Toxicokinetics/Toxicodynamic Correlations: Goals,Methods,and Limitations

Abstract

Toxicokinetic (TK) studies are the basis for demonstrating dose-related drug exposure in animals and for ensuring that drug exposure is substantially greater in animals than that expected in humans at therapeutic doses. The usefulness of TK studies can be further enhanced by correlating TK parameters with relevant toxicologic end points. The so-called TK/toxicodynamic (TD) correlations can be extremely useful in bridging data from studies both within and across species and in designing early Phase I clinical trials. These correlations assume that toxicologic responses are comparable among species at comparable plasma concentrations. This assumption may apply for certain drugs but not for others. Therefore, TK/TD correlations should be developed and utilized on a case-by-case basis. Such correlations have proven to be extremely useful with anticancer drugs in formulating dose escalation strategies in cancer patients to rapidly attain the maximum tolerated and/or effective dose. However, these correlations have not been utilized effectively in other therapeutic areas. The development of TK/TD correlations, their scope, and limitations are discussed in this paper.

Keywords

Toxicokinetics toxicodynamics toxicokinetic/toxicodynamic correlations pharmacokinetics drug exposure extrapolation to humans

References

Alcock SJ (1971). An anti-inflammatory compound non-toxic to animals but with an adverse action in man. Proc. Eur. Soc. Study Drug Toxicity XII (Suppl. ICS 220): 184.

Bums JJ (1955). Effect of phenylbutazone (Butazolidine) on experimentally induced ocular inRammation. AMA Arch. Ophtftalmol. 53: 264-268.

Collins JM (1987). Prospective predictions and validations in anticancer therapy. In: Pharmacokinetics in Risk Assessment, Workshop Proceedings. Vol. 8. National Academy Press, Washington, D.C., pp. 431-440.

Collins JM Grieshaber CK and Chabner BA (1990). Pharmacologically guided Phase I clinical trials based upon preclinical drug development. J. Natl. Cancer Inst . 82: 1321-1326.

Collins JM , Zaharko DS Dedrick RL , and Chabner BA (1986). Potential roles for preclinical pharmacology in Phase I clinical trials. Cancer Treatment Rep. 70: 73-80.

Duncan WAM (1963). The importance of metabolism studies in relation to drug toxicity. Proc. Eur. Soc. Drug Toxicity 2: 67-70.

Halladay SC , Carter DE , and Sipes IG (1978). A relationship between the metabolism of bumetanide and its diuretic activity. Drug Metab. Dispos. 6: 45-49.

Hendrie TA , Rowland JR , Binkerd PE , and Hendrickx AG (1990). Developmental toxicity and pharmacokinetics of phenytoin in the rhesus macaque: An interspecies comparison. Reprod. Toxicol. 4: 257-266.

Mordenti J. and Chappell W. (1989). The use of interspecies scaling in toxicokinetics . In: Toxicokinetics and New Drug Development, A Yacobi , JP Skelly , and VK Batra (eds). Pergamon Press, New York, pp. 42-96.

10.

Nau H. (1991). Pharmacokinetic considerations in the design and interpretation of developmental toxicity studies. Fund. Appl. Toxicol. 16: 219-221.

11.

Patel BA , Boudinot FD , Schinazu RF , Gallo JM , and Chu CK (1990). Comparative pharmacokinetics and interspecies scaling of 3'-deoxythymidine (AZT) in several mammalian species. J. Pharmacobiol. Dyn. 13:206-211.

12.

Powell SH , Thompson WL , Luthe MA , Stem RC , Grossniklaus DA , Bloxham DD , Groden DL , Jacobs MR , DiScenna AO , Cash HA , and Klinger JD (1983). Once daily vs continuous aminoglycoside dosing: Efficacy and toxicity in animals and clinical studies of gentamicin, nethilmicin and tobramycin. J. Infect. Dis. 147: 918-932.

13.

Quinn GP , Axelrod J. , and Brodie BB (1958). Species, strain and sex differences in metabolism of hexobarbitone, amidopyrine, antipyrine, and aniline. Biochem. Pharmacol. 1: 152-159.

14.

Ramzan I. (1990). Pharmacodynamics of phenytoin-induced ataxia in rats. Epilepsy Res. 5: 80-83.

15.

Wu WH , Henderson R. , Lanc R. , Ganes D. , Yacobi A. , and Silber BM (1988). Relationship between the pharmacokinetic and pharmacodynamic profile of nilvadipine in the dog. Drug. Metab. Dispos. 16: 222-227.