Half-life dosing interval

If a drug is given repetitively with a constant dose (D) and a constant administration interval (Tau) accumulation occurs until a steady-state concentration (Css) is obtained after 4.32 times the elimination half-life (/ss -4.32 Tl/2). 

A second, completely different dose adjustment tule exists. Calvin Kunin proposed to start with the standard dose and to administer one half of the standard dose after one individual half-life. The halfdosage rule of Kunin should only be applied if the individual half-life is longer than the standard administration interval. 

If a drug is repeatedly administered at dosing intervals that are equal to its elimination half-life, the number of doses required for the plasma concentration of the drug to reach the steady state is... 

The plasma concentration will continue to rise until it reaches a plateau, or steady state. At this time, the plasma concentration will fluctuate between a maximum (Cmav) and a minimum (CrnLn) level, but, more important, the amount of drug eliminated per dose interval will equal the amount of drug absorbed per dose. When a drug is given at a dosing interval that is equal to its elimination half-life, it will reach 50% of its steady-state plasma concentration after one half-life, 75% after two half-lives, 87.5% after three, 93.75% after four, and 96.87% after five. Thus, from a practical viewpoint,... 

Allopurinol and its major metabolite, oxypurinol, are xanthine oxidase inhibitors and impair the conversion of hypoxanthine to xanthine and xanthine to uric acid. Allopurinol also lowers the intracellular concentration of PRPP. Because of the long half-life of its metabolite, allopurinol can be given once daily orally. It is typically initiated at a dose of 100 mg/day and increased by 100 mg/day at 1-week intervals to achieve a serum uric acid level of 6 mg/dL or less. Serum levels can be checked about 1 week after starting therapy or modifying the dose. Although typical doses are 100 to 300 mg daily, occasionally doses of 600 to 800 mg/day are necessary. The dose should be reduced in patients with renal insufficiency (200 mg/day for CLcr 60 mL/min or less, and 100 mg/day for CLcr 30 mL/min or less). 

The progressive increase of chemical and/or metabolites in the body. Accumulation is influenced by the dosing interval and half-life of the chemical. The process can be characterized by an accumulation factor, which is the ratio of the plasma concentration at steady state to that following the first dose in a multiple dosing regimen. 

Sampling Interval To be able to perform valid toxicokinetic analysis, it is not only necessary to properly collect samples of appropriate biological fluids, but also to collect a sufficient number of samples at the current intervals. Both of these variables are determined by the nature of the answers sought. Useful parameters in toxico-kinetic studies are Cmax, which is the peak plasma test compound concentration Tmax, which is the time at which the peak plasma test compound concentration occurs, Cmin, which is the plasma test compound concentration immediately before the next dose is administered AUC, which is the area under the plasma test compound concentration-time curve during a dosage interval, and t which is the half-life for the decline of test compound concentrations in plasma. The samples required to obtain these parameters are shown in Table 18.12. Cmin requires one blood sample immediately before a dose is given and provides information on accumulation. If there is no accumulation in plasma, the test compound may not be detected in this sample. 

Individual metabolism cages are recommended for collecting urine and feces in oral dosing studies. Excreta should be collected for at least 5 elimination half-lives of the test substance. When urine concentrations will be used to determine elimination rates, sampling times should be less than one elimination half-life (taken directly from the bladder in IV studies) otherwise, samples should be taken at equal time intervals. 

What would be the dosing interval of a drug that has a volume of distribution of 5 L When a dose of 250 mg is given, 200 mg of the drug is absorbed and the average plasma concentration is 4 mcg/mL. The plasma half-life is 3 hours. 

What is the average plasma concentration when a 500 mg drug is administered with an interval of 6 hours and has a volume of distribution of 50 L It is known that the fraction of dose absorbed is 0.8 and the plasma half-life is 2 hours. 

If the fraction of drug absorbed is 0.9, dose is 25 mg, dosing interval is 6 hours, volume of distribution is 20 L and the average plasma concentration is 25 mcg/mL, what is the plasma half-life of the drug ... 

What would be the loading dose of an antibiotic drug with a maintenance dose of 300 mg, half-life of 9 hours and a dosing interval also of 9 hours ... 

When a single 250 mg bolus dose of an antibiotic is given, the C0 was found to be 25 mcg/mL and the elimination half-life was 5 hours. What would be the dose required to achieve a new minimum steady-state concentration of 12 mcg/mL with a dosing interval of 6 hours Also what would be the new maximum steady-state concentration Assume that the drag follows first-order kinetics. 

Upon the administration of 0.27 mg of a therapeutic agent to a normal individual, the elimination half-life was found to be 2 hour1. The normal dosing regimen included 0.27 mg qid. If the elimination rate constant in renally impaired condition is 70% of the normal elimination rate constant, how can the dose be adjusted maintaining the same dosing interval of six hours ... 

A clinical pharmacist has recommended that the dose of a diuretic be reduced from 50 mg to 25 mg in a renally impaired patient. In both the normal and renally impaired patients, the dosing interval was six hours. If the elimination half-life of the drag in normal individual was 4 hours, what would be the elimination rate constant value in the renally impaired patient ... 

The therapy of a chronic disease requires repeated drug dosing. In the case of a short biological half-life, the drug has to be administered up to several times daily within short intervals. To reduce the application frequency, sustained formulations have been developed. For this purpose liquid crystalline excipients are appropriate candidates, because in a liquid crystalline vehicle the drug diffusion is reduced by a factor of 10 to 1000 in comparison with a liquid vehicle such as a solution [35-37]. The factor depends on liquid crystal. 

Receptor ligand complex Receptor occupancy Substrate concentration time after drug administration Dosing interval Flimination half-life Volume of distribution... 

Apparent volume of distribution of free (unbound) drug Maximum rate of reaction (Michaebs-Menten enzyme kinetics) Dosing interval in terms of half-life (= Tjtip)... 

True steady state is usually only achieved for a prolonged period with intravenous infusion. If we assume that we wish for a similar steady value after oral administration, then we need to balance our dosing frequency with the rate of decline of drug concentration and the rule of thumb referred to earlier (dosing interval equal to drug half-life) can be applied. Unbound clearance and free drug are particularly applicable to drugs delivered by the oral route. For a well-absorbed compound the free plasma concentrations directly relate to Cli (intrinsic unbound clearance). 

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