Population Pharmacokinetic Modeling and Simulation of TV-46000: A Long-Acting Injectable Formulation of Risperidone.

TV-46000 is a long-acting subcutaneous antipsychotic that uses a novel copolymer drug delivery technology in combination with a well-characterized molecule, risperidone, that is in clinical development as a treatment for schizophrenia. A population pharmacokinetic (PPK) modeling and simulation approach was implemented to identify TV-46000 doses and dosing schedules for clinical development that would provide the best balance between clinical efficacy and safety. The PPK model was created by applying pharmacokinetic data from a phase 1 study of 97 patients with a diagnosis of schizophrenia or schizoaffective disorder who received either single or repeated doses of TV-46000. The PPK model was used to characterize the complex release profile of the total active moiety (TAM; the sum of the risperidone and 9-OH risperidone concentrations) concentration following subcutaneous injections of TV-46000. The PK profile was best described by a double Weibull function of the in vivo release rate and by a 2-compartment disposition and elimination model. Simulations were performed to determine TV-46000 doses and dosing schedules that maintained a median profile of TAM concentrations similar to published TAM exposure following oral risperidone doses that have been correlated to a 40% to 80% dopamine-D2 receptor occupancy therapeutic window. The simulations showed that therapeutic dose ranges for TV-46000 are 50 to 125 mg for once-monthly and 100 to 250 mg for the once every 2 months regimens. This PPK model provided a basis for prediction of patient-specific exposure and dopamine-D2 receptor occupancy estimates to support further clinical development and dose selection for the phase 3 studies.

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

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 single-dose 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.