Multiple-dose study

Russell D, Bakhtyari A, Jazrawi RP, Whitlock L, Ridgway C, McHale M, Abel S (2003) Multiple dose study to investigate the safety of UK-427,857 (100 mg or 300mg) BID for 28 days in healthy males and females. In 43rd interscience conference on antimicrobial agents and chemotherapy, Chicago, IL, USA... 

Reesink HW, Zeuzem S, Weegink CJ, Eorestier N, van Vliet A, van de Wetering de Rooij J, McNair L, Purdy S, Chu HM, Jansen PLM (2005) Final results of a phase lb multiple dose study of VX950, a hepatitis C vims protease inhibitor. Hepatology 42(1) 234A... 

Traditionally, the duration of a toxicity study depends on the intended clinical use and disease duration. The potential immunogenicity of the human protein is a significant issue since antibody binding can partially or completely inhibit the biological activity of that protein, affect its catabolism or alter its distribution and clearance. Any multiple-dose study therefore should include evaluation of the impact of antibody formation, including their neutralizing capacity. However, antibody formation in itself should not be a reason for termination of a toxicity study, particularly if the antibodies are not neutralizing or do not alter the pharmacodynamics of the protein. 

Includes data for oral and IV formulations. From single- and multiple-dose studies. 

Katz, N. P. Morphidex (MS.DM) double-blind, multiple-dose studies in chronic pain patients, J. Pain Symptom Manage. 2000, 19, S37-S41. 

In a randomized, open, three-way crossover, multiple-dose study in 12 healthy adult men there was no clinically significant interaction of ezetimibe with gemfibrozil (7). 

Table 10.4 Summary of plasma oligonucleotide pharmacokinetics after the first single 200-mg oral dose in a multiple dose study.

Single-Dose/Multiple-Dose Studies Instances where multiple-dose studies may be useful are defined under 320.27(a)(3). However, this guidance generally recommends single-dose pharmacokinetic studies for both immediate- and modified-release drug products to demonstrate BE... 

Zhao RK, Cheng G, Tang J et al (2009) Pharmacokinetics of duloxetine hydrochloride enteric-coated tablets in healthy Chinese volunteers a randomized, open-label, single- and multiple-dose study. Clin Ther 31 1022-1036... 

Zhang L et al (2011) Pharmacokinetics and tolerability of vandetanib in Chinese patients with solid, malignant tumors an open-label, phase I, rising multiple-dose study. Clin Ther 33 315-327... 

For an inhibitor drug that induces its own metabolism, a multiple-dose study design should be used so that the extent of interaction is not overestimated. Multiple doses of ritonavir have been shown to have smaller inhibitory effects on other CYP3A substrates (18,19) than a single dose. This inhibition may be partially explained by the lower exposure to ritonavir after multiple doses than after a single dose. 

The interoccasion variability (IOV) or intraindividual variability [11] arises when a parameter of the model, e.g. CL, varies within a subject between study occasions. The term occasion can be defined arbitrarily, usually logical intervals for an occasion are chosen, e.g. each dosing interval in multiple dose studies or each treatment period of a cross-over study can be defined as an occasion. To assess the IOV of a specific parameter more than one measurement per individual has to be available per occasion. The IOV can be implemented in the random effect model as described in the following ... 

Effects on Metabolic Blood and Tissue Parameters in Conscious Rats (Multiple Dose Study)... 

For studying the side effect potential of candidate compounds on blood triglycerides and cholesterol as well as on metabolic rate, insulin sensitivity and body weight development multiple dose studies for at least 1 week are necessary. For transcriptional active compounds like the PPAR agonist (peroxisome... 

At the end of such multiple dose studies the animals are killed in terminal anesthesia and maximal blood collection is possible. Therefore, not only the target metabolic parameters (e.g. glucose, lactate, free fatty acids, triglycerides, cholesterol) but also other parameters, which reflect intermediary metabolism (e.g. keton bodies, urea, uric acid) as well as safety parameters (e.g. ASAT, ALAT, AP, LDH) can be determined by clinical chemistry. 

The additional anti-atherosclerotic potential of a candidate compound with a different primary indication does not represent a safety concern. In contrast, the atherogenic potential of a candidate compound, identified during safety pharmacological evaluation, represents a serious safety issue. Development of atherosclerosis needs time and therefore multiple dose studies are necessary to detect a putative anti-atherosclerotic or atherogenic side effect potential of a candidate compound. 

On an explorative basis, the relationship of concentrations resulting from the different doses can be conveniently studied, using an evaluation as described here. Typically, this evaluation is part of the first study in humans (which is always a single dose study), but could also be applied for early multiple dose studies in analogy. 

Furthermore, if non-linearities are observed for the ADME characteristics instead of a single dose, multiple dose studies may be needed, where the radio labeled drug is administered under steady-state conditions. 

Thus, a multiple dose study was performed in which all healthy and hepatic impaired individuals, received the same dose. It was the aim to include 12 patients with various and well distributed degrees of hepatic impairment (according to the Child-Pugh score) and 12 pair-matched (based on demographic characteristics) healthy subjects, in order to have 10 patients and 10 subjects evaluable. The pharmacokinetics of XYZ123 in plasma (total and unbound) and in urine was assessed after the first dose and at steady state after the seventh dose. The pharmacokinetics in plasma of its main metabolite XYZ456 was also assessed. 

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