Estimated maximum tolerated dose

For most pharmaceutical companies, the doses selected are as follows. The highest dose is selected to be the estimated maximum tolerated dose (MTD). The lowest dose is usually a small multiple (1 to 5 times) of the MRHD, and the middose approximates the geometric mean of the other two doses (PMA, 1988 McGregor, 2000). 

The use in animal cancer bioassays of the estimated maximum tolerated dose, MTD, is perhaps the one issue that provokes the most heated scientific debates, as well as the greatest public skepticism about the meaning of animal data. First, what is the MTD Second, why is its use problematic ... 

Dose level Not really predictable Relative to estimated therapeutic dose or maximum tolerated dose... 

D. W. Gaylor and L. S. Gold, Regulatory Cancer Risk Assessment Based on a Quick Estimate of a BenchmarkDose Derived from the Maximum Tolerated Dose, Regal. Toxicol. Pharmacol. 28 (1998) 222-25. 

Gaylor DW. 1989. Preliminary estimates of the virtually s afe dose for tumors obtained from the maximum tolerated dose. Regul Toxicol Pharmacol9 101-108. 

Gaylor, D.W., and L.S. Gold. 1995. Quick estimate of the regulatory virtually safe dose based on the maximum tolerated dose for rodent bioassays. Regul. Toxicol. Pharmacol. 22 57-63. 

The maximum tolerated dose (MTD) is commonly estimated to be the maximum dose that can be administered for the duration of a specific study that will not compromise the survival of the animals by causes other than carcinogenicity. If the MTD has been chosen appropriately, there should be no adverse effect on survival, only a modest decrement in body weight gain and minimal overt signs of toxicity. The MTD has been exceeded if there is increased mortality, severe body weight decrement, or marked signs of toxicity. It should be noted that another meaning for MTD has sometimes been minimum toxic dose . 

Gay lor DW and Gold LS (1998) Regulatory cancer risk assessment based on a quick estimate of a benchmark dose derived from the maximum tolerated dose. Regulatory Toxicology and Pharmacology 28 222-225. 

Gombar VK, Enslein K, Hart JB, Blake BW, Borgstedt HH. Estimation of maximum tolerated dose for long-term bioassays from acute lethal dose and structure by QSAR. Risk Anal 1991 Sep ll(3) 509-17. 

By comparing the maximum sublethal doses for laboratory mice with the maximum tolerated doses (MTDs) obtained from human clinical trials, and assuming a similar LD50/MTD ratio for the two species, an estimate of the LD50 of ricin or abrin for humans would be about 0.6-1 pg/kg (i.v.)... 

Phase I should estimate a range of safe dose levels up to a maximum tolerated dose, and characterize the pharmacokinetic profile of the study drug in humans. Generally a single dose study and a 1 week repeated-dose study are conducted in a small number (6 8) of healthy male volunteers. Food effects, drug interactions, and bioequivalence studies nowadays belong to this clinical pharmacology phase, as well as pharmacokinetics in the elderly and studies in subjects with poor kidney or hepatic function. 

Examples of these comparisons are shown for two of the drugs in Tables 3 and 4. The predicted maximum tolerated dose for man estimated from the... 

The body excretes tritium with a biological half-life of 8—14 d (10.5 d average) (75), which can be reduced significantly with forced fluid intake. For humans, the estimated maximum permissible total body burden is 37 MBq (1 mCi). The median lethal dose (LD q) of tritium assimilated by the body is estimated to be 370 GBq (10 Ci). Higher doses can be tolerated with forced fluid intake to reduce the biological half-life. 

Samples of blood and excreta are taken for laboratory analysis. It is expected that, at the end of this phase, you will have a preliminary estimate of the maximum dose that may be safely tolerated in humans, and also a basic profile of the drug s pharmacokinetic behaviour. Depending on the availability of appropriate analytical indicators, pharmacodynamic and indicative efficacy data may also be generated. The data acquired must be carefully analysed and assessed so that, based on the findings, appropriate Phase II trials can be planned. 

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