Multiple dosing kinetics

Dettli L, Spring P, Ryter S. Multiple dose kinetics and drug dosage in patients with kidney disease. Acta Pharmacol Toxicol 1971, 29 (suppi 3) 211-224. 

It is important to note that, in multiple-dosing kinetics, t> 0 and tdosing interval) following the administration of the dose. 

Information on single-dose pharmacokinetics is considered essential, although opinion is divided on the need for multiple-dose kinetic studies. An acute dose will provide useful information in case of accidental overdose. 

Renwick and Lazarus (1998) analyzed the default UF for human variability based on the evaluation of an extensive database in relation to a subdivision of the 10-fold factor due to variability in toxicokinetics and toxicodynamics, as well as the adequacy of the 10-fold factor. Papers giving kinetic data were selected on the basis of the quality and/or size of the study, the interest of the results, and the physiological/metabolic process determining the kinetic parameter. Papers giving dynamic data were selected on the basis of the adequate separation of variability due to kinetics and dynamics. The data on kinetics and dynamics were tabulated, the coefficients of variation were averaged for different studies which measured a common endpoint, or for multiple doses which measured the same endpoint. 

A placebo-controlled, randomized clinical trial with monitoring of hypericin and pseudohypericin plasma concentrations was performed to evaluate the increase in dermal photosensitivity in humans after application of high doses of SJW extract (Table 2) (73). The study was divided into a single-dose and a multiple-dose part. In the single dose crossover study, each of the 13 volunteers received either placebo or 900, 1800, or 3600 mg of the SJW extract LI 160. Maximum total hypericin plasma concentrations were observed about four hours after dosage and were 0, 28, 61, and 159ng/mL, respectively. Pharmacokinetic parameters had a dose relationship that appeared to follow linear kinetics (73). 

Bates TR, Carrigan PJ. Apparent absorption kinetics of micronized griseofulvin after its oral administration on single- and multiple-dose regimens to rats as a corn oil-in-water emulsion and aqueous suspension. J Pharm Sci, 1975 64 1475-1481. 

As previously discussed, compartmental models can be effectively used to project plasma concentrations that would be achieved following different dosage regimens and/or multiple dosing. However, for these projections to be accurate, the drug PK profile should follow first-order kinetics where various PK parameters such as CL, V,h T /2, and F% do not change with dose. 

Multiple-dosing input systems and steady-state kinetics. 

Kragh-Sorensen P, Overo KF, Petersen OL, Jensen K, Parnas W. The kinetics of citalopram single and multiple dose studies in man. Acta Pharmacol Toxicol (Copenh) 1981 48(l) 53-60. 

These linear kinetic models and diffusion models of skin absorption kinetics have a number of features in common they are subject to similar constraints and have a similar theoretical basis. The kinetic models, however, are more versatile and are potentially powerful predictive tools used to simulate various aspects of percutaneous absorption. Techniques for simulating multiple-dose behavior evaporation, cutaneous metabolism, microbial degradation, and other surface-loss processes dermal risk assessment transdermal drug delivery and vehicle effects have all been described. Recently, more sophisticated approaches involving physiologically relevant perfusion-limited models for simulating skin absorption pharmacokinetics have been described. These advanced models provide the conceptual framework from which experiments may be designed to simultaneously assess the role of the cutaneous vasculature and cutaneous metabolism in percutaneous absorption. 

Jensen, J.C. Gugler, R. (1983) Single- and multiple-dose metronidazole kinetics. Clinical Pharmacology and Therapeutics, 34, 481-487. 

Toxicokinetics is a term used for describing kinetic studies conducted in conjunction with toxicology evaluations (Di Carlo 1982) that deal with absorption, distribution, and elimination processes of chemicals present at concentrations that produce toxic effects. By monitoring the blood concentrations of the chemical and/or metabolites over time after administration by different routes, the test chemical s bioavailability and kinetic characteristics can be readily obtained. The data also permit the determination of the so-called linear dose range based on area under the plasma versus time curve and clearance or other related toxicokinetic parameters, as well as the prediction of possible bioaccumulation after multiple doses. Changes in kinetic parameters after multiple exposures... 

To reduce within-subject variability, multiple-dose steady-state studies have been considered (24,41). It has been shown that the observed variation of PK parameters is often lower at steady state than after single dosing (41-43). The reduced variation of Cma at steady state is probably due to its lower kinetic sensitivity in reflecting absorption rate... 

In a drug discovery environment, the elimination rate is used to estimate accumulation after multiple dosing. Many terms of half-lives were introduced with the attempt to simplify multicompartment kinetics for the estimation of accumulation. A recent article by Sahin and Benet compared and commented on various terms of half-life [32], The accumulation after multiple dosing is not only a function of elimination rate but also a function of dosing interval for multicompartmental distribution compounds. In addition, the accumulation of Cmax is a function of absorption rate [32], Furthermore, the accumulation for Cmax, Cmin, and AUC can be different with the same compound and same dosing interval. Therefore, the half-life calculated based on accumulation ratios from different exposure parameters and with different dosing intervals for the same compound can be different. It is not practical to use... 

The superposition principle, which forms the basis of all multiple-dose models in this section, is true only as long as all elimination processes follow first-order (linear) elimination kinetics. Since the assumption of first-order elimination kinetics has already been made for all the previous single-dose models that are being combined by superposition, the application of the superposition principle does not add any new model assumptions. 

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