Population Pharmacokinetics of Intramuscular Paliperidone Palmitate in Patients with Schizophrenia A Novel Once-Monthly, Long-Acting Formulation of an Atypical Antipsychotic

• Published in: Clinical pharmacokinetics Vol. 48; no. 9; pp. 585 - 600
• Main Authors: Samtani, Mahesh N., Vermeulen, An, Stuyckens, Kim
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.09.2009; Adis International; Wolters Kluwer Health, Inc; Springer Nature B.V
• Subjects: Adolescent; Adult; Adult and adolescent clinical studies; Aged; Antipsychotic Agents - administration & dosage; Antipsychotic Agents - pharmacokinetics; Antipsychotic Agents - therapeutic use; Antipsychotic drugs; Bayes Theorem; Biological and medical sciences; Chemistry, Pharmaceutical; Clinical Trials as Topic; Computer Simulation; Data Collection; Delayed-Action Preparations; Dosage and administration; Drug Administration Schedule; Drug Interactions; Drug therapy; General pharmacology; Humans; Injections, Intramuscular; Internal Medicine; Isoxazoles - administration & dosage; Isoxazoles - pharmacokinetics; Isoxazoles - therapeutic use; Male; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Models, Biological; Original Research Article; Paliperidone Palmitate; Pharmacokinetics; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pharmacotherapy; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychoses; Pyrimidines - administration & dosage; Pyrimidines - pharmacokinetics; Pyrimidines - therapeutic use; Retrospective Studies; Schizophrenia; Schizophrenia - drug therapy; Young Adult; Belgium; United States; Deltoid Muscle; Gluteal Muscle; Paliperidone; Population Pharmacokinetic Analysis; Paliperidone Palmitate; Psychosis; Human; Population pharmacokinetics; Atypical antipsychotic; Monthly; Psychotropic; Formulation; Schizophrenia; Antidepressant agent; Intramuscular administration
• ISSN: 0312-5963; 1179-1926; 1179-1926
• DOI: 10.2165/11316870-000000000-00000

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 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 (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.