Dose selection

However, there is a caveat that the relative sensitivities of genetically different mice may lead some animals to manifest side effects that were wholly unanticipated by either the classical strain or cUiiical studies. As more studies are conducted, estimates of the frequency of these events will become more readily available. 

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To date, the most extensively studied polyboron hydride compounds in BNCT research have been the icosahedral mercaptoborane derivatives Na2[B22H22SH] and Na [(B22H22S)2], which have been used in human trials with some, albeit limited, success. New generations of tumor-localizing boronated compounds are being developed. The dose-selectivity problem of BNCT has been approached using boron hydride compounds in combination with a variety of deUvery vehicles including boronated polyclonal and monoclonal antibodies, porphyrins, amino acids, nucleotides, carbohydrates, and hposomes. Boron neutron capture therapy has been the subject of recent reviews (254). 

S1 C(R1) Dose Selection for Carcinogenicity Studies of Pharmaceuticals Limit Dose S2A Guidance on Specific Aspects of Regulatory Genotoxicity Tests for Pharmaceuticals S2B Genotoxicity A Standard Battery for Genotoxicity Testing of Pharmaceuticals Toxicokinetics and Pharmacokinetics... 

Sheiner LB. PK/PD Approach to Dose Selection. Presented at the Esteve Foundation Symposium IX Optimal Dose Identification, Lloret de Mar, Spain, October 2000. 

Experimental design Groups of 12 male NMRI mouse pups were treated by gavage with 0, 50, or 290 mg/kg/day trichloroethylene in a 20% peanut oil emulsion. The pups were treated for 7 days begiiming at 10 days of age. The doses selected did not sedate the mice. At 17 and 60 days of age behavior was tested. The tests were performed between 8 am-12 pm. Locomotion, rearing, and total activity were measured in an automated device with high and low level infrared beams. 

Boxenbaum, H., DiLea, C., First-time-in-human dose selection allometric... 

Proper dose selection is essential for effective and efficient screen design and conduct. If insufficient data are available, a suitably broad range of doses must be evaluated (however, this technique is undesirable on multiple grounds, as has already been pointed out). 

The desire to achieve at least such minimal therapeutic indices and to also identify levels associated with toxicity (and the associated toxic effects) form the basis of dose selection for systemic (and most other in vivo) toxicity studies. 

SICa Guidance on Dose Selection for Carcinogenicity Studies of Pharmaceuticals Addendum on a Limit Dose and Related Notes Availability Notice Dec 97... 

ICH has also given guidance on design, dose selection, statistical analysis and interpretation for such studies (1995, 1996, 1997). FDA has also offered guidance, the most recent form (FDA, 2001) in a 44-page document available on line. 

Dose selection is one of the most important activities in the design of a toxicology study. It is especially critical in carcinogenicity studies because of their long duration. Whereas faulty dose selection in an acute or subchronic toxicity study can easily be corrected by repeating the study, this situation is much less desirable in... 

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 may 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 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). 

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 maximum plasma levels, administration of higher... 

Haseman, J.K. (1985). Issues in carcinogenicity testing Dose selection. Fundam. Appl. Toxicol. 5 66-78. 

Dose The dose selected is chosen to evaluate the severity of irritation, and represents a concentration that might be used clinically. This volume has been widely used in irritation testing. 

Doses selected for safety pharmacology studies are typically based on the criteria established in the ICH S7A guidance.25 Doses should exceed those projected for clinical efficacy and at the upper limit be bound by (1) adverse pharmacodynamic effects in the safety pharmacology study (2) moderately adverse effects in other non-clinical studies that follow a similar route and duration of dosing or (3) limit of solubility/toxicity. In the absence of adverse effects, the maximum administrable dose can be used. If nonreusable animals enter the study, then the maximum tolerated dose may be appropriate. Most importantly, the doses/concentrations should establish the dose/concentration-response relationship of the adverse effect. 

Dose selection for carcinogenicity stndies of pharmaceuticals limit dose... 

Strains/species/cell line Dose selection criteria Basis of dose selection Range hnding studies Test agent stability Metabolic activation system Controls Vehicle... 

Note that the true no-effect dose may be greater than the NOAEL the latter is in part an artifact of dose selection by the designers of the study. As the acronym suggests the LOAEL is the lowest dose at which some adverse effect is observable. Note also that dose could be any... 

The usual object of test dose selection is to pick, at one extreme, a dose sufficiently high to produce serious adverse effects without causing early death of the animals, and, at the other, one that should produce minimal or, ideally, no observable adverse effect - a NOAEL. At least one and ideally several doses between these extremes are also selected. We wish to come out of the experiment with a dose-response curve such as that depicted in Figure 3.2. 

Some sophisticated guessing goes into dose selection. Knowledge of the minimum acutely toxic dose helps the toxicologist pick the highest dose to be used it will be somewhere below the minimum lethal dose. There is usually little basis for deciding the lowest dose it is often set at some small fraction of the high dose. Whether it turns out to be a NOAEL will not be known until the experiment is completed. Sometimes bioassays have to be repeated to identify the NOAEL. 

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