Population Pharmacokinetics of a Novel Once-Every 3 Months Intramuscular Formulation of Paliperidone Palmitate in Patients with Schizophrenia
- 717 Downloads
Our objective was to characterize the population pharmacokinetics of paliperidone after intramuscular administration of its long-acting 3-month formulation palmitate ester at various doses and at different injection sites (deltoid and gluteal muscles).
This retrospective analysis included pooled data from 651 subjects from one phase I study (single injection of the 3-month formulation) and one phase III study (multiple injections of both 1- and 3-month formulations). A total of 8990 pharmacokinetic samples with valid concentration time points were available for this analysis. Nonlinear mixed-effects modelling of the pooled data was conducted using NONMEM software. Knowledge from a previously developed 1-month formulation model was used as a starting point to build the 3-month formulation model.
The final model describing the plasma concentrations after administration of the 3-month formulation was a one-compartment model with first-order elimination and two saturable absorption processes (rapid and slow). The apparent volume of distribution estimated for the 3-month formulation was not the same as for the previously modelled 1-month formulation. Apparent clearance (CL), apparent volume of distribution (V), and fraction of the absorbed dose (F3) were estimated to be 3.84 l/h, 1960 L, and 20.9 %. For slow absorption, the maximum absorption rate constant (k a1 max), amount of paliperidone at the absorption site when half of the maximum absorption rate was achieved (k amt1 50), and Hill factor (γ) were estimated to be 90.4 µg/h, 120 mg, and 1.44, respectively. For rapid absorption, the maximum absorption rate constant (k a3 max) and amount of paliperidone at the absorption site when half of the maximum absorption rate was achieved (k amt3 50) were estimated to be 164 µg/h and 21.4 mg, respectively.
The final model with two saturable absorption processes provided a good description of the pharmacokinetic characteristics of paliperidone after intramuscular administration of its long-acting 3-month formulation palmitate ester. In addition to the structural covariates (creatinine clearance on CL, body mass index on V, and injection volume on both absorption rates), injection site and sex were identified as covariates on k a max of the slow absorption process (k a1 max).
Clinical trial registration numbers: NCT01559272, NCT01529515, and NCT01515423
KeywordsPaliperidone Absorption Parameter Population Pharmacokinetic Model Objective Function Value Visual Predictive Check
The authors thank Tinka Tuinstra PhD, an employee of AUTHOR! et al. BV, for her medical writing assistance.
Compliance with Ethical Standards
Conflict of interest
M. O. Magnusson, E. L. Plan and E. N. Jonsson are employees of Pharmetheus and received consultancy fees from Janssen Research & Development. M. N. Samtani, S. Rossenu, A. Vermeulen, and A. Russu are employees of Janssen Research & Development and own Johnson & Johnson stocks and/or stock options.
- 10.Weiden PJ, Zygmunt A. The road back: working with the severely mentally ill. Medication noncompliance in schizophrenia. J Pract Psychiatr Behav Health. 1997;3:106–10.Google Scholar
- 11.US label of INVEGA® SUSTENNA® (Revised 01/2016). http://www.invegasustenna.com/important-product-information. Accessed 15 Feb 2016.
- 13.Ravenstijn P, Remmerie B, Savitz A, De Meulder M, Hough D, Gopal S, et al. Pharmacokinetics, safety, and tolerability of paliperidone palmitate 3-month formulation in patients with schizophrenia: a phase-1, single-dose, randomized, open-label study. J Clin Pharmacol. 2016;56(3):330–9.CrossRefPubMedGoogle Scholar
- 15.American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th edn. Arlington: American Psychiatric Association; 2000. (Text revision [DSM-IV-TR]).Google Scholar
- 16.De Meulder M, Remmerie BM, de Vries R, et al. Validated LC-MS/Msmethods for the determination of risperidone and the enantiomers of 9-hydroxyrisperidone in human plasma and urine. J Chromatogr. 2008;870(1):8–16.Google Scholar
- 17.R Development Core Team. R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing. ISBN 3-900051-07-0. http://www.R-project.org. Accessed 18 Jan 2016.
- 18.Beal SL, Sheiner LB, Boeckmann AJ, Bauer RJ. NONMEM users guides. Ellicott City: Icon Development Solutions; 1989.Google Scholar
- 24.Hirano K, Yamada H. Studies on the absorption of practically water-insoluble drugs following injection: IV. An approach for predicting relative intramuscular absorption rates of a drug in oily solution, aqueous suspension and aqueous surfactant solution in rats. Chem Pharm Bull. 1981;29(5):1410–5.CrossRefPubMedGoogle Scholar
- 30.Magnusson MO, Samtani MN, Plan EL, Jonsson EN, Rossenu S, Vermeulen A, et al. Population pharmacokinetic simulations of two paliperidone palmitate formulations. Poster presented at PAGE 24 (2015) Abstr 3643 http://www.page-meeting.org/?abstract=3643.
- 31.Label of INVEGA® TRINZA® (Revised 03/2016). https://www.janssenmd.com/pdf/invega-trinza/INVEGA-TRINZA_PI.pdf. Accessed 4 July 2016.
- 32.Educational Dose Illustrator for: INVEGA SUSTENNA® (paliperidone palmitate) INVEGA TRINZA™ (paliperidone palmitate) http://www.educationaldoseillustrator.com/pp3m/schizophrenia).