Population Pharmacokinetics of Intramuscular Paliperidone Palmitate in Patients with Schizophrenia: A Novel Once-Monthly, Long-Acting Formulation of an Atypical Antipsychotic
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 (f(2)) to enter relatively quickly into the central compartment via a zero-order 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 (V(d)) and the absorption rate constant (k(a)) were estimated at a 40%, 69% and 59% coefficient of variation (CV), respectively. The IIV on f(2) 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, V(d) and f(2) 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 k(a): sex, age, injection volume (IVOL) and injection site (INJS). Similarly, the following variables had a significant influence on f(2): sex, body mass index (BMI), needle length (NDLL), INJS and IVOL. In addition, CL was related to creatinine clearance (CL(CR)), whereas V(d) 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, CL(CR), INJS, IVOL and NDLL.
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As injection volume (and hence dose) increases, the absorption rate constant decreases, leading to an increase in half-life.
“As injection volume (and hence dose) increases, the absorption rate constant decreases, leading to an increase in half-life [78].”
From Pharmacokinetic Characteristics of Long-Acting Injectable Antipsychotics for Schizophrenia: An Overview (2021) · cites this paper as [78]
The half-life of PP1M increases as the dose increases because of flip-flop kinetics, whereby the half-life is dependent on the absorption rate constant, which in turn is dependent on the injection volume.
“The half-life increases as the dose increases because of flip-flop kinetics, whereby the half-life is dependent on the absorption rate constant, which in turn is dependent on the injection volume [78].”
From Pharmacokinetic Characteristics of Long-Acting Injectable Antipsychotics for Schizophrenia: An Overview (2021) · cites this paper as [78]
Paliperidone palmitate is nearly insoluble in water; therefore, it dissolves slowly at the intramuscular injection site (either deltoid or gluteal), and is rapidly hydrolyzed to release paliperidone, the active ingredient (and the major metabolite of risperidone).
“Paliperidone palmitate is nearly insoluble in water; therefore, it dissolves slowly at the intramuscular injection site (either deltoid or gluteal), and is rapidly hydrolyzed to release paliperidone, the active ingredient (and the major metabolite of risperidone) [77, 78].”
From Pharmacokinetic Characteristics of Long-Acting Injectable Antipsychotics for Schizophrenia: An Overview (2021) · cites this paper as [78]
Steady state of PP1M is achieved 8-9 months after the initial injection (with the 234 mg dose).
“Steady state is achieved 8–9 months after the initial injection (with the 234 mg dose) [78, 80].”
From Pharmacokinetic Characteristics of Long-Acting Injectable Antipsychotics for Schizophrenia: An Overview (2021) · cites this paper as [78]
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References 25 · Cited by 170
- Authors
- Samtani, M. N., Vermeulen, A., & Stuyckens, K.
- Affiliations
- Janssen Research & Development (United States) (US)
- Janssen (Belgium) (BE)
- Corresponding author
- Samtani, Mahesh N.
- Venue
- Clinical Pharmacokinetics
- Published
- 2009-09
- Volume
- 48
- Issue
- 9
- Pages
- 585-600
- ISSN
- 0312-5963 (ISSN-L)
- OpenAlex
- W1906145619
- Cited by
- 170
- References
- 25
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 13 · 2023: 9 · 2022: 6 · 2021: 13 · 2020: 5 · 2019: 6 · 2018: 14 · 2017: 8 · 2016: 14 · 2015: 10 · 2014: 10 · 2013: 12 · 2012: 14
- FWCI
- 7.84
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Pharmacokinetics (publishedVersion)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- paliperidone palmitate, population pharmacokinetics, intramuscular administration, long-acting antipsychotics, schizophrenia, injection site, deltoid muscle, gluteal muscles, interindividual variability, interoccasion variability, covariate effects, creatinine clearance, body mass index, needle length, injection volume, nonlinear mixed-effects modelling, one-compartment model
- MeSH terms
- Paliperidone Palmitate, Adolescent, Adult, Aged, Bayes Theorem, Chemistry, Pharmaceutical, Clinical Trials as Topic, Computer Simulation, Data Collection, Delayed-Action Preparations, Drug Administration Schedule, Drug Interactions, Humans, Injections, Intramuscular, Isoxazoles, Male, Middle Aged, Models, Biological, Pyrimidines, Retrospective Studies, Schizophrenia, Antipsychotic Agents, Young Adult
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