Maximum repeatable dose studies

Spurhng NW, Carey PR Dose selection for toxicity studies a protocol for determining the maximum repeatable dose. Hum Exp Toxicol 1992 11 449-58. 

Human clinical studies Plasma levels of hyperforin were followed for 24 hours in two studies with healthy volunteers after administration of film-coated tablets containing 300 mg SJW extract representing 14.8 mg hyperforin (Table 2) (72). In the first crossover study, six male volunteers received 300, 600, or 1200 mg of a SJW extract preparation (WS 5572, Dr. Willmar Schwabe Arzneimittel, Karlsruhe, Germany) after a 10-hour fasting time. Maximum plasma levels of 150 ng/mL (approximately 280 nM) were reached after 3.5 hours after intake of 300 mg SJW extract. Half-life and MRT were 9 and 12 hours, respectively. Hyperforin pharmacokinetics were linear up to 600 mg of the extract. Increasing the doses to 900 or 1200 mg resulted in lower Cmax and AUC values than those expected from linear extrapolation of data from lower doses. In a repeated dose study with seven healthy volunteers, no accumulation of hyperforin in plasma was observed after intake of 900mg/day SJW extract for seven days. The estimated steady-state plasma concentrations of hyperforin after intake of 3 x 300mg/day was approximately 100 ng/mL (approximately 180 nM) (Table 2) (72). 

As discussed above, the extent of additional repeated-dose studies are generally outlined in Tables 6.2 and 6.3. The maximum duration of chronic studies is generally 6 months, although the ICH guidelines describe situations where studies of 9-12-month duration may be necessary in a non-rodent species. 

No toxicologically significant findings were made on single-dose administration of 1,500 times the maximum equivalent human dose, or on 14-day repeat dose studies at a level of 100 times the maximum human dose. No mortalities have occurred (Kelly et al. 1993). 

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. 

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. 

It is necessary to determine the toxicity of a drug. The maximum tolerable dose and area under the curve are established in rodents and nonrodents. There are two types of toxicity studies single dose and repeated dose. Single... 

The pharmacokinetics of hyperforin have been studied in rats and humans (Biber et ai. 1998). In rats, after a 300 mg/kg orai dose of hypericum extract (WS 5572, containing 5% hyperforin), maximum piasma ieveis of 370 ng/mi (690 nM) are achieved at 3 hours. The haif-iife of hyperforin is 6 hours. Humans given a 300 mg tabiet of hypericum (containing 14.8 mg hyperforin) showed maximum piasma ieveis of 150 ng/mi (280 nM) at 3.5 hours. The haif-iife is 9 hours, and mean residence time is 12 hours. Pharmacokinetics of hyperforin are iinear up to 600 mg, and no accumuiation occurs after repeated doses. By comparison, effective and safe piasma ieveis of paroxetine and fluoxetine vary between 40 and 200 ng/mi (Preskorn 1997). The effective piasma concentration of hyperforin predicted from computer-fit data is approximateiy 97 ng/mi (180 nM), which couid be easiiy monitored (Biber et ai. 1998). There is a iinear correiation between orai dose of hyperforin and piasma ieveis, and steady-state concentrations of 100 ng/mi (180 nM) couid be achieved with three-times-daiiy dosing. 

Hyperfractionated radiation decreases the fraction size but is repeated hours later. So, the overall days of treatment are decreased. The total dose is maintained similar to once-daily (conventional) radiation or a slightly higher dose is given. Theoretically, twice-daily radiation therapy decreases the repopulation of tumor cells. Choi established the maximum tolerated dose of hyperfractionated radiation therapy given twice-daily as 45 Gy in 30 fractions over three weeks and the maximum tolerated conventional dose was 70 Gy in 35 fractions over 7 wk (3/). Several phase II studies demonstrated the efficacy of hyperfractionated radiation therapy combined with chemotherapy (31-34). 

Once the phase 1 has been completed, next steps include the comparison of observed human exposure data (maximum concentration, Cmax and area under the concentration-time curve, AUC) to the exposures observed in the supportive preclinical studies, prediction of the human exposure in future clinical trials (based on dose level and frequency) and the calculation of the actual safety margins provided by the repeat-dose preclinical toxicology studies. The need for safety margins (based on preclinical safety and single-dose human data) to support phase lb or phase 2 dosing is usually considered on a case-by-case basis. 

Preclinical safety. Acute intravenous toxicity studies were performed in rats and rabbits, using up to 1,500 times the maximum single human dose. Repeat dose toxicity was assessed in rats and rabbits at 0, 10, 100, and 1,000 times the maximum human dose daily for 14 days. 

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