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IONIS‐FXIRX (BAY2306001) is an antisense oligonucleotide that inhibits the synthesis of coagulation factor XI (FXI) and has been investigated in healthy volunteers and patients with end‐stage renal disease (ESRD). FXI‐LICA (BAY2976217) shares the same RNA sequence as IONIS‐FXIRX but contains a GalNAc‐conjugation that facilitates asialoglycoprotein receptor (ASGPR)‐mediated uptake into hepatocytes. FXI‐LICA has been studied in healthy volunteers and is currently investigated in patients with ESRD on hemodialysis. We present a model‐informed bridging approach that facilitates the extrapolation of the dose‐exposure‐FXI relationship from IONIS‐FXIRX to FXI‐LICA in patients with ESRD and, thus, supports the selection of FX‐LICA doses being investigated in patients with ESRD. A two‐compartment pharmacokinetic (PK) model, with mixed first‐ and zero‐order subcutaneous absorption and first‐order elimination, was combined with an indirect response model for the inhibitory effect on the FXI synthesis rate via an effect compartment. This PK/pharmacodynamic model adequately described the median trends, as well as the interindividual variabilities for plasma drug concentration and FXI activity in healthy volunteers of IONIS‐FXIRX and FXI‐LICA, and in patients with ESRD of IONIS‐FXIRX. The model was then used to predict dose‐dependent steady‐state FXI activity following repeat once‐monthly doses of FXI‐LICA in a virtual ESRD patient population. Under the assumption of similar ASGPR expression in patients with ESRD and healthy volunteers, doses of 40 mg, 80 mg, and 120 mg FXI‐LICA are expected to cover the target range of clinical interest for steady‐state FXI activity in the phase IIb study of FXI‐LICA in patients with ESRD undergoing hemodialysis.

Inhibiting the human ether-a-go-go-related gene (hERG)-encoded potassium ion channel is positively correlated with QT-interval prolongation in vivo, which is considered a risk factor for the occurrence of Torsades de Pointes (TdP). A pharmacokinetic/pharmacodynamic model was developed for four compounds that reached the clinic, to relate drug-induced QT-interval change in awake dogs and humans and to derive a translational scaling factor a 1. Overall, dogs were more sensitive than humans to QT-interval change, an a 1 of 1.5 was found, and a 10% current inhibition in vitro produced a higher percent QT-interval change in dogs as compared to humans. The QT-interval changes in dogs were predictive for humans. In vitro and in vivo information could reliably describe the effects in humans. Robust translational knowledge is likely to reduce the need for expensive thorough QT studies; therefore, expanding this work to more compounds is recommended.

Background In the OPTIMIZE study, 4 weeks of roflumilast 250 µg once daily before escalation to the approved 500 µg once daily maintenance dose reduced treatment discontinuations and improved tolerability to roflumilast among patients with chronic obstructive pulmonary disease (COPD). In this study, we present the pharmacokinetic (PK) results and PK/pharmacodynamic (PD) modelling data from OPTIMIZE. Methods OPTIMIZE was a multicentre, double-blind, phase III study in which patients with severe COPD were randomized 1:1:1 to receive oral roflumilast 250 μg once daily, 500 μg every other day, or 500 μg once daily for 4 weeks, followed by 500 μg once daily for 8 weeks. A population PK (popPK) model characterized roflumilast exposure levels (total phosphodiesterase-4 inhibition [tPDE4i]). Furthermore, models characterized the percentage of patients with adverse events (AEs) of interest (PK/AE model), and time to discontinuation due to such AEs (PK/time-to-event model). Results The popPK model adequately described average plasma concentrations and variability from 1238 patients. The percentage of patients with AEs of interest increased with predicted tPDE4i exposure (logit scale slope 0.484; confidence interval 0.262–0.706; p = 2 × 10−5). PK/time-to-event model analysis predicted that patients receiving the 250 μg up-titration regimen had significantly lower discontinuation rates and longer time to discontinuation compared with roflumilast 500 μg every other day or 500 μg once daily (p = 0.0014). Conclusions In this PK/PD model, a 4-week up-titration regimen with roflumilast 250 µg once daily was found to reduce discontinuations and improve tolerability, confirming the main clinical findings of the OPTIMIZE study. However, use of this lower dose as long-term maintenance therapy may not induce sufficient phosphodiesterase-4 inhibition to exert clinical efficacy, supporting the approval of 500 µg as maintenance dose. Trial Registration OPTIMIZE: NCT02165826; REACT: NCT01329029. Electronic supplementary material The online version of this article (10.1007/s40262-018-0671-4) contains supplementary material, which is available to authorized users.

Safety pharmacology studies are performed to assess whether compounds may provoke severe arrhythmias (e.g. Torsades de Pointes, TdP) and sudden death in man. Although there is strong evidence that drugs inducing TdP in man prolong the QT interval in vivo and block the human ether-a-go-go-related gene (hERG) ion channel in vitro, not all drugs affecting the QT interval or the hERG will induce TdP. Nevertheless, QT-interval prolongation and hERG blockade currently represent the most accepted early risk biomarkers to deselect drugs. An extensive pharmacokinetic/pharmacodynamic (PK/PD) analysis is developed to understand moxifloxacin's-induced effects on the QT interval by comparing the relationship between results of an in vitro patch-clamp model to in vivo models. The frequentist and the fully Bayesian estimation procedures were compared and provided similar performances when the best model selected in NONMEM is subsequently implemented in WinBUGS, which guarantees a straightforward calculation of the probability of QT-interval prolongation greater than 2.5 % (10 ms). The use of the percent threshold to account for the intrinsic differences between species and a new calculation of the probability curve are introduced. The concentration providing the 50 % probability indicates that dogs are more sensitive than humans to QT-interval prolongation. However, based on the drug effect, a clear distinction between species cannot be made. An operational PK/PD model of agonism was used to investigate the relationship between effects on the hERG and QT-interval prolongation in dogs. The proposed analysis contributes to establish a translational relationship that could potentially reduce the need for thorough QT studies.

This paper addresses the problem of modelling longitudinal data describing patients’ responses in clinical trials. In particular, a systematic approach relying on a system theoretic paradigm is proposed to deal with contexts where limited physiopathological knowledge is available on disease, drug response, and patients’ characteristics. The model relies on the notion of patient’s health state which summarizes the patient’s condition. In order to cope with the limited number of clinical data usually available, the paper considers a very parsimonious realization where the two state variables are the clinical endpoint and its derivative. Within a population framework, the individual response is modelled as the sum of an individual shift and the average response of subjects belonging to the same study, both described as Markovian processes and identified by empirical Bayes techniques. The proposed approach is validated with experimental data from a Phase II, flexible-dose, depression trial. The dose changes due to the flexible-dose scheme are handled as perturbations on the state. The connection between inter-individual variability and model stability is evaluated showing that the introduction of stable poles helps to describe populations whose range of individual responses does not diverge with time. In this way, good individual fittings and visual predictive checks were obtained for the clinical data. The proposed analysis provides a systematic approach to semi-mechanistic modelling when a precise knowledge of the physiological mechanisms of the disease is incomplete or missing.

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.

SummaryObjective 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. Design and subjects GH responsiveness was measured following the combined administration of GHRH+arginine to 65 PWS adults (24 males, 41 females) aged 18–41·2 years, and 17 age-, gender- and body mass index-matched obese controls. PWS subjects were analysed considering the stratification on different genotypes. Measurements GH response to GHRH+arginine was analysed in terms of peak values, standard area under the curves (AUCs), AUCs due to the stimulus, AUCs of the Instantaneous Secretion Rate signal and Secretion Response Analysis. Results In terms of both peak values and AUC, GH responses were statistically different between PWS UPD15 and PWS DEL15 subjects as well as between PWS UPD15 and obese controls. PWS subjects showed a lower and a more delayed GH response compared with obese controls. Moreover, PWS UPD15 subjects had the most delayed GH response. Conclusions Our findings demonstrate that impaired GH secretion in PWS subjects compared with obese controls regards not only amplitude parameters such as peak value and AUC, but also the shape of the secretory response, which is more delayed, especially for UPD15 subjects.

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.

In the current study, we investigated the metoprolol absorption kinetics of an in-house produced oral sustained-release formulation, matrices manufactured via prilling, and two commercially available formulations, ZOK-ZID® (reservoir) and Slow-Lopresor® (matrix) in both New Zealand White rabbits and Beagle dogs, using a population pharmacokinetic analysis approach. The aim of this study was to compare the in vivo pharmacokinetic (PK) profiles of different formulations based on metoprolol, a selective adrenergic β1-receptor antagonist, in dogs and rabbits and to contrast the observed differences. To that end, metoprolol (50 to 200mg) was administered to 6 Beagle dogs and 6 New Zealand White rabbits as a single intravenous (IV) bolus injection and to 8 dogs and 6 rabbits as an oral modified release formulation. To derive pharmacokinetic parameters from the data, a non-linear mixed-effects model was developed using NONMEM® where the contribution of observations below the limit of detection (BDL, below detection limit) to the parameter estimates was taken into account in the parameter estimation procedure. In both species and for the three modified release formulations, different absorption models were tested to describe the PK of metoprolol following oral dosing. In Beagle dogs, plasma concentration-time profiles were best described using a sequential zero- and first-order absorption model. In rabbits though, the absorption phase was best described using a first-order process only. In both species, the reservoir formulation ZOK-ZID® was behaving quite similarly. In contrast, the absorption properties of both matrix formulations were rather different between species. This study indicates that the PK of the reservoir formulation is similar in both species, even after accounting for the almost completely missed absorption phase in rabbits. The insights gained further illustrate that rabbits are not very well suited to study the PK of the current matrix formulations in view of their less optimal prolonged release characteristics and the resulting fast decline in metoprolol plasma levels.

Ibrutinib is an oral Bruton's tyrosine kinase inhibitor, recently approved for the treatment of mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) patients with at least one prior therapy. We developed a population pharmacokinetic (PK) model for ibrutinib in patients.Ibrutinib PK data (3,477 observations/245 patients) were available from the following clinical studies: (1) A phase I dose-escalation study in recurrent B cell malignancies (dose levels of 1.25-12.5 mg/kg/day and fixed dose of 560 mg/day); (2) a phase II study in MCL (fixed dose level of 560 mg/day); (3) a phase Ib/II dose-finding study in CLL (fixed dose levels of 420 and 840 mg/day). Different compartmental PK models were explored using nonlinear mixed effects modeling.A two-compartment PK model with sequential zero-first-order absorption and first-order elimination was able to characterize the PK of ibrutinib. The compound was rapidly absorbed, had a high oral plasma clearance (approximately 1,000 L/h) and a high apparent volume of distribution at steady state (approximately 10,000 L). PK parameters were not dependent on dose, study, or clinical indication. The fasting state was characterized by a 67 % relative bioavailability compared with the meal conditions used in the trials and administration after a high-fat meal. Body weight and coadministration of antacids marginally increased volume of distribution and duration of absorption, respectively.The proposed population PK model was able to describe the plasma concentration-time profiles of ibrutinib across various trials. The linear model indicated that the compound's PK was dose independent and time independent.

Asthma is an obstructive lung disease where the mechanism of disease progression is not fully understood hence motivating the use of empirical models to describe the evolution of the patient's health state. With reference to placebo response, measured in terms of FEV1 (Forced Expiratory Volume in 1 s), a range of empirical models taken from the literature were compared at a single trial level. In particular, eleven GSK trials lasting 12 weeks in mild-to-moderate asthma were used for the modelling of longitudinal placebo responses. Then, the chosen exponential model was used to carry out an individual participant data meta-analysis on eleven trials. A covariate analysis was also performed to find relevant covariates in asthma to be accounted for in the meta-analysis model. Age, gender, and height were found statistically significant (e.g. the taller the patients the higher the FEV1, the older the patients the lower the FEV1, and females have lower FEV1). By truncating each trial at week 4, the predictive properties of the meta-analysis model were also investigated, showing its ability to predict long-term FEV1 response from truncated trials. Summarizing, the study suggests that: (i) the exponential model effectively describes the placebo response; (ii) the meta-analysis approach may prove helpful to simulate new trials as well as to reduce trial duration in view of its predictive properties; (iii) the inclusion of available covariates within the meta-analysis model provides a reduction of the inter-individual variability.

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.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.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 (p0.0001), 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 (p0.001).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.

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. Clinical Pharmacology & Therapeutics (2012); 91 5, 863–871. doi:10.1038/clpt.2011.322

Ibrutinib (IBRU) is an oral Bruton's 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 O'Brien, 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.

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 Bruton's 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 O'Brien, John C. Byrd, Ranjana Advani, Jesse McGreivy, Italo Poggesi. Population pharmacokinetic model of ibrutinib, a Bruton's 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