Single dose safety study

The initial strategy for Phase I is to conduct a single-dose safety study in normal volunteers. The first trial demands close 24-hour supervision in a clinical setting. Ethical considerations may, however, demand that only patients be used, for example, when evaluating an anticancer agent with predictable toxicity. A repeat dose tolerance and pharmacokinetic study in normal or patient volunteers is then conducted for chronically administered drugs. These studies will provide the necessary safety information to support efficacy testing. 

Glund, K., Hoffmann, T., Demuth, H.-U., Banke-Bochita, J., Rost, K.-L. and Fuder, H. (2000) Single dose-escalation study to investigate the safety and tolerability of the DP IV inhibitor P32/98 in healthy volunteers. Experimental and Clinical Endocrinology and Diabetes, 108, 159. 

The pharmacokinetic evaluation of biopharmaceuticals is generally simplified by the usual metabolism of products to small peptides and to amino acids, and thus classical biotransformation and metabolism studies are rarely necessary. Routine studies to assess mass balance are not useful. However, both single- and multiple-dose toxicokinetic data are essential in safety pharmacology asessments, and these can be complicated by two factors (1) biphasic clearance with a saturable, initial, receptor-dependent clearance phase, which may cause nonlinearity in dose-exposure relationships and doseresponses [14] and (2) antibody production against an antigenic biopharmaceutical that can alter clearance or activity in more chronic repeat-dose safety studies in the preclinical model. 

With respect to safety and the use of phospholipids, no NDA-supporting chronic inhalation studies have been conducted except for those found in commercial pulmonary surfactants. These studies presumably will have involved intratracheal instillation and not aerosolization, since the primary indication is respiratory distress syndrome of the newborn. Nevertheless, the fact that these products are available suggests that synthetic versions of natural lipids such as dipalmitoyl phosphatidylcholine (DPPC) and dipalmitoyl phosphatidylglycerol (DPPG) are likely to be well tolerated. This assumption has been supported from subchronic aerosol studies in mice [60] and acute single-dose aerosol studies in man, the latter involving soy-derived phosphatidylcholines [61]. 

In safety pharmacology, a number of renal functional tests, such as creatinine and electrolyte measurements, can be supported by most clinical chemistry laboratories (Kinter, Gossett, and Kerns 1994 Seuter 1996 ICH 2000). In some of the later chapters discussing assessments of hepatotoxicity and renal toxicity, a few functional tests are mentioned. Although it may be desirable to include function tests in repeated-dose toxicity studies, given the additional and sometimes invasive procedures, these tests may be better performed by incorporation into single-dose toxicity studies or separate additional studies (Matsuzawa et al. 1997). 

Minematsu, S., T. Yanagisawa, M. Watanabe, et al. 1996. Safety evaluation of processed aconiti tuber (TJ-3022) Single dose toxicity studies in rats and mice and one month repeated dose toxicity study in rats. Jpn. Pharmacol. Therapeut. 24(10) 19-33. 

MDS. 2000. MDS Pharma Services. Single dose toxicity study by the oral route in the rat. Unpublished data. In Bergfeld et al. 2004. Safety assessment of aloe. Cosmetic Ingredient Review. 

Whereas pharmacological responses tend to be fairly rapid in onset and are therefore detectable after a single dose, some diminish on repeated dosing, and others increase in magnitude and therefore can be missed or underestimated in single-dose safety pharmacology studies. Safety pharmacology measurements can be incorporated into repeat-dose toxicity studies, either routinely or on an ad... 

Pivotal safety studies in a single relevant species are usually appropriate for MAbs, as are single-dose pharmacokinetic studies, a multiple-dose toxicity assessment with toxico-kinetic sampling, and immunogenicity studies. 

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