Population Pharmacokinetic Modeling and Simulation of TV‐46000: A Long‐Acting Injectable Formulation of Risperidone
- Resource Type
- Authors
- Itay, Perlstein; Avia, Merenlender Wagner; Roberto, Gomeni; Michael, Lamson; Eran, Harary; Ofer, Spiegelstein; Attila, Kalmanczhelyi; Ryan, Tiver; Pippa, Loupe; Micha, Levi; Anna, Elgart
- Source
- Clinical Pharmacology in Drug Development. 11:865-877
- Subject
- Receptors, Dopamine D2
Delayed-Action Preparations
Paliperidone Palmitate
Humans
Pharmaceutical Science
Pharmacology (medical)
Risperidone
Antipsychotic Agents
- Language
- ISSN
- 2160-7648
2160-763X
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.