Safety pharmacology biopharmaceuticals

Safety Pharmacology Similarities and Differences between Small Molecules and Novel Biopharmaceuticals... 

SAFETY PHARMACOLOGY REGULATORY REQUIREMENTS FOR SMALL MOLECULES AND BIOPHARMACEUTICALS... 

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. 

Separate safety pharmacology studies were completed for many peptides in the survey. Separate safety pharmacology studies are usually performed for NCEs but not biopharmaceuticals. Since rodents are typically used for stand-alone central nervous system and respiratory studies, the usefulness of these studies for NCEs is based on the assumption that rodents are pharmacologically responsive or have some of the same metabolites as would be expected in humans. The lack of concern for metabolism and the significant reduction or absence of pharmacology in rodents with most biopharmaceuticals eliminates the relevance of these studies. In contrast to the larger... 

Cells by themselves or by secreting pharmacologically active substances may have effects on the CNS, cardiac, respiratory, renal, or GI systems. Safety pharmacology should therefore be considered on a case-by-case basis depending on the specific characteristics of the cell-based product [52], In general, specific assessments are made as part of the toxicology assessments rather than as stand-alone studies consistent with the assessments made with protein-based biopharmaceuticals [50]. The fundamental physiological differences (e.g., total blood volume,pulmonary capillary surface area, and volume) should... 

Safety pharmacology studies in rodent and nonrodent These studies are designed to identify undesirable pharmacological effects in several systems primarily the cardiovascular, respiratory, and CNS systems. Other studies may be included based on the pharmacological activity of the test article. In many cases these studies are not required for biopharmaceuticals and/or may be included in the 4- and 13-week studies and 6- and 9-month studies. 

The safety pharmacology studies in which the respiratory, CNS, and cardiovascular systems are evaluated in a nonrodent model are not de facto for a biopharmaceutical. Quite frequently the safety endpoints are in the protocols for the pivotal repeat-dose studies, such as a cynomolgus study, obviating the need for separate safety pharmacology studies. 

TABLE 9.2 Cardiovascular Safety Pharmacology Comparison of Small Molecules and Biopharmaceuticals... 

Amouzadeh HR, Engwall Ml, Vargas HM (2015). Safety pharmacology evaluation of biopharmaceuticals. Handb Exp Pharmacol 229 385-404. 

Vargas HM, Amouzadeh HR, EngwaU MJ (2013). NoncUnical strategy considerations for safety pharmacology evaluation of biopharmaceuticals. Expert Opin Drug Saf 12(1) 91-102. 

Biotechnology-derived pharmaceuticals or biopharmaceuticals (BPs) are molecules such as monoclonal antibodies, soluble/decoy receptors, hormones, enzymes, cytokines, and growth factors that are produced in various biological expression systems and are used to diagnose, treat, or prevent various diseases. Safety pharmacology (SP) assessment of BPs has evolved since the approval of the first BP (recombinant human insulin) in 1982. This evolution is ongoing and... 

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