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

Abstract

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 (C ) ranged between 11.0 and 11.3 μg/mL, and area under the plasma concentration-time curve (AUC ) ranged between 177.6 and 185.0 μg·day/mL across treatments. The 90% confidence intervals for the ratios of adjusted geometric means for C and AUC 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.

Population PK/PD modeling of low‐density lipoprotein cholesterol response in hypercholesterolemic participants following administration of bococizumab, a potent anti‐PCSK9 monoclonal antibody

“…Immunogenicity assessments were done regularly in phase II and III studies. Primary observations from these clinical studies have been presented in full elsewhere 11–18 …”

“…All participants provided written, informed consent. Full detail is given in the primary publications 11–18 …”

“…[7][8][9] Thus, PCSK9 plays a central role in the physiology of LDL-C processing, 4,5 and since 2017 anti-PCSK9 mAbs have become a key addition to the pharmaceutical management of LDL-C and atherosclerotic cardiovascular risk. 10 The safety, efficacy, and pharmacokinetics (PK) of bococizumab were evaluated as part of a clinical development program, [11][12][13][14][15][16][17][18][19][20] but global development was discontinued in November 2016 as a result of the emerging profile observed from the Studies of PCSK9 Inhibition and the Reduction of vascular Events (SPIRE) phase III lipid-lowering program. 15,19,21 The SPIRE program reported an unanticipated attenuation of LDL-C lowering over time, alongside a higher incidence of antidrug antibodies (ADAs), and a higher rate of injectionsite reactions compared with other agents in this drug class.…”

Pharmacokinetic improvement provided by microneedle patch in delivering bee venom, a case study in combating scopolamine-induced neurodegeneration in mouse model

“…Drugs administered trans dermally exhibit high bioavailability as they avoid gastrointestinal processing and the first-pass metabolic process (Nagarkar et al, 2020 ). However, raw drugs injections under the skin usually result in a sharp rise in blood plasma concentrations within the early stage of administration, and dramatically decreases after a max concentration is reached, thereby effectively pushing the drug concentration beyond its useful therapeutic window (Kagan, 2014 ; Wang et al, 2019 ). In the case of bee venom solution injections, as concentration levels increase sharply, the injection method can induce sharp and painful sensations and other adverse effects (Chen et al, 2016 ; Burzyńska & Piasecka-kwiatkowska, 2021 ).…”

Assessing the Potential Risk of Cross-Reactivity Between Anti-Bococizumab Antibodies and Other Anti-PCSK9 Monoclonal Antibodies

“…Bococizumab is a humanized IgG2Δa mAb targeting the LDL receptor-binding domain of PCSK9 [12]; it has been studied in phase I–III clinical studies, and has been found to both lower LDL-C and reduce cardiovascular event rates [13–21]. In November 2016, clinical development of bococizumab was discontinued as a result of the emerging clinical profile observed from the SPIRE (Studies of PCSK9 Inhibition and the Reduction of vascular Events) phase III lipid-lowering program [15, 22].…”