Chemical formula: C₆₅₅₄H₁₀₀₇₆N₁₇₃₆O₂₀₄₈S₄₀
Olaratumab is an antagonist of platelet derived growth factor receptor-α (PDGFR-α), expressed on tumour and stromal cells. Olaratumab is a targeted, recombinant, fully human immunoglobulin G subclass 1 (IgG1) monoclonal antibody that specifically binds PDGFR-α, blocking PDGF AA, -BB, and CC binding and receptor activation. As a result, in vitro olaratumab inhibits PDGFRα pathway signalling in tumour and stromal cells. In addition, in vivo olaratumab has been shown to disrupt the PDGFR-α pathway in tumour cells and inhibit tumour growth.
As with all therapeutic proteins, there is the potential for immunogenicity.
Overall, a low incidence of both treatment emergent anti-drug antibodies and neutralising antibodies were detected in clinical trial samples.
Olaratumab is administered as an intravenous infusion only.
The population pharmacokinetic (PopPK) model-based mean (CV%) volume of distribution of olaratumab at steady state (Vss) was 7.7 L (16%).
The PopPK model-based mean (CV%) clearance for olaratumab was 0.56 L/day (33%). This corresponds to a mean terminal half-life of approximately 11 days.
Age, sex, and race had no clinically meaningful effect on the PK of olaratumab based on a PopPK analysis. Clearance and volume of distribution had a positive correlation with body weight.
No formal studies have been conducted to evaluate the effect of renal impairment on the PK of olaratumab. Based on a PopPK analysis, no clinically meaningful differences in the clearance of olaratumab were observed in patients with mild (calculated creatinine clearance [CLcr] 60-89 mL/min, n = 43), or moderate (CLcr 30-59 mL/min, n = 15) renal impairment compared to patients with normal renal function (CLcr ≥90 mL/min, n = 85). No data were available from patients with severe renal impairment (CLcr 15-29 mL/min).
No formal studies have been conducted to evaluate the effect of hepatic impairment on the PK of olaratumab. Based on a PopPK analysis, no clinically meaningful differences in the clearance of olaratumab were observed in patients with mild (total bilirubin within upper limit of normal [ULN] and AST>ULN, or total bilirubin >1.0-1.5 times ULN and any AST level, n = 16), or moderate (total bilirubin >1.5-3.0 times ULN, n = 1) hepatic impairment compared to patients with normal hepatic function (total bilirubin and AST ≤ ULN, n = 126). No data were available from patients with severe hepatic impairment (total bilirubin >3.0 times ULN and any AST level).
Non-clinical data reveal no special hazard for humans based on repeat dose toxicity studies in monkeys.
No animal studies have been performed to test olaratumab for potential of carcinogenicity, genotoxicity, or fertility impairment. Administration of an anti-murine PDGFR-α surrogate antibody to pregnant mice during organogenesis at 50 and 150 mg/kg resulted in increased malformations (abnormal eyelid development) and skeletal alterations (frontal/parietal additional ossification site). The foetal effects in mice administered the surrogate antibody occurred at exposures less than the AUC exposure at the maximum recommended human dose of 15 mg/kg olaratumab.
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