Bayesian population approaches to the analysis of dose escalation studies

In dose escalation studies cohorts of subjects are given increasing doses of a candidate drug to assess safety and tolerability, pharmacokinetics and pharmacological response. The escalation is carried on until a predefined stopping limit is achieved, often identified by a pharmacokinetic endpoint such as peak plasma concentration or area under the plasma concentration-time profile. In the present work, the application of Bayesian methodologies to Phase I dose escalation studies is explored. A Bayesian population model is devised, which provides predictions of dose-response and dose-risk curves, both for individuals already enrolled in the trial and for a new, previously untested subject. Empirical and fully Bayesian estimation algorithms are worked out. Such methods provide equivalent performances on both experimental and simulated datasets. With respect to previous work, it is quantitatively proven not only that a more general and flexible model is identifiable, but also that such flexibility is needed in real scenarios

Dosing and switching strategies for paliperidone palmitate 3-month formulation in patients with schizophrenia based on population pharmacokinetic modeling and simulation, and clinical trial data

Paliperidone palmitate 3-month formulation (PP3M), a long-acting injectable atypical antipsychotic, was recently approved in the US and Europe for the treatment of schizophrenia in adult patients who have already been treated with paliperidone palmitate 1-month formulation (PP1M) for >= 4 months. This article reviews the pharmacokinetic rationale for the approved dosing regimens for PP3M, dosing windows, management of missed doses and treatment discontinuation, switching to other formulations, and dosing in special populations. Approved PP3M dosing regimens are based on the comparisons of simulations with predefined dosing regimens using paliperidone palmitate and oral paliperidone extended release (ER) population pharmacokinetic models (one-compartment model with two saturable absorption processes for PP3M; one-compartment model with parallel zero- and first-order absorption for PP1M; two-compartment model with sequential zero- and first-order absorption for ER) versus clinical trial data. Covariates were obtained by resampling subject covariates from the pharmacokinetics database for PP1M and PP3M. Simulation scenarios with varying doses and covariate values were generated. The population median and 90% prediction interval of the simulated concentration-time profiles were plotted for simulation outcomes evaluation. Simulations described in this paper provide (a) simulated plasma exposures for switching from PP1M to PP3M, (b) support for a once-every-3-months injection cycle, (c) information on dosing windows and managing missed doses of PP3M, (d) important guidance on PP3M dosing in special patient populations, and () key PP3M pharmacokinetic exposure metrics based on the population pharmacokinetic PP3M model. Population pharmacokinetics provided practical guidance to establish dosing regimens for PP3M

Population pharmacokinetics of a novel once-every 3 months intramuscular formulation of paliperidone palmitate in patients with schizophrenia

Objectives: 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). Methods: 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. Results: 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 (F-3) 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 (gamma) were estimated to be 90.4 mu g/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 mu g/h and 21.4 mg, respectively. Conclusion: 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))