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Maximum Tolerated Dose
Maximum Tolerated Dose SC Gad, Gad Consulting Services, Cary, NC, USA Ó 2014 Elsevier Inc. All rights reserved.
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.’ The information used for dose selection usually comes from subchronic toxicity studies, but other information about the pharmacological effects of a drug and its metabolism and pharmacokinetics may also be considered. The maximum recommended human dose (MRHD) of the drug might be an additional criterion, if this is known when the carcinogenicity studies are being designed. For most pharmaceutical companies, the doses selected are as follows: The highest dose is selected to be the estimated MTD, the lowest dose is usually a small multiple of the MRHD (one to five times), and the mid-dose approximates the geometric mean of the other two doses. The procedures for dose selection described previously are generally consistent with major regulatory guidelines for carcinogenicity and other studies, for example, the Redbook from the US Food and Drug Administration. Earlier versions of the Redbook focused on direct food additives and color additives used in food. The Redbook 2000 provides guidance for the safety assessment of food ingredients, including direct food additives, color additives used in food, generally recognized as safe substances, food contact substances and constituents, or impurities of any of the above. There are, however, exceptions to the general approach described previously. For example, for nontoxic drugs, the difference between the high and the low doses may be many orders of magnitude if the high dose is set at the estimated MTD and the low dose is a small multiple of the clinical dose. Some guidelines require that the low dose be no less than 10% of the high dose. In this situation, it may be acceptable to set the high dose at 100 times the MRHD, even if the MTD is not achieved. Similarly, when a drug is administered in the diet, the highest concentration should not exceed 5% of the total diet, whether or not the MTD is achieved. Metabolism and/or pharmacokinetic data, when available, should also be considered in the dose selection process. It is desirable that a drug not be administered at such a high dose that it is excreted in a different manner than at lower doses, such as the MRHD. Similarly, the high dose should not lead to the formation of metabolites other than those formed at lower (clinical) doses. If data show that a given dosage produces
164
maximum plasma levels, administration of higher doses should be unnecessary. These considerations may be very useful when interpreting the results of the study or attempting to extrapolate the results to humans. The dose range–finding study is necessary in most cases, but the suppression of body weight gain is a scientifically questionable benchmark when dealing with the establishment of safety factors. Physiologic, pharmacologic, or metabolic markers generally serve as better indicators of systemic response than body weight. A series of well-defined acute and subchronic studies designed to determine the ‘chronicity factor’ and to study onset of pathology can be more predictive for dose setting than body weight suppression. Also, the MTD may well be at a level at which the metabolic mechanisms for handling a compound at real-life exposure levels have been saturated or overwhelmed, bringing into play entirely artifactual metabolic and physiological mechanisms. The regulatory response to questioning the appropriateness of the MTD as a high level has been to acknowledge that occasionally an excessively high dose is selected, but to counter by saying that using lower doses would seriously decrease the sensitivity of detection.
See also: Food Safety and Toxicology; Toxicity, Acute; Toxicity, Subchronic and Chronic; Acceptable Daily Intake (ADI); Food and Drug Administration, US; Redbook (Redbook 2000 : Toxicological Principles for the Safety of Food Ingredients); Threshold of Toxicological Concern (TTC); Dose–Response Relationship.
Further Reading Gad, S.C., 2005. Statistics and Experimental Design for Toxicologists, fourth ed. CRC Press, Boca Raton, FL. Gad, S.C., Chengelis, C.P., 1999. Acute Toxicology: Principles and Methods, second ed. Academic Press, San Diego, CA. McFadden, L.G., Bartels, M.J., Rick, D.L., Price, P.S., Fontaine, D.D., Saghir, S.A., 2012 July. Statistical methodology to determine kinetically derived maximum tolerated dose in repeat dose toxicity studies. Regul. Toxicol. Pharmacol. 63 (2), 344–351. Takimoto, C.H., 2009 Apr. Maximum tolerated dose: clinical endpoint for a bygone era? Targeted Oncology 4 (2), 143–147. USFDA, 2000. Redbook 2000. US Food and Drug Administration.
Relevant Website http://www.nap.edu – US National Academy of Science, National Academies Press. Issues in Risk Assessment (1993) (Part 1 deals with ‘Use of the Maximum Tolerated Dose in Animal Bioassays for Carcinogenicity’).
Encyclopedia of Toxicology, Volume 3
http://dx.doi.org/10.1016/B978-0-12-386454-3.00874-5
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.’ The information used for dose selection usually comes from subchronic toxicity studies, but other information about the pharmacological effects of a drug and its metabolism and pharmacokinetics may also be considered. The maximum recommended human dose (MRHD) of the drug might be an additional criterion, if this is known when the carcinogenicity studies are being designed. For most pharmaceutical companies, the doses selected are as follows: The highest dose is selected to be the estimated MTD, the lowest dose is usually a small multiple of the MRHD (one to five times), and the mid-dose approximates the geometric mean of the other two doses. The procedures for dose selection described previously are generally consistent with major regulatory guidelines for carcinogenicity and other studies, for example, the Redbook from the US Food and Drug Administration. Earlier versions of the Redbook focused on direct food additives and color additives used in food. The Redbook 2000 provides guidance for the safety assessment of food ingredients, including direct food additives, color additives used in food, generally recognized as safe substances, food contact substances and constituents, or impurities of any of the above. There are, however, exceptions to the general approach described previously. For example, for nontoxic drugs, the difference between the high and the low doses may be many orders of magnitude if the high dose is set at the estimated MTD and the low dose is a small multiple of the clinical dose. Some guidelines require that the low dose be no less than 10% of the high dose. In this situation, it may be acceptable to set the high dose at 100 times the MRHD, even if the MTD is not achieved. Similarly, when a drug is administered in the diet, the highest concentration should not exceed 5% of the total diet, whether or not the MTD is achieved. Metabolism and/or pharmacokinetic data, when available, should also be considered in the dose selection process. It is desirable that a drug not be administered at such a high dose that it is excreted in a different manner than at lower doses, such as the MRHD. Similarly, the high dose should not lead to the formation of metabolites other than those formed at lower (clinical) doses. If data show that a given dosage produces
164
maximum plasma levels, administration of higher doses should be unnecessary. These considerations may be very useful when interpreting the results of the study or attempting to extrapolate the results to humans. The dose range–finding study is necessary in most cases, but the suppression of body weight gain is a scientifically questionable benchmark when dealing with the establishment of safety factors. Physiologic, pharmacologic, or metabolic markers generally serve as better indicators of systemic response than body weight. A series of well-defined acute and subchronic studies designed to determine the ‘chronicity factor’ and to study onset of pathology can be more predictive for dose setting than body weight suppression. Also, the MTD may well be at a level at which the metabolic mechanisms for handling a compound at real-life exposure levels have been saturated or overwhelmed, bringing into play entirely artifactual metabolic and physiological mechanisms. The regulatory response to questioning the appropriateness of the MTD as a high level has been to acknowledge that occasionally an excessively high dose is selected, but to counter by saying that using lower doses would seriously decrease the sensitivity of detection.
See also: Food Safety and Toxicology; Toxicity, Acute; Toxicity, Subchronic and Chronic; Acceptable Daily Intake (ADI); Food and Drug Administration, US; Redbook (Redbook 2000 : Toxicological Principles for the Safety of Food Ingredients); Threshold of Toxicological Concern (TTC); Dose–Response Relationship.
Further Reading Gad, S.C., 2005. Statistics and Experimental Design for Toxicologists, fourth ed. CRC Press, Boca Raton, FL. Gad, S.C., Chengelis, C.P., 1999. Acute Toxicology: Principles and Methods, second ed. Academic Press, San Diego, CA. McFadden, L.G., Bartels, M.J., Rick, D.L., Price, P.S., Fontaine, D.D., Saghir, S.A., 2012 July. Statistical methodology to determine kinetically derived maximum tolerated dose in repeat dose toxicity studies. Regul. Toxicol. Pharmacol. 63 (2), 344–351. Takimoto, C.H., 2009 Apr. Maximum tolerated dose: clinical endpoint for a bygone era? Targeted Oncology 4 (2), 143–147. USFDA, 2000. Redbook 2000. US Food and Drug Administration.
Relevant Website http://www.nap.edu – US National Academy of Science, National Academies Press. Issues in Risk Assessment (1993) (Part 1 deals with ‘Use of the Maximum Tolerated Dose in Animal Bioassays for Carcinogenicity’).
Encyclopedia of Toxicology, Volume 3
http://dx.doi.org/10.1016/B978-0-12-386454-3.00874-5