Eleonora Marostica

Deconvolution‐based assessment of pituitary GH secretion stimulated with GHRH+arginine in Prader‐Willi adults and obese controls

The assessment of GH deficiency in adult patients with Prader‐Willi syndrome (PWS) has been previously assessed through the evaluation of quantitative parameters, such as the peak value of GH response to exogenous stimuli. A comprehensive description of the pattern of secretory response obtainable by deconvolution analysis is still lacking. The aim of our study was to characterize the time evolution of responses of PWS subjects compared with obese controls.

The GHRH+arginine stimulated pituitary GH secretion in children and adults with Prader-Willi syndrome shows age- and BMI-dependent and genotype-related differences

OBJECTIVE The quantitative and qualitative aspects of the pituitary response in children and adults with Prader-Willi syndrome (PWS) are compared in order to verify the possible age-dependent and genotype-related differences in terms of GH secretion. DESIGN 29 young subjects (21 males and 8 females) and 65 adults (24 males and 41 females) with PWS were studied. All subjects underwent a standard GH Releasing Hormone (GHRH 1-29, 1 μg/kg as i.v. bolus at 0 minutes)+arginine (0.5 g/kg) test. Peak GH values, standard GH area under the curve (AUC), AUC of the instantaneous secretion rate (ISR), and secretion response analysis (i.e. half-secretion time) were evaluated. A regression analysis was performed to investigate which are the patient characteristics that affect the amplitude and shape of the GH secretion response. RESULTS Peak GH values and AUCGH were significantly higher in PWS children than in PWS adults, these differences being also significant both in PWS DEL15 (only peak GH value) and PWS UPD15. Moreover, PWS children showed significantly lower half secretion time than PWS adults, this delayed response being present both in PWS DEL15 and PWS UPD15. Significant negative correlations between AUCGH and BMISDS were observed in the two groups (adults and children), as well as in adults and children DEL15, but not in adults and children PWS UPD15. A regression analysis performed on the whole dataset showed that for PWS DEL15 the statistically significant variable explaining GH responsiveness was BMISDS (p<0.0001), while for UPD15 no statistically significant covariate was found. Conversely, when the delay of the secretion response was considered, the regression model yielding the best performances was the one with only age as a regressor (p<0.001). CONCLUSIONS The quantitative and qualitative analyses of GH responsiveness to GHRH+arginine highlight relevant differences between PWS children and PWS adults and genotype-related traits. The negative influence of BMISDS on GH secretion reinforces the need for an early start of life-long weight management in PWS subjects.

Joint Modeling of Efficacy, Dropout, and Tolerability in Flexible‐Dose Trials: A Case Study in Depression

Many difficulties may arise during the modeling of the time course of Hamilton Rating Scale for Depression (HAMD) scores in clinical trials for the evaluation of antidepressant drugs: (i) flexible designs, used to increase the chance of selecting more efficacious doses, (ii) dropout events, and (iii) adverse effects related to the experimental compound. It is crucial to take into account all these factors when designing an appropriate model of the HAMD time course and to obtain a realistic description of the dropout process. In this work, we propose an integrated approach to the modeling of a double‐blind, flexible‐dose, placebo‐controlled, phase II depression trial that comprises response, tolerability, and dropout. We investigate three different dropout mechanisms in terms of informativeness. Goodness of fit is quantitatively assessed with respect to response (HAMD score) and dropout data. We show that dropout is a complex phenomenon that may be influenced by HAMD evolution, dose changes, and occurrence of drug‐related adverse effects.

A PCA approach to population analysis: with application to a Phase II depression trial.

For psychiatric diseases, established mechanistic models are lacking and alternative empirical mathematical structures are usually explored by a trial-and-error procedure. To address this problem, one of the most promising approaches is an automated model-free technique that extracts the model structure directly from the statistical properties of the data. In this paper, a linear-in-parameter modelling approach is developed based on principal component analysis (PCA). The model complexity, i.e. the number of components entering the PCA-based model, is selected by either cross-validation or Mallows’ Cp criterion. This new approach has been validated on both simulated and clinical data taken from a Phase II depression trial. Simulated datasets are generated through three parametric models: Weibull, Inverse Bateman and Weibull-and-Linear. In particular, concerning simulated datasets, it is found that the PCA approach compares very favourably with some of the popular parametric models used for analyzing data collected during psychiatric trials. Furthermore, the proposed method performs well on the experimental data. This approach can be useful whenever a mechanistic modelling procedure cannot be pursued. Moreover, it could support subsequent semi-mechanistic model building.

Abstract B19: Population pharmacokinetic-pharmacodynamic (PKPD) modeling of ibrutinib in patients with B-cell malignancies.

Ibrutinib (IBRU) is an oral Bruton9s tyrosine kinase (BTK) inhibitor, approved by US FDA for the treatment of chronic lymphocytic leukemia (CLL/SLL) and mantle cell lymphoma (MCL) patients having received at least one prior therapy. A nonlinear mixed-effects population model was developed to describe the PK of IBRU in patients with B-Cell malignancies and to establish the effect of pathophysiological covariates on its PK behavior. The relationship between PK and BTK engagement in peripheral blood mononuclear cells (PBMC) was also explored. IBRU PK data (3477 observations in 245 patients) were available in patients with MCL, CLL/SLL and recurrent B-cell malignancies at dose levels from 1.25 to 12.5 mg/kg and at fixed doses from 420 to 840 mg once daily. An additional phase 2 study in 119 patients with MCL (772 observations) treated at 560 mg once daily was used to validate the PK model. BTK occupancy was assessed (694 observations in 127 patients) in PBMCs using a fluorescent affinity probe. Various models were tested on the data using the first-order conditional estimation method as implemented in NONMEM version 7.1. A 2-compartment linear model with sequential zero-first order absorption and first order elimination was able to accommodate available PK data, including those of the validation dataset (prediction errors Citation Format: Italo Poggesi, Maria Luisa Sardu, Eleonora Marostica, Juthamas Sukbuntherng, Betty Y. Chang, Jan de Jong, Xavier Woot de Trixhe, An Vermeulen, Giuseppe De Nicolao, Susan Mary O9Brien, John C Byrd, Ranjana H Advani, Danelle Frances James, William Deraedt, Darrin Beaupre, Michael Wang. Population pharmacokinetic-pharmacodynamic (PKPD) modeling of ibrutinib in patients with B-cell malignancies. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr B19.

Continuous-time Markov modelling of flexible-dose depression trials

The aim of this paper is to provide a systematic methodology for modelling longitudinal data to be used in contexts of limited or even absent knowledge of the physiological mechanism underlying the disease time course. Adopting a system-theoretic paradigm, a population response model is developed where the clinical endpoint is described as a function of the patient’s health state. In particular, a continuous-time stochastic approach is proposed where the clinical score and its time-derivative summarize the patient’s health state affected by a random term accounting for exogenous unpredictable factors. The proposed approach is validated on experimental data from the placebo and drug arms of a Phase II depression trial. Since some subjects in the trial may undergo changes in their treatment dose due to the flexible dosing scheme, dose escalations are modelled as instantaneous perturbations on the state. In its simplest form—an integrated Wiener process—was able to correctly capture the individual responses in both treatment arms. However, a better description of inter-individual variability was obtained by means of a stable Markovian model. Parameter estimation has been carried out according to the empirical Bayes method.

Abstract 4634: Population pharmacokinetic model of ibrutinib, a Bruton's tyrosine kinase inhibitor, for the treatment of B-cell malignancies

Chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) are B-cell malignancies with initial high response rate to chemoimmunotherapy, but are largely considered incurable. Ibrutinib (PCI-32765), an oral Bruton9s tyrosine kinase inhibitor recently approved to treat MCL, is under development for other B-cell malignancies. We developed a population pharmacokinetic (PK) model for describing data collected to date in clinical trials with ibrutinib. Ibrutinib plasma data were available from 3 clinical trials: 1) a phase 1 dose-escalation study in recurrent B-cell malignancies (doses: 1.25-12.5 mg/kg and 560 mg fixed); 2) a phase 1b/2 dose-finding study in CLL (doses: 420 and 840 mg); 3) an open-label, phase 2, fixed-dose study in MCL (dose: 560 mg). Overall, ≈3477 observations were collected in 245 patients following single and repeated daily dosing on different treatment days. A 2-compartment model with sequential zero to first order absorption and first order elimination was implemented. Analyses were performed with a log-transform-both-sides approach. Additive and exponential models were used to describe residual and inter-individual variability, respectively. The first-order conditional estimation method was implemented using NONMEM v 7.1. A linear model constructed with data collected following single and repeated doses of ibrutinib at different dose levels demonstrated that the PK was dose and time independent. Ibrutinib was rapidly absorbed and was characterized by a high oral plasma clearance (≈1000 L/h with between-subject variability of 21.9%; this, for a dose of 560 mg, would lead to an average steady state concentration of ≈22 ng/mL, ie, ≈50 nM) and a high apparent volume of distribution at steady state (≈10,000 L). Though both values are confounded by absolute bioavailability, these values suggest that ibrutinib clearance and volume are high. The half-lives of distribution and terminal phases were estimated to be In conclusion, the proposed population PK model was able to accommodate the plasma concentration-time profiles of ibrutinib across various trials. Citation Format: Eleonora Marostica, Juthamas Sukbuntherng, David Loury, Jan De Jong, Xavier Woot de Trixhie, An Vermeulen, Giuseppe de Nicolao, Susan O9Brien, John C. Byrd, Ranjana Advani, Jesse McGreivy, Italo Poggesi. Population pharmacokinetic model of ibrutinib, a Bruton9s tyrosine kinase inhibitor, for the treatment of B-cell malignancies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4634. doi:10.1158/1538-7445.AM2014-4634