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Pharmacodynamic and pharmacokinetic measurements of antitumor agents
Author(s) -
Mellett L. B.
Publication year - 1974
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt1974161part2230
Subject(s) - pharmacology , toxicity , pharmacokinetics , methotrexate , pharmacodynamics , amethopterin , drug , chemistry , biology , medicine , immunology
Blood level assays of antitumor drugs in the mouse, rat, hamster, dog, monkey, and man were done to determine the toxicologic and therapeutic responses by species. F or cyclophosphomide and amethopterin, the predicted maximum tolerated dose for man, based on all animal data, correlated rrwre closely with clinical toxicity when related to body surface area thon to body weight. Doses of 18 drugs including antimetabolites, alkylating agents, and other antitumor agents carried to the toxicologic end point, LD 10 in small animals, the maximum tolerated dose (MTD) in dogs and monkeys, showed that the ratios of animal/human toxicity on the mg per square meter basis were remarkably close to unity. Also, when doses are expressed on this basis, equal doses give equivalent values in difJerent species for the area under the serum curve, i.e., the product of drug concentration × time, C × T (µg/ml × minutes). Three agents, arabinosylcytosine (ARA‐C), methotrexate (MTX), and CTX, selected for their differential presumed sites of primary biochemical action and the concept of unbalanced growth and cell death, were studied for the interrelationships between dosage, schedule, and blood levels and turrwr response in the L1210 leukemia system. The optimal schedules both regarding the total tolerated dose and increase in host life span vs untreated control subfeets difJered fOT the three classes of agents. The difJerences may be related to the difJering mechonisms of action, e.g., ARA‐C, which inhibits deoxyribonucleic acid (DNA) synthesis, killing the cells in S phase; MTX, which inhibits DNA, ribonucleic acid (RNA), and protein synthesis, may destroy only proliferative integrity in S phase; and alkylating agents, which complex with DNA may affect proliferative integrity, regardless of cell cycle phase. Clinical results in adults with acute myelogenous leukemia (AML) treated with ARA‐C indicate that the principles of optimal scheduling developed in the mouse L1210 system are applicable to this disease in humans. Optimal scheduling of MTX in the treatment of L1210 leukemia, human acute lymphocytic leukemia, and choriocarcinoma is also similar. The clinical results of long‐term, tumor‐free survivors in some patients with disseminated Burkitt's lymphoma on a single high dose of CTX or several high doses at appropriate intervals are not inconsistent with the data obtained in the L1210 system.