First‐Time‐in‐Human Dose Selection: Allometric Thoughts and Perspectives

Some of the many factors that influence dose selection in first‐time‐in‐human studies are examined. These include animal toxicology, toxicokinetics, allometric scaling, pharmacokinetics, body surface area correlations, and integration of preclinical pharmacologic and toxicologic data. Appropriate preclinical evaluation and analysis may reduce the frequency and severity of unexpected toxic events arising during single‐dose, phase I testing. However, significant intrinsic uncertainties in this process presently exist and will continue to exist well into the foreseeable future. With our present state of knowledge, we cannot provide a realistic and reasonable algorithm for ascertaining first‐time‐in‐human doses: any decision tree would be too unwieldy. There are several rules of thumb that do have a place in the evaluation and decision‐making process, however.

[1]  U. Thorgeirsson,et al.  Isoniazid liver injury: clinical spectrum, pathology, and probable pathogenesis. , 1976, Annals of internal medicine.

[2]  I. Otterness,et al.  Nonsteroidal anti-inflammatory drugs: an analysis of the relationship between laboratory animal and clinical doses, including species scaling. , 1988, Journal of pharmaceutical sciences.

[3]  M Slavik,et al.  Quantitative prediction of drug toxicity in humans from toxicology in small and large animals. , 1975, Cancer research.

[4]  W. Calder Size, Function, and Life History , 1988 .

[5]  Willard R. Chappell,et al.  Extrapolation of Toxicological and Pharmacological Data from Animals to Humans , 1991 .

[6]  L. J. West,et al.  Lysergic Acid Diethylamide: Its Effects on a Male Asiatic Elephant. , 1962, Science.

[7]  W. Barker Ontogeny and phylogeny. , 1980, Archives of surgery.

[8]  T. Clutton‐Brock,et al.  LIFE HISTORY VARIATION IN PRIMATES , 1985, Evolution; international journal of organic evolution.

[9]  Brian T. Shea,et al.  Heterochrony in human evolution: The case for neoteny reconsidered , 1989 .

[10]  P. N. Kugler,et al.  Similarity principles and intrinsic geometries: contrasting approaches to interspecies scaling. , 1986, Journal of pharmaceutical sciences.

[11]  H. Boxenbaum,et al.  Interspecies pharmacokinetic scaling, biological design and neoteny , 1990 .

[12]  B. Chabner,et al.  Potential roles for preclinical pharmacology in phase I clinical trials. , 1986, Cancer treatment reports.

[13]  K H Antonin,et al.  Pharmacokinetics and plasma binding of diazepam in man, dog, rabbit, guinea pig and rat. , 1976, The Journal of pharmacology and experimental therapeutics.

[14]  Henry D. Prange,et al.  Scaling of Skeletal Mass to Body Mass in Birds and Mammals , 1979, The American Naturalist.

[15]  J. Litchfield Forecasting drug effects in man from studies in laboratory animals. , 1961, JAMA.

[16]  P. D. Harwood Therapeutic Dosage in Small and Large Mammals. , 1963, Science.

[17]  P. Abelson Incorporation of new science into risk assessment , 1990, Science.

[18]  J. Haldane Possible Worlds, and other Essays , 1928, Nature.

[19]  E. Richelson,et al.  Binding of benzodiazepines and some major metabolites at their sites in normal human frontal cortex in vitro. , 1991, The Journal of pharmacology and experimental therapeutics.

[20]  W. R. Stahl,et al.  Scaling of respiratory variables in mammals. , 1967, Journal of applied physiology.

[21]  E J Freireich,et al.  Quantitative comparison of toxicity of anticancer agents in mouse, rat, hamster, dog, monkey, and man. , 1966, Cancer chemotherapy reports.

[22]  Scaling of bodily proportions in adult terrestrial mammals. , 1992, The American journal of physiology.

[23]  J. Prothero,et al.  Scaling of blood parameters in mammals , 1980 .

[24]  J. Caldwell,et al.  The current status of attempts to predict species differences in drug metabolism. , 1981, Drug metabolism reviews.

[25]  J. Mordenti Dosage regimen design for pharmaceutical studies conducted in animals. , 1986, Journal of pharmaceutical sciences.

[26]  A. Sedman,et al.  New Drugs: First Time in Man , 1989, Journal of clinical pharmacology.

[27]  W. Colburn Controversy V: Phase I, First Time in Man Studies , 1990, Journal of clinical pharmacology.

[28]  K. Bergmann,et al.  Handbook of the biology of aging , 1979 .