Safety Pharmacology Assessment of Biopharmaceuticals

Abstract

Since the approval of the first recombinant protein therapeutic (insulin) in 1982, the number of biopharmaceuticals that have been approved as new medicines has grown steadily (Gosse et al. 1996; Lowe and Jones 2007). In one decade (1992–2002), 56 biopharmaceuticals were approved by FDA (Schwieterman 2006) and more than 170 biopharmaceuticals have been approved for clinical use worldwide (Giezen et al. 2008; Leader et al. 2008). Biopharmaceuticals have been successful as new therapeutics because of their high specificity for a given molecular target, favorable pharmacokinetic properties such as long half-life, and low volume of distribution that provide better target coverage and low “off-target” liability. This latter property translates into fewer non-clinical and clinical toxicity failures, when compared to small molecule therapeutics. A recent review of regulatory actions for safety concerns for all approved biopharmaceuticals in USA/EU (total: 174) indicated that the most frequent warnings (41 products) were related to immunomodulatory effects such as injection site reactions and infections, but none of these biopharmaceuticals have been withdrawn from human use (Giezen et al. 2008). However, recently two biopharmaceuticals were withdraws from market - efalizumab (2009) because of increased risk of progressive multifocal leukoencephalopathy and gemtuzumab ozogamicin (2010) due to lack of efficacy and safety concerns (WWW.FDA.gov). This is in stark contrast with a large number of conventional “small molecule” drugs withdrawn from medical use because of safety issues, especially cardiovascular toxicity (Guengerich 2011).