Repeated dose administration

In this method, the repeated dose administration with a design similar to toxicology studies is preferred. Studies of up to four weeks duration need to include function tests for hormone secretion (basal concentrations, stimulation or inhibition), and for hormone contents of endocrine organs and tissues (e.g. hypothalamus, pituitary gland, reproductive organs). In the Endocrine Survey, 5 to 7 days of treatment are mandatory because adaptation and response of hormone-dependent organs to the treatment requires that a steady state be reached. Repeated-dose treatment with at least two doses is also needed for a sufficient... 

The methods described here are applied for Supplemental Safety Pharmacology Studies (ICH S7A), if the test substance has shown indications of effects on the hypothalamic-pituitary-adrenal system in the preceding pharmacology studies. The in vitro studies are generally performed with several increasing doses to investigate concentration-effect relationships. The preliminary information from these in vitro studies is then compared with the biological information available from in vivo for studies, to assess the need for additional animal studies based on repeated dose administration of the test compound. 

The core of this method is the assessment of adrenal steroid excretion during minimum invasive conditions, during repeated-dose administration of the test substance. 

Pacifici R, Zuccaro P, Farre M, Pichini S, Di Carlo S, Roset PN, Palmi I, Ortuno J, Menoyo E, Segura J, de la Torre R. Cell-mediated immune response in MDMA users after repeated dose administration studies in controlled versus noncontrolled settings. Ann NY Acad Sci 2002 965 421-33. 

There is often a need to evaluate clinically significant PK interactions in terms of rate and extent of absorption, by estimating C ax, time to C ax (tmax), and AUC. These are considered important variables for describing exposure. Rate of absorption can be increased, more often decreased, resulting in changes of tmax and Cmax or the extent of absorption can be increased or decreased, affecting both Cmax and AUC (11). When efficacy and/or safety can be related to Cmax in plasma or in another tissue or compartment, it may be important to describe accurately the absorption phase after single or repeat dose administration (12). 

Prior to model estimation the question that it will be used to answer and the specific manner in which it will be used should be explicitly stated. Using a model to answer a question is the act of simulation. There are two types of simulation deterministic and stochastic. In a deterministic simulation, the statistical model is ignored and no error is introduced into the model—the results are error-free. For example, given data from single-dose administration of a drug it may be of interest to predict the typical concentration-time profile at steady-state under a repeated dose administration regimen. A deterministic simulation would be useful in this case. 

Albendazole is a broad-spectrum antihelminthic drug used to treat the tropical parasitic disease, human neurocysticercosis. Albendazole contains a sulfur group that is subject to oxidation to an active sulfoxide metabolite. The S-oxide metabolite forms a center of asymmetry at the sulfur atom, thus conferring chirality to the molecule. Albendazole sulfoxide steady-state pharmacokinetics have been studied in 18 patients with confirmed active neurocysticercosis after repeated dose administration of 5mg/kg thrice daily for 8 days [44]. A high degree of stereoselectivity was observed in the plasma concentrations of the sulfoxide metabolite, with Cmax and AUCss (-I-) (—) ratios of 5.5 and 9.2, respectively. It is not known if there is stereoselectivity in the antihelminthic activity of the (-1-)- and (—)-sulfoxide metabolites of albendazole. 

After single doses of racemic sotalol administered to healthy volunteers, vitually no stereoseelectivity is observable in the plasma concentrations of the enantiomers. The (—) ( ) ratios of Cm v and AUC were 1.0 and 0.97, respectively, and the differences between enantiomers did not attain the level required for statistical significance [42]. There was some stereoselectivity, however, noted in another study when repeated doses of sotalol were administered to patients with supraventricular tachycardia [44]. After at least 3 days of therapy with 80 or 160 mg of the racemate q 12 h, the (—) ( ) of AUCr were 0.87 and 0.91 for the 80 and 160 mg doses, respectively. For both doses, the differences between enantiomers were significantly different. It is not known why a greater degree of stereoselectivity appears to be present after repeated dose administration. 

Prior to administration of an NCE in humans, the compound s effect on respiratory function is evaluated in a non-clinical setting (typically in a rodent) as per ICH S7A. Simple visual inspection is not considered adequate, so quantitative measurements (tidal volume and minute volume) in addition to respiratory rate are recorded. While quantitative assessment is typically conducted with singledose administration, microscopic evaluation of the lung, trachea, and nasal passages are conducted as part of the repeat-dose administration toxicology studies. 

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