Rep. 50: 219.Google Scholar
  17. Garraffo, R., Cassuto Viguier, E., Bullion, J., Lapalus, P., and Duplay, H., 1989. Influence of Hemodialysis on Zidovudine (AZT) and its Glucuronide (GAZT) Pharmacokinetics: Two Case Reports. Int. J. Clin. Pharmaco. Ther. Toxicol. 27: 535.Google Scholar
  18. Hollander, H., Lifson, A., Maha, M., Blum, M.R., Rutherford, G.W., and Nusinoff-Lehrman, S., 1989. Phase I Study of Low Dose Zidovudine and Acyclovir in Asymptomatic Human Immunodeficiency Virus Seropositive Individuals. Am. J. Med. 87: 628.PubMedCrossRefGoogle Scholar
  19. Karnofsky, D.A. and Berchenal, J.H., 1949. The clinical evaluation of chemotherapeutic agents in cancer. In: Evaluation of Chemotherapeutic Agents ( C.M. Macleod ed.), page 191. Columbia University Press, New York.Google Scholar
  20. Klecker, R.W., Collins, J.M., Yarchoan, R., Thomas, R., Jenkins, J.F., Broder, S., and Myers, C.E., 1987. Plasma and Cerebrospinal Fluid Pharmacokinetics of 3-Azido-3-deoxythymidine: A Novel Pyrimidine Analog with Potential Application for the Treatment of AIDS and Related Diseases. Clin. Pharm. Ther. 41: 407.CrossRefGoogle Scholar
  21. Meng, T C., Fischi, M.A., and Richman, D.D., 1990. AIDS Clinical Trials Group: Phase I/II Study of Combination 2,3 Dideoxycytidine and Zidovudine in Patients with Acquired Immunodeficiency Syndrome (AIDS) and Advanced AIDS Related Complex. Am J. Med. 88:Suppl. 5B, p. 27S.Google Scholar
  22. Mitsuya, H., Weinhold, K.L., Furman, P.A., St. Clair, M.H., Nusinoff-Lehrman, S., Gallo, R.C., Bolognesi, D., Barry, D.W., and Broder, S., 1985. 3-azido3-deoxythymidine (BW A509U): A New Antiviral Agent that Inhibits the Infectivity and Cytopathic Effect of Human T-lymphotrophic virus type III/lymphadenopathy-associated virus in vitro. Proc. Natl. Acad. Sci.(USA) 82: 7096.Google Scholar
  23. Morse, G.D., Portmore, A., Olson, J., Taylor, C., Plank, C., and Reichman, R.C., 1990. Multiple Dose Pharmacokinetics of Oral Zidovudine in Hemophilia Patients with Human Immunodeficiency Virus Infection. Antimicro. Agts. Chemother. 34: 394.Google Scholar
  24. Pizzo, P., 1990. Treatment of Human Immunodeficiency Virus Infected Infants and Young Children with Dideoxynucleosides. Am. J. Med. 88: Suppl. 5B, p. 16S.Google Scholar
  25. Ruprecht, R.M., O’Brien, L.G., Rossoni, L.D., and Nussinoff-Lehrman, S., 1987. Suppression of mouse viremia and retroviral disease by 3-azido-3deoxythymidine. Nature 323: 467.CrossRefGoogle Scholar
  26. Schurig, J.E., Rose W.C., Catino, J.J., Gaver R.C., Long B.H., Madissoo, H., and Canetta, R., 1990. The Pharmacologic Characteristics of Carboplatin: Preclinical Experience. In: Carboplatin (JM 8) Current Prospectives and Future Directions ( P.A. Bunn, Jr., R.F. Canetta, R.F. Ozols, and M. Rozencweig, eds.), page 39. W.B. Saunders Co., Philadelphia.Google Scholar
  27. Singlas, E., Pioger, J.C., Taburet, A.M., Colin, J.N., and Fillastre, J.P., 1989. Zidovudine Disposition in Patients with Severe Renal Impairment: Influence of Hemodialysis. Clin.Phann. Ther. 46: 190.Google Scholar
  28. Skowron, G., and Merigan T.C., 1990. Alternating and Intermittent Regimens of Zidovudine (31-azido-deoxythymidine) and Deoxycytidine (2’,3-deoxycytidine) in the Treatment of Patients with Acquired Imtnunodeficiency Syndrome (AIDS) and AIDS Related Complex. Am. J. Med. 88:Suppl. 5B, p. 20S.Google Scholar
  29. Terasaki, T. and Pardridge, W.P., 1988. Restricted Transport of 3 Azido 3 Deoxythymidine and Deoxynucloesides Through the Blood Brain Barrier. J. Infect. Dis. 158: 630.PubMedCrossRefGoogle Scholar
  30. Van Echo, D.A., Egorin, Mi., Whitacre, M.Y., Olman, E.A., and Aisner, J., 1984. Phase I clinical and Pharmacologic Trial of Carboplatin Daily for 5 Days. Cancer Treat. Rep. 44: 1103.Google Scholar
  31. Van Echo, D.A., Egorin, M.J., and Aisner, J., 1989. The Pharmacology of Carboplatin. Seminars in Oncology 16:Suppl. 5, p. 1.Google Scholar
  32. Yarchoan, R., Weinhold, K.J., Lyerly, H.K., Blum, M.R., Shearer, G.M., Mitsuya, H., Collins, J.M., Myers, C.E., Klecker, R.W., Markham, P.D., Durack, D.T., Nusinoff-Lehrman, S., Barry, D.W., Fischl, M.A., Bolognesi, D.P., and Broder, S., 1986. Administration of 3-Azido-3-deoxythymidine, an Inhibitor of HTLV III/LAV Replication, to Patients with AIDS or AIDS Related Complex. Lancet 1: 575.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Julie L. Eiseman
    • 1
    • 2
  1. 1.Division of Developmental TherapeuticsUniversity of Maryland Cancer CenterBaltimoreUSA
  2. 2.Department of PathologyUniversity of Maryland School of MedicineBaltimoreUSA

Personalised recommendations