Comparative Pharmacokinetics and Pharmacodynamics of Bococizumab Following a Single Subcutaneous Injection Using Drug Substance Manufactured at Two Sites or Administration via Two Different Devices.

The pharmacokinetics (PK) and pharmacodynamics (PD) of bococizumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, were compared following a single 150-mg subcutaneous dose administered to healthy subjects (n = 156-158/arm) via: (1) a prefilled syringe (PFS) using drug substance (DS) manufactured by Pfizer, (2) a PFS using DS manufactured by Boehringer Ingelheim Pharma, (3) a prefilled pen using DS manufactured by Pfizer (NCT02458209). Blood samples were collected for 12 weeks postdose. Safety was monitored throughout. Mean maximum plasma concentration (Cmax ) ranged between 11.0 and 11.3 µg/mL, and area under the plasma concentration-time curve (AUCinf ) ranged between 177.6 and 185.0 µg·day/mL across treatments. The 90% confidence intervals for the ratios of adjusted geometric means for Cmax and AUCinf fell within the 80%-125% range for both DS and delivery device comparisons. Comparable low-density lipoprotein cholesterol profiles were observed, with nadir values of 54.3-56.1 mg/dL across treatments. Similar PCSK9 responses were also observed. Safety profiles were similar across treatments, and the majority of adverse events (AEs) were mild. Three subjects reported serious AEs. The most frequently reported AEs were headache, injection-site reaction, and upper respiratory tract infection, with no clear differences across treatments. Comparable PK, PD, and safety were observed following a single bococizumab 150-mg subcutaneous injection regardless of site of DS manufacture or delivery device used.

Pharmacokinetics, pharmacodynamics, and safety of bococizumab, a monoclonal antibody against proprotein convertase subtilisin/kexin type 9, in healthy subjects when administered in co-mixture with recombinant human hyaluronidase: A phase 1 randomized trial.

AIM: Prior to the discontinuation of bococizumab's clinical development, it was considered advantageous to develop an infrequent dosing regimen (eg, monthly). Therefore, we conducted a phase 1 study to evaluate the pharmacokinetics, pharmacodynamics, and safety of bococizumab when administered in co-mixture with recombinant human hyaluronidase (rHuPH20). METHOD: Healthy subjects (N = 60) were randomized equally among 4 groups that received a single subcutaneous dose of either bococizumab 150, 300, or 450 mg co-mixed with rHuPH20 or bococizumab 300 mg alone. Bioavailability and lipid-lowering effect of bococizumab were evaluated by using ANCOVA models. RESULTS: In the groups administered bococizumab co-mixed with rHuPH20, dose-normalized C max and AUCinf were 26.6 to 39.1% and 18.3 to 36.6% greater, respectively, compared with bococizumab 300 mg alone. Despite these increases, mean percent reductions from baseline in low-density lipoprotein cholesterol were smaller in the bococizumab 300 mg + rHuPH20 group than in the bococizumab 300-mg group at Day 21 (52.2% and 59.5%, respectively) and were similar at Day 29 (51.7% and 49.6%, respectively). Compared with the group administered bococizumab 300 mg alone, the bococizumab 300 mg + rHuPH20 group did not show a significantly altered AUEC85 (ratio of adjusted means: 102.5%, 90% confidence interval: 96.1-109.3%) but did show a higher MaxELDL-C (ratio of adjusted means: 125.4%, 90% confidence interval: 103.3-152.2%), indicating diminution of efficacy. The most frequent adverse events were injection-site erythema, injection-site bruising, and nasopharyngitis; all injection-site adverse events were mild. CONCLUSION: Co-mixture with rHuPH20 increased the bioavailability of bococizumab without proportional increase in pharmacodynamic effect. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02667223.