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Population Pharmacokinetics of Intramuscular Paliperidone Palmitate in Patients with Schizophrenia

A Novel Once-Monthly, Long-Acting Formulation of an Atypical Antipsychotic

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Abstract

Objectives

To characterize the population pharmacokinetics of paliperidone after intramuscular administration of its long-acting palmitate ester at various doses and at two different injection sites (deltoid and gluteal muscle).

Methods

The retrospective analysis included pooled data from 1795 subjects from six phase I trials and five phase II and III trials. A total of 18 530 pharmacokinetic samples with valid concentration timepoints were available for this analysis. Nonlinear mixed-effects modelling of the pooled data was conducted using NONMEM® software. The full dataset was divided into an index dataset (model development) and a validation dataset. After validation both the index and validation datasets were combined and the final model was re-run on the full dataset.

Results

The concentration-time data for paliperidone following intramuscular administration of its palmitate ester were best fitted to a one-compartment model with first-order elimination. The absorption component of the model allowed a fraction of the dose (f2) to enter relatively quickly into the central compartment via a zeroorder process. After a lag time, the remaining fraction then entered the systemic circulation via a first-order process. Interindividual variability (IIV) in clearance (CL), central volume of distribution (Vd) and the absorption rate constant (Ka were estimated at a 40%, 69% and 59% coefficient of variation (CV), respectively. The IIV on f2 for paliperidone absorption via the dual-input process was fitted through logit transformation, and its standard deviation (SD) was 0.064. Similarly, the interoccasion variability (IOV) on CL, Vd and f2 was 26% CV, 14% CV and 0.07 SD, respectively. An additive-error model with log-transformed data was used to describe the residual variability (RV), and its SD was 0.22. The final covariate model indicated that the following variables had a significant influence on ka: sex, age, injection volume (IVOL) and injection site (INJS). Similarly, the following variables had a significant influence on f2: sex, body mass index (BMI), needle length (NDLL), INJS and IVOL. In addition, CL was related to creatinine clearance (CLCR), whereas Vd was related to BMI and sex.

Conclusions

A dual-absorption pharmacokinetic model best described the complex pharmacokinetics of paliperidone after intramuscular administration of its palmitate ester. These results suggest that the pharmacokinetics of paliperidone palmitate are mostly influenced by BMI, CLCR, INJS, IVOL and NDLL.

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Acknowledgements

We would like to thank the hundreds of subjects and investigators and the medical, nursing and laboratory staff who participated in the clinical trials included in this report. The authors would also like to thank Herta Crauwels, Adriaan Cleton, Partha Nandy, Nancy Van Osselaer, Virginie Herben, David Hough and Paul Soons for their comments and suggestions provided during the analysis.

The results presented in this paper accurately reflect the results of this analysis as outlined in the Methods section of the paper. The sponsor, Johnson & Johnson Pharmaceutical Research & Development, was involved in the study design of the clinical trials from which the pharmacokinetic samples were taken. It provided financial support to the authors and those acknowledged in the Acknowledgments section in the process of data collection/analysis and in the editorial development of and decision to publish this manuscript. Mahesh N. Samtani, An Vermeulen and Kim Stuyckens are employees of Johnson & Johnson Pharmaceutical Research & Development. The authors have no other conflicts of interest to declare.

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Authors and Affiliations

  1. Advanced PK-PD Modeling & Simulation, Johnson & Johnson Pharmaceutical Research & Development, LLC, Clinical Pharmacology, Raritan, New Jersey, USA

    Mahesh N. Samtani

  2. Advanced PK-PD Modeling & Simulation, Johnson & Johnson Pharmaceutical Research & Development, a Division of Janssen Pharmaceutica NV, Clinical Pharmacology, Beerse, Belgium

    An Vermeulen & Kim Stuyckens

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  1. Mahesh N. Samtani
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  2. An Vermeulen
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  3. Kim Stuyckens
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Correspondence to Mahesh N. Samtani.

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Samtani, M.N., Vermeulen, A. & Stuyckens, K. Population Pharmacokinetics of Intramuscular Paliperidone Palmitate in Patients with Schizophrenia. Clin Pharmacokinet 48, 585–600 (2009). https://doi.org/10.2165/11316870-000000000-00000

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