A Randomized Study of the Relative Pharmacokinetics, Pharmacodynamics, and Safety of Alirocumab, a Fully Human Monoclonal Antibody to PCSK9, After Single Subcutaneous Administration at Three Different Injection Sites in Healthy Subjects

Abstract

AimsWe investigated the relative pharmacokinetics, pharmacodynamics, and safety of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab following injection at three different sites.MethodsSixty healthy subjects (39 male, 21 female; age 20–45 years) were randomized to receive a single subcutaneous injection of alirocumab 75 mg via 1-mL prefilled pen into the abdomen, upper arm, or thigh (NCT01785329). Subjects were followed for 85 days ± 2 days following study drug administration. Pharmacokinetic (PK) parameters for the systemic exposure of alirocumab were calculated, and levels of free PCSK9 were assessed. Percentage changes from baseline in LDL-C were compared between injection site groups using linear mixed-effects models.ResultsAlirocumab concentration–time profiles were similar, and free PCSK9 levels were reduced to approximately zero between Day 3 and Day 4 postinjection in all groups. LDL-C levels reached nadir on Day 15 postinjection in all groups with mean percentage reductions of 48.4% (abdomen), 39.5% (upper arm), and 45.6% (thigh) at this time point. A similar effect on LDL-C levels was seen across the entire time course of the study at all three injection sites. Treatment-emergent adverse events were experienced by 8/20 (abdomen), 11/20 (upper arm), and 13/20 (thigh) subjects. There were 2 mild/transient injection site reactions. There were no serious adverse events.DiscussionA single subcutaneous administration of alirocumab 75 mg via prefilled pen was well tolerated with similar pharmacokinetics and pharmacodynamics when injected into the abdomen, upper arm, or thigh.ConclusionThese results suggest that alirocumab can be interchangeably injected in the abdomen, upper arm, or thigh.

Gingival Ischemia and Petechiae in a Patient Medicated With PCSK9 Inhibitor for Hypercholesterolemia: An Adverse Drug Event?

“…It may be hypothesized that alirocumab could negatively affect blood clotting after trauma, as PSCK9 positively affects platelets’ activation and thrombosis . In our case, hemorrhage developed in the masticatory mucosa of the gingiva and the palate, a commonly traumatized site of the oral mucosa, 3 days after the injection of the drug, when alirocumab reaches its maximum concentration and free PCSK9 its minimum level, while the patient was synchronously medicated with two antiplatelet drugs, clopidogrel and aspirin. This hypothesis cannot explain the lack of hemorrhage in other commonly traumatized intraoral sites, such as the buccal mucosa and the tongue, or ischemia.…”

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 observed near-complete suppression of unbound PCSK9 is in line with data reported for alirocumab and evolocumab. [25][26][27][28] Total PCSK9, which includes both unbound PCSK9 and PCSK9 bound to bococizumab, increased following bococizumab administration and reached a maximum response on day 15, before gradually returning toward baseline levels. Elevations in total PCSK9 have also been reported in the SPIRE lipid-lowering program 12 and following alirocumab administration.…”

Alternative Treatment Regimens With the PCSK9 Inhibitors Alirocumab and Evolocumab: A Pharmacokinetic and Pharmacodynamic Modeling Approach

“…Stein et al reported the PD of alirocumab after single‐dose administration of 50 mg, 100 mg, 150 mg, and 250 mg . Lunven et al examined the PK and PD of alirocumab after single sc administration at 3 different injection sites in healthy volunteers …”

“…19 Stein et al reported the PD of alirocumab after single-dose administration of 50 mg, 100 mg, 150 mg, and 250 mg. 20 Lunven et al examined the PK and PD of alirocumab after single sc administration at 3 different injection sites in healthy volunteers. 21 For evolocumab, data from 6 studies were used for model development. Dias et al reported 2 phase 1 studies that investigated the PK and PD of evolocumab: 21 mg and 420 mg were administered intravenously, and doses between 7 mg and 420 mg were administered sc to healthy subjects (Study 20080397).…”