Maximum repeatable dose

Acute toxicity - two species by two routes of administration (one is usually intravenous to ensure systemic exposure and the other is by the proposed chnical route). Usually an evaluation of the maximum repeatable dose (MRD) and possibly local irritancy... 

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

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 this special case when the time between dosings is equal to the half-life time of the drug, we can deduce that the minimum (steady-state) plasma concentration with repeated dosing is equal to the peak concentration, obtained from a single dose. Under this condition, the corresponding maximum (steady-state) concentration is twice as much as the minimum one. 

Dexa-BEAM dexamethasone/ carmustine (BCNU)/ etoposide (VP-16)/ cytarabine (Ara-C)/ melphalan Dexamethasone 8 mg PO Q8H days 1 -10 BCNU 60 mg/M2 IV day 2 VP-16 75 mg/M2 IV days 4-7 Ara-C 100 mg/M2 IVQ12H days 4-7 Melphalan 20 mg/M2 IV day 3 REF Pfreundschuh etal. J Clin Oncol 1994 12 580-586 PREMEDICATIONS 1. Kytril 1 mg PO/IV 30 minutes before and 12 hours after chemotherapy on days 2 and 3 2. Compazine 10 mg PO/IV 30 minutes before chemotherapy on days 4-7 OTHER MEDICATIONS 1. Give non-cisplatin delayed emesis prophylaxis Repeat every 28 days Carmustine—maximum total dose is 1440 mg/M2 causes delayed myelosuppression... 

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... 

Oral tablets 25,50, or 100 mg at onset can repeat after 2 hours if needed Optimal dose is 50-100 mg maximum daily dose is 200 mg... 

Single dose or repeated dosage not exceeding 1 week Repeated dosing exceeding 1 week and to a maximum of 4 weeks Repeated dosing exceeding 4 weeks and to a maximum of 6 months... 

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. 

Reversal of conscious sedation or in general anesthesia The recommended initial dose is 0.2 mg (2 mL) administered IV over 15 seconds. If the desired level of consciousness is not obtained after waiting an additional 45 seconds, a further dose of 0.2 mg (2 mL) can be injected and repeated at 60 second intervals where necessary (up to a maximum of 4 additional times) to a maximum total dose of 1 mg (10 mL). Individualize the dose based on the patient s response, with most patients responding to doses of 0.6 to 1 mg. 

If, after the initial dose, the headache improves but then returns, a repeat dose may be beneficial. If a second dose is required, it should be taken at least 2 hours after the initial dose. If the initial dose is ineffective, controlled clinical trials have not shown the second dose to be beneficial in treating the same attack. The maximum daily dose should not exceed 80 mg. 

Nasal spray - Administer 1 dose of 5 mg for the treatment of acute migraine. If the headache returns, the dose may be repeated after 2 hours. Do not exceed a maximum daily dose of 10 mg in any 24-hour period. Individuals may vary in response to zolmitriptan. The pharmacokinetics of a 5 mg nasal spray dose is similar to the 5 mg oral formulations. Doses lower than 5 mg can only be achieved through the use of an oral formulation. Therefore, choose the dose and route of administration on an individual basis. The efficacy of a second dose has not been established in placebo-controlled trials. 

IM (range) 5 to 15 mg repeated every 4 hours, up to 60 mg maximum daily dose. 

For severe diarrhea, repeat dose every 30 min do not exceed maximum daily dose. 

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). 

Reversal of conscious sedation or general anesthesia IV Initially, 0.2 mg (2 ml) over 15 sec may repeat dose in 45 sec then at 60-sec intervals. Maximum 1 mg (10-ml) total dose. 

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