Population Pharmacokinetic Modeling and Simulation of TV-46000: A Long-Acting Injectable Formulation of Risperidone.
Clin Pharmacol Drug Dev
; 11(7): 865-877, 2022 07.
Article
en En
| MEDLINE
| ID: mdl-35245409
ABSTRACT
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Antipsicóticos
/
Risperidona
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Clin Pharmacol Drug Dev
Año:
2022
Tipo del documento:
Article
País de afiliación:
Estados Unidos