OBJECTIVES: To characterize the population pharmacokinetics of @entity7302 after intramuscular administration of its long-acting @entity47371 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 @entity7302 following intramuscular administration of its @entity47371 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 @entity7302 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 @entity1011 clearance (CL(CR)), whereas V(d) was related to BMI and sex. CONCLUSIONS: A dual-absorption pharmacokinetic model best described the complex pharmacokinetics of @entity7302 after intramuscular administration of its @entity47371 . These results suggest that the pharmacokinetics of @entity16864 are mostly influenced by BMI, CL(CR), INJS, IVOL and NDLL.

Population pharmacokinetics of intramuscular XXXX in patients with schizophrenia: a novel once-monthly, long-acting formulation of an atypical antipsychotic.

@entity7302 :: ('MESH:C079150', 'Chemical') :: ['paliperidone'] @entity16864 :: ('MESH:C548956', 'Chemical') :: ['paliperidone palmitate'] @entity47371 :: ('CHEBI:25835', 'Chemical') :: ['palmitate ester'] @entity1011 :: ('MESH:D003404', 'Chemical') :: ['creatinine']
@entity16864 :: (MESH:C548956,Chemical) :: ['paliperidone palmitate']
