Dose maximum tolerated

For carckiogen pesticides (70,71), animal testkigs are subject to maximum tolerated doses (M I L)). M I D is the maximum amount of a substance that can be administered to an experimental animal without causkig extreme health consequences, such as death, to occur but while continuing to produce some measurable toxic effects. Current regulatory theory holds that carckiogen effects do not have a threshold and caimot be related to reference doses. 

Savolainen, K. M. (1997). The use of maximum tolerated dose in rodent carcinogenicity bioas says and its relevance to human risk assessment. Hum. Exp. Toxicol. 16, 190-192. 

Numerous experimental therapeutics have shown potency in vitro however, when they are tested in vivo, they often lack significant efficacy. This is often attributed to unfavorable pharmacokinetic properties and systemic toxicity, which limit the maximum tolerated dose. These limitations can be overcome by use of drug carriers. Two general types of carrier systems have been designed drug conjugation to macromolecular carriers, such as polymers and proteins and drug encapsulation in nanocarriers, such as liposomes, polymersomes and micelles. 

Experiments were conducted in which purified trichloroethylene (1 mg in acetone) was applied to the shaved backs of female ICR/Ha Swiss mice (Van Duuren et al. 1979). In an initiation-promotion study, a single application of trichloroethylene was followed by repeated application of phorbol myristate acetate (PMA) promoter. In a second study, mice were treated with trichloroethylene three times per week without a promoter. No significant tumor incidences were observed in these studies. Doses used in these studies were well below the maximum tolerated dose, which is often not reached in dermal studies. 

In practice it is obviously difficult to actually determine the toxic and effective dose in 50% of treated patients in the same population but the concept of a maximum tolerated dose compared with an effective dose is of great importance. 

Mitotane—if well-tolerated, dose may be doubled on day 3 then, from day 5 onwards, may increase dose by 500 mg every 2-3 days until maximum tolerated dose (8-12 grams daily) has been reached glucocorticoid and mineralocorticoid replacement necessary to prevent adrenal insufficiency increased steroid doses may be needed at times of physiologic stress... 

Repeat every 4-6 weeks for 2 cycles, then adjust to maximum tolerated dose (1 -2 mg/M2/d CIV X 5 days) every 4-8 weeks to a maximum of 12 cycles... 

In general, very dilute solutions are given initially once or twice per week. The concentration is increased until the maximum tolerated dose is achieved. This maintenance dose is continued every 2 to 6 weeks, depending on clinical response. Better results are obtained with year-round rather than seasonal injections. 

Oxybutynin IR is best tolerated when the dose is gradually escalated from less than or equal to 2.5 mg twice daily to 2.5 mg three times daily after 1 month. Oxybutynin IR can be further increased in 2.5-mg/day increments every 1 to 2 months until the desired response, maximum recommended dose of 5 mg three times daily, or maximum tolerated dose is attained. 

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). 

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

In the development of cytotoxic drugs in oncology, dose-finding usually means establishing a maximum tolerated dose (MTD). This is the dose associated with serious but reversible side effects in a sizable proportion of patients and the one that... 

Nevertheless, this study had several limitations. Initial doses were not well tolerated because of exceedence of the Maximum Tolerated Dose (MTD) as indicated by excessive deaths. Doses were reduced 17-33% from initial doses once or twice during the experiment. During the final 75 days of treatment, high dose males received chlordecone on alternative weeks only. Doses above the MTD were used for 42-386 days. An unusually high mortality rate occurred in control animals also, and only pooled controls were used in this bioassay. 

Burchfield HP, Storrs EE, Kraybill HF. 1975. The maximum tolerated dose in pesticide carcinogenicity studies. Environ Qual Saf Suppl 3 599-603. 

Phase I - Involves 20 to 80 patients and investigates drug toxicity in healthy volunteers. Outcomes are the maximum tolerated dose and API concentration profile in the body. 

---