Maximum recommended human 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 may be an additional criterion, if this is known when the carcinogenicity studies are being designed. 

Fertility Impairment A significant reduction in number of corpora lutea with consequent reduction in implantations and live fetuses was observed at 155 times the maximum recommended human dose. 

Incomplete reversal of buprenorphine In animals, nalmefene doses up to 10 mg/kg (437 times the maximum recommended human dose) produced incomplete reversal of buprenorphine-induced analgesia. Hence, nalmefene may not completely reverse buprenorphine-induced respiratory depression. 

Eievated ANA titers Positive ANA titers have occurred. They have been reversible upon cessation of treatment and may disappear even with continued therapy. Carefully evaluate patients who develop an abnormal ANA test and, if persistent or worsening elevation of ANA titers is detected, consider discontinuing therapy. Renai/Hepatic changes Renal changes have been observed in the rat following 6 months of oral administration of propafenone at doses of 180 and 360 mg/kg/day (2 to 4 times the maximum recommended human dose). Both inflammatory and noninflammatory changes in the renal tubules with accompanying interstitial nephritis were observed. 

Fertility Impairment In a fertility study in rats, estrous cyclicity was disrupted and numbers of corpora lutea, implantations, and live embryos were reduced in females receiving the highest dose (approximately 2 times the maximum recommended human dose on a mg/m basis). 

In determining the high dose for carcinogenicity studies, it may not be necessary to exceed a dose of 1500 mg/kg/day. This limit dose applies only in cases where there is no evidence of genotoxicity and where the maximum recommended human dose does not exceed 500 mg/day. 

Pregnancy Category C, although no animal studies have demonstrated tetratogenic effects, even at doses 400 times the maximum recommended human dose. 

Saw palmetto is generally regarded as safe with high long-term tolerability. " One case, however, was recently reported in which saw palmetto appeared to be responsible for development of recurrent pancreatitis in a 55-year-old male." A study to investigate its effect on liver functions in rat showed that saw palmetto did not result in any toxicity at 5 x the maximum recommended human doses. The pharmacology and therapeutic signifi-... 

Ad 2) A systemic exposure representing a 25 times multiple of the human AUC (at the maximum recommended daily dose) may be an appropriate endpoint for dose selection for carcinogenicity studies for non-genotoxic pharmaceuticals, as a pragmatic solution. 

Contrera, J. F., Matthews, E. J., Kruhlak, N. L, Benz, R. D. Estimating the safe starting dose in phase 1 clinical trials and no observed effect level based on QSAR modeling of the human maximum recommended daily dose. Regulatory Toxicol. Pharmacol. 2004, 40,185-206. 

Systemic exposure of the drug candidate in the test species that represents a large multiple of human exposure, based on the plasma concentration versus time curve (AUC), at the maximum proposed human daily dose may be used for carcinogenicity study dose selection. The AUC is the most comprehensive pharmacokinetic endpoint, because this value includes both the plasma concentration of the drug candidate and the residence time in vivo. For pharmacokinetic endpoints to be used for dose selection, the information needed to establish the recommended 25-fold ratio of rodent to human normalized (using mg/m2 dose levels) AUC include that (a) rodent pharmacokinetic data are derived with the... 

No data have been published concerning pre-clin-ical carcinogenic or reproductive studies for mepivacaine and no carcinogenic studies have been published for bupivacaine. Decreased pup survival in rats and embryocidal effect in rabbits have been observed when bupivacaine was administered to these species in doses comparable to nine and five times, respectively, the maximum recommended daily human dose. 

Dietary supplements are compotmds that are fotmd naturally in the human body or are part of a normal diet and are sold over-the-coxmter, similar to vitamins. There may be no recommended minimum daily requirement established for a dietary supplement. However, the Food and Dmg Administration follows reports of adverse events so that maximum recommended doses are known and published when appropriate. OTC supplements are bulk products and as such, these compounds are similar to commodity chemicals even though they are sold for human use. 

The drug should be administered at three levels by the route proposed for humans. The high dose level should be set so as to have relevance in humans. For drugs that display significant toxic effects, this may be related to the maximally tolerated dose in the toxicity tests, for example, the dose causing less than 10% deviation in body weight versus controls. If there is little evidence of toxicity it may be more appropriate to base the dose level on a multiple (usually 25-fold) of the maximum therapeutic dosage recommended in humans. 

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