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.

IONIS-FXI RX (BAY2306001) is an antisense oligonucleotide that inhibits the synthesis of coagulation factor XI and has been investigated in healthy volunteers and end-stage renal disease (ESRD) patients. FXI-LICA (BAY2976217) shares the same RNA sequence as IONIS-FXI RX 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 ESRD patients on hemodialysis.We present a model-informed bridging approach that facilitates the extrapolation of the dose-exposure-FXI relationship from IONIS-FXI RX to FXI-LICA in ESRD patients and, thus, supports the selection of FX-LICA doses being investigated in ESRD patients. A two-compartment 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/PD model adequately described the median trends, as well as the inter-individual variabilities for plasma drug concentration and FXI activity in healthy volunteers of IONIS-FXI RX and FXI-LICA, and in ESRD patients of IONIS-FXI RX . The Accepted ArticleThis article is protected by copyright. All rights reserved 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 ESRD patients and healthy volunteers, doses of 40mg, 80mg, and 120mg FXI-LICA are expected to cover the target range of clinical interest for steadystate FXI activity in the Phase 2b study of FXI-LICA in ESRD patients undergoing hemodialysis.

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.

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