A Pharmacokinetic Bioequivalence Study of Fremanezumab Administered Subcutaneously Using an Autoinjector and a Prefilled Syringe

Abstract

Fremanezumab (AJOVY; Teva Pharmaceutical Industries Ltd, Netanya, Israel), approved for the preventive treatment of migraine, is available as a subcutaneous injection either once a month or once every 3 months using an autoinjector or a prefilled syringe. The present study evaluated the pharmacokinetic (PK) bioequivalence of a single subcutaneous injection of fremanezumab 225 mg administered using an autoinjector compared to a prefilled syringe in healthy volunteers. Blood samples for PK and antidrug antibodies were collected before and after dosing. Safety and tolerability assessments included physical examinations, adverse event reporting, laboratory evaluations, and immunogenicity. Following singledose administration,the mean concentration-time profiles for the 2 treatment groups (autoinjector,n = 106;and prefilled syringe, n = 110) were similar. The point estimates for the back-transformed ratio (autoinjector/prefilled syringe) of geometric least squares means of maximum plasma concentration, area under the plasma concentration-time curve from time 0 to the time of the last measurable drug concentration, and area under the plasma concentration-time curve from time 0 extrapolated to infinity were 1.03, 1.04, and 1.05, respectively, with the 90% confidence intervals entirely contained within bioequivalence margins of 0.8 to 1.25. For both groups, median time to maximum observed concentration was 5 days and mean terminal elimination half-life was approximately 29 days. Treatment-related adverse events were reported by 39 (36%) subjects in the autoinjector group and 26 (24%) in the prefilled syringe group, and the majority were nonserious injection site reactions. The incidence of treatment-emergent antidrug antibody response was low and evenly distributed between the autoinjector (n = 3; 3%) and prefilled syringe (n = 4; 4%) groups. These results indicate that the fremanezumab autoinjector presentation provides an easy-to-use bioequivalent PK profile with a similar safety and tolerability profile to that of the prefilled syringe.

Dose selection for fremanezumab (AJOVY) phase 3 pediatric migraine studies using pharmacokinetic data from a pediatric phase 1 study and a population pharmacokinetic modeling and simulation approach

“…The exposure parameters (C max and AUCs) of fremanezumab were moderately variable with CVs ranging from 47.9 to 54.8%. These findings suggest that the systemic exposure following a 75 mg sc dose was lower in the pediatric study compared to adult patients exposed to 225 mg (11), therefore 75 mg was deemed to be a suboptimal dose. For the pediatric patients, as in adult patients, differences due to body weight were observed; the geometric mean C max of the 17 to < 30 kg weight group was approximately two-fold higher than that of the ≥30–45 kg weight group and the AUC values were about 1.5-fold higher in the 17 to < 30 kg weight group than in the ≥30–45 kg weight group.…”

“…The samples were analyzed using a validated ELISA method with a concentration detection range from 250–3500 ng/mL as described in detail in Cherniakov et al. (11). Safety was assessed throughout the study by monitoring the occurrence of adverse events, including injection site reactions, clinical laboratory test results (chemistry, hematology, coagulation, and urinalysis), vital sign measurements, 12-lead ECG findings, physical examination findings, and use of concomitant medications.…”

“…Simulated exposure measures AUC 28d and C max were calculated at steady-state for the virtual pediatric patients and compared to simulated exposure measures at steady-state in the adult population receiving fremanezumab 225 mg sc monthly (11). Boxplots of the simulated steady-state exposure parameters following fremanezumab doses of 60–225 mg sc monthly are shown in Figure 5, panels (a)–(c) for virtual pediatric patients (6–17 years with body weight < 45 kg).…”

Scaling Approaches for Pediatric Dose Selection: The Fremanezumab (AJOVY®) Journey to Select a Phase 3 Dose Using Pharmacokinetic Data from a Phase 1 Study

“…A validated chemiluminescence enzyme-linked immunosorbent assay (ELISA) was used for the determination of fremanezumab plasma concentrations. The lower limit of quantitation value for the PK assay was 0.25 μg/mL [ 31 ].…”

Tratamiento preventivo de la migraña con fremanezumab subcutáneo

“…-Autoinyector vs. jeringuilla de fremanezumab. Se han comparado ambos mecanismos de inyección y no se han observado diferencias en seguridad y tolerabilidad 57 .…”