Injection-site Malignant Fibrous Histiocytomas in a Pegvisomant Carcinogenicity Study in SD Rats

Abstract

In a 2-year rat carcinogenicity study, pegvisomant injected subcutaneously on a daily basis at doses of 0, 2, 8, or 20 mg/kg/day produced malignant fibrous histiocytomas (MFHs) at the injection sites of 3 male rats (5%) given 8 mg/kg/day and 5 males (8%) given 20 mg/kg/day. MFH was characterized by unencapsulated dermal and subcutaneous sheets of fusiform and spindle-shaped cells sometimes with areas of round and/or irregular, pleomorphic cells and variable numbers of large multinucleated giant cells. Some regions of MFH had a fibroblastic appearance with streaming cells forming storiform patterns, while other areas consisted primarily of round to plump irregular cells with more giant cells. Pegvisomant did not increase the incidence of MFH in female rats and did not produce any other neoplastic responses in rats. In the dermis and subcutis at the injection sites of many males and females, pegvisomant produced dose-related increased incidences and severity of histiocytic infiltrates consisting of vacuolated macrophages with variable mature or immature fibrous tissue. Neoplasms at injection sites did not result in marketing restrictions or a label warning for human cancer risk, highlighting that injection-site neoplasms in rats have low relevance for human risk assessment.

Regulatory Forum Opinion Piece

“…Administration-site MFH is a well-known finding and has been reported in rodent long-term studies with drugs, nongenotoxic chemicals, plant extracts, and inert materials when administered or implanted sc (Bartholomew, Kreeger, and Morton 2014;Thomas et al 1977). Chronic irritation and inflammation were considered to constitute the key etiologic trigger of administration-site MFH (Thomas et al 1977;Stammberger et al 2002;Bartholomew, Kreeger, and Morton 2014). Interestingly, administration-site MFH was seen in preclinical rodent studies with a number of other marketed drugs (Bartholomew, Kreeger, and Morton 2014).…”

“…In a 12-month toxicity study in rats with insulin glulisine and 24-month carcinogenicity studies both in rats and mice with insulin glargine, respectively, treatmentrelated malignant fibrous histiocytoma (MFH) was diagnosed in male and, occasionally, in female rats and mice (Greaves and Faccini 1981;Ward et al 1981) of most groups, including the vehicle control group, at the sc administration site on a background of chronic irritation and inflammation (Stammberger et al 2002; European Medicines Evaluation Agency [EMEA], 2005). Administration-site MFH is a well-known finding and has been reported in rodent long-term studies with drugs, nongenotoxic chemicals, plant extracts, and inert materials when administered or implanted sc (Bartholomew, Kreeger, and Morton 2014;Thomas et al 1977). Chronic irritation and inflammation were considered to constitute the key etiologic trigger of administration-site MFH (Thomas et al 1977;Stammberger et al 2002;Bartholomew, Kreeger, and Morton 2014).…”

“…Chronic irritation and inflammation were considered to constitute the key etiologic trigger of administration-site MFH (Thomas et al 1977; Stammberger et al 2002; Bartholomew, Kreeger, and Morton 2014). Interestingly, administration-site MFH was seen in preclinical rodent studies with a number of other marketed drugs (Bartholomew, Kreeger, and Morton 2014). Even after decades of clinical use of insulin and insulin analogues, no reports of administration-site MFH or other injection-site neoplasia in diabetic patients were identified in the available literature.…”