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

Clin Pharmacol Drug Dev. 2022 Jul;11(7):865-877. doi: 10.1002/cpdd.1078. Epub 2022 Mar 4.


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.

Keywords: LAI; TV-46000; dose selection; long-acting injectable; modeling and simulations; population pharmacokinetics; risperidone; schizophrenia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antipsychotic Agents*
  • Delayed-Action Preparations / pharmacokinetics
  • Humans
  • Paliperidone Palmitate
  • Receptors, Dopamine D2
  • Risperidone* / pharmacokinetics


  • Antipsychotic Agents
  • Delayed-Action Preparations
  • Receptors, Dopamine D2
  • Risperidone
  • Paliperidone Palmitate