Dose-conversion factors for risperidone and paliperidone formulations based on steady-state PK similarity
Alberto Russu (1), Jennifer Kern-Sliwa (2), Paulien Ravenstijn (1), Arun Singh (2), Maju Mathews (2), Edward Kim (2), Srihari Gopal (2)
(1) Janssen Research & Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium; (2) Janssen Research & Development, Titusville, NJ
Objectives: Several risperidone and paliperidone oral and long-acting injectable (LAI) formulations, each characterized by a unique pharmacokinetic (PK) profile, are available for schizophrenia treatment. In clinical practice, it is important to know how to switch patients from one formulation to another. This work aims to assess the dose strengths of oral risperidone and risperidone LAI (RLAI) resulting in similar steady-state (SS) exposures to dose strengths of paliperidone palmitate 1-month (PP1M) LAI and oral paliperidone extended-release (ER), and to provide prescribers with a practical guidance on transition between formulations.
Methods: Population PK simulations of SS PK were performed using the PK models of oral risperidone [1], RLAI [2], PP1M [3], and oral paliperidone ER [2]. For the two risperidone formulations, active-moiety (ie. risperidone plus paliperidone) concentrations were compared to paliperidone concentrations from PP1M and oral paliperidone ER administration. Similarity was assessed via graphical evaluation of median and 90% prediction intervals of SS PK profiles over 28 days.
Results: Oral risperidone doses of 1, 2, 3, 4, and 6 mg/day are expected to result in similar PK to PP1M doses of 25, 50, 75, 100, and 150 mg eq., respectively (i.e. 25-fold PP1M-to-oral risperidone conversion factor). RLAI doses of 12.5, 25, 37.5, and 50 mg every 2 weeks provide similar PK to PP1M doses of 25, 50, 75, and 100 mg eq., respectively (i.e. 2-fold PP1M-to-RisConsta factor). PP1M 150 mg eq. does not have a marketed RLAI dose resulting in PK similarity (50 mg is the highest marketed RLAI dose strength). Oral risperidone doses of 2, 3, 4, and 6 mg/day result in similar PK to oral paliperidone ER 3, 6, 9, and 12 mg, respectively.
Conclusions: This work established dose-conversion factors for risperidone and paliperidone formulations based on SS PK similarity. Dosing at the time of switching should be in accordance to the respective approved product information (PI). Actual oral risperidone or RLAI doses should take into account concomitant medication with CYP2D6 inhibitors or CYP3A4 inducers [4,5]. In addition to PK considerations, clinical symptoms should always be considered when switching medications. Patients undergoing a switch should be monitored closely before and after the switch. This work provides the clinician with a practical guidance to establish an adequate maintenance dose level when transitioning patients from one formulation to another.
References:
[1] Thyssen A et al. Population pharmacokinetics of oral risperidone in children, adolescents and adults with psychiatric disorders. Clinical Pharmacokinetics 2010;49(7):465-478
[2] Samtani MN et al. Management of antipsychotic treatment discontinuation and interruptions using model-based simulations. Clinical Pharmacology: Advances and Applications 2012;4:25-40
[3] Samtani MN et al. Population pharmacokinetics of intramuscular paliperidone palmitate in patients with schizophrenia. Clinical Pharmacokinetics 2009;48(9):585-600
[4] Risperdal® (risperidone) tablets/oral solution: US prescribing information. Titusville (NJ): Janssen Pharmaceuticals, 2016 Mar [online]. Available from URL: http://www.janssen.com/us/sites/www_janssen_com_usa/files/products-documents/risperdal-prescription-information.pdf [Accessed 2017 Feb 6]
[5] Risperdal Consta® (risperidone) injectable: US prescribing information. Titusville (NJ): Janssen Pharmaceuticals, 2016 Mar [online]. Available from URL: http://www.risperdalconsta.com/important-product-information [Accessed 2017 Feb 6]