Repeated oral doses

In order that a drug is therapeutically effective its plasma concentration must be maintained within its therapeutic window for a long enough period of time to 

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A study of GSK1278863A (structure undisclosed) in healthy adult subjects for the safety, tolerability, pharmacokinetics, and pharmacodynamics of repeat oral doses up to 300 mg for 14 days has also been completed [69]. Finally, AKB-6548 (structure undisclosed) has completed Phase la clinical trials in 48 healthy volunteers for the potential treatment of anemia. Preliminary results claim that doses that significantly increase plasma EPO without raising VEGF levels were identified and that further clinical trials are planned [70]. 

In another study, rats received [14C] disulfoton at a single oral dose of 0.2 mg/kg or 1.0 mg/kg or repeated oral doses of 0.2 mg/kg/day for 14 days (Lee et al. 1985). In the rats given a single dose of 0.2 mg/kg, the respective percentages of administered radioactivity 72 hours later in lemales and males were 97.1% and 96.9% in urine and 1.1% and 1.4% in feces. In the rats given a single dose of 1.0 mg/kg, the respective percentages of administered radioactivity for females and males were... 

In rats a 4-hour exposure at 8000 ppm was fatal to four of six animals. There were no neurotoxic effects in rats given repeated oral doses. ... 

II.a.3. Repeated Oral Dosing with Measurements of Blood Plasma Concentration over Time... 

Activated charcoal adsorbs salicylate effectively, and has been given in repeated oral doses (50 g 4 hourly) to enhance clearance, although its effect on outcome is unknown. Fluid and electrolyte replacement are important and special care should be taken to maintain normal potassium concentrations. Patients with signs of poisoning, especially when plasma salicylate concentration exceeds 500 mg/1, should receive specitic elimination therapy. 

Thornton-Manning, J.R., Seely, J.C. Pegram, R.A. (1994) Toxicity of bromodichloromethane in female rats and mice after repeated oral dosing. Toxicology, 94. 3-18... 

Yao, M., Swaminathan, A., and Srinivas, N. (2007). Assessment of dose proportionality of muraglitazar after repeated oral dosing in rats via a sparse sampling methodology. Biopharm. Drug Dispos. 28 35-42. 

Hematological Effects. No hematological effects have been observed in humans after inhalation, oral, or dermal exposure. Anemia was seen in rats exposed to repeated oral doses of both inorganic tin and organotin compounds. No such effects were observed in rats after inhalation or dermal exposure. It is unlikely that tin compounds would cause hematological effects in people in the vicinity of hazardous waste sites. 

Rose JQ, Ramsey JC, Wentzler TH, et al. 1976. The fate of 2,3,7,8-tetrachlorodibenzo-p-dioxin following single and repeated oral doses to the rat. Toxicol Appl Pharmacol 36 209-226. 

Figure 8.11 The general changes in plasma concentration with time for repeated oral doses. Repeat doses were administered at regular times intervals x...

Safety, tolerability and the effect on CYP 1A2 and CYP 3A4 mediated metabolism, of single and repeated oral doses of 400 mg and 1200 mg drug XYZ or placebo in overweight or obese, but otherwise healthy men. 

Fig. 9. Individual XYZ123 pharmacokinetic parameters after single and repeated oral doses of XYZ123 (800 mg) once a day.

After the administration of repeated oral doses (0.5 mg, 1 mg, or 1.5 mg) over 14 days, steady-state plasma concentrations of HA were achieved within 3-5 days, which shows about a 2-fold accumulation compared with concentrations found after administration of single doses. No accumulation was observed for ZT-1. Drug exposure was fairly proportional to dose in the 1-1.5-mg dose range. The terminal half-lives of ZT-1 and HA were fairly similar across all dose levels (about 5 h and 20 h, respectively), and they were consistent with values measured after single administration of ZT-1. 

Following a single oral dose of 2 mg to 8 subjects, a mean peak serum concentration of 0.0097 pg/ml was attained in 2.4 hours. Following repeated oral doses of 2 mg daily for 8 days, a mean peak serum concentration of 0.012 pg/ml was reported 2.2 hours after the last dose (L. A. Stevens et al., Eur. J. din. Pharmac., 1983, 25, 651-655). 

Figure 3 Plasma concentration time profiles for repeated oral doses of the drug given every 8 hours, which illustrates the approach of the plasma concentrations to steady state.

However, the best evidence of the usefulness of repeated oral doses of activated charcoal in cardiac glycoside poisoning comes from the results of a randomized, placebo-controlled study in 402 individuals who took overdoses of the seeds of the yellow oleander tree in Sri Lanka. Repeated doses of activated charcoal reduced mortahty from 8.0% to 2.5% (26). 

Ferry N, Cuisinaud G, Pozet N, Zech PY, Sassard J. Nalidixic acid kinetics after single and repeated oral doses. Clinical pharmacology and therapeutics. 1981 May 29(5) 695-8. 

Phenobarbital stimulates the microsomal enzymes in the liver. This results in increases in liver enzyme concentrations and more rapid metabolism of not only phenobarbital but also other concurrently administered drugs. In the horse, it has been shown that the half-life of phenobarbital decreases (to around 11 h) following repeated oral dosing (Knox et al 1982). Dosage adjustments of phenobarbital may be required to maintain plasma concentrations within the therapeutic window and can be made using the equation ... 

Ferrara, S.D., Zotti, S., Tedeschi, L., Prison, G., Castagna, F, GalUmberti, L., Gessa, G.L. and Palatini, P. (1992). Pharmacokinetics of y-hydroxybutyric acid in alcohol dependent patients after single and repeated oral doses. Br. J. Clin. Pharmacol. 34 231-235. 

RepeateJ doses of activated charrmil. Repeated oral doses of charcoal may incrca.se eiiininailon by ga.siroiniestlnal dialysis it has the merit of being relatively safe (unless aspirated),... 

Repeated oral doses of cholestyramine have been reported to increase the clearance of meloxicam and piroxicam. 

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