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Pharmacokinetic approach to rational therapeutic doses for human tumor-bearing nude mice
M Inaba1, T Kobayashi, T Tashiro
1Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo.
Abstract:
To improve clinical predictability from therapeutic results of various antitumor agents in human tumor/nude mouse models it seems to be important to use a dose pharmacokinetically equivalent to the clinical dose. Thus, we attempted to find the dose of a given drug that can reproduce in the nude mouse a plasma level similar to that seen in human patients treated with an effective dose of the drug based on comparative pharmacokinetic studies between man and nude mouse. As a result, those of 3 alkylating agents, mitomycin C, 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea (ACNU) and cyclophosphamide, and those of 2 antimitotic agents, vincristine and vinblastine, were estimated to be one-fourth or one-fifth of their maximum tolerated doses (MTD's). On the other hand, in the case of adriamycin, its MTD was approximately equivalent to its clinical dose pharmacokinetically. In contrast, clinically equivalent doses of 2 antimetabolites tested, 5-fluorouracil and methotrexate, were significantly greater than their MTD's; i.e., their plasma levels did not reach the effective clinical ones even when their MTD's were administered to the nude mice. These results suggest that the antitumor effects of most antitumor agents are over- or underestimated in this model when MTD's are used as a therapeutic dose, and indicate that the use of clinically equivalent doses determined pharmacokinetically is desirable.
Insights
Pharmacokinetically equivalent dosing in nude mouse models improves prediction of antitumor drug efficacy. Using equivalent doses, rather than maximum tolerated doses, better reflects clinical outcomes for most anticancer agents.
Area of Science:
- Pharmacology
- Oncology
- Translational Medicine
Background:
- Predicting antitumor agent efficacy in human tumor/nude mouse models requires doses that are pharmacokinetically equivalent to clinical doses.
- Current reliance on maximum tolerated doses (MTD) may lead to over- or underestimation of therapeutic effects in preclinical models.
Purpose of the Study:
- To determine pharmacokinetically equivalent doses for various anticancer agents in nude mouse models.
- To compare these equivalent doses with MTDs for predicting clinical outcomes.
Main Methods:
- Comparative pharmacokinetic studies between humans and nude mice were conducted for several anticancer agents.
- Doses were adjusted to achieve plasma levels in nude mice similar to those in human patients.
- Calculated doses were compared to the MTDs of the respective agents.
Main Results:
- For alkylating agents (mitomycin C, ACNU, cyclophosphamide) and antimitotic agents (vincristine, vinblastine), equivalent doses were 1/4 to 1/5 of MTDs.
- Adriamycin's MTD was pharmacokinetically equivalent to its clinical dose.
- Clinically equivalent doses for antimetabolites (5-fluorouracil, methotrexate) exceeded MTDs, with effective plasma levels not achievable at MTDs in mice.
Conclusions:
- Using MTDs in nude mouse models can lead to inaccurate predictions of antitumor agent efficacy.
- Pharmacokinetically determined, clinically equivalent doses are essential for improving the predictability of preclinical antitumor studies.
- This approach enhances the translational value of xenograft models in oncology drug development.