Abstract IONIS‐FXI RX (BAY2306001) is an antisense oligonucleotide that inhibits the synthesis of coagulation factor XI (FXI) and has been investigated in healthy volunteers patients with end‐stage renal disease (ESRD). FXI‐LICA (BAY2976217) shares same RNA sequence as but contains a GalNAc‐conjugation facilitates asialoglycoprotein receptor (ASGPR)‐mediated uptake into hepatocytes. studied currently ESRD on hemodialysis. We present model‐informed bridging approach extrapolation...

Abstract Background and Purpose Cotadutide is a dual GLP‐1 glucagon receptor agonist with balanced agonistic activity at each designed to harness the advantages on promoting liver health, weight loss glycaemic control. We characterised effects of cotadutide glucose, insulin, GLP‐1, GIP, over time in quantitative manner using our glucose dynamics systems model (4GI model), combination clinical data from multiple ascending dose/Phase 2a (MAD/Ph2a) study overweight obese subjects history Type 2...

Finerenone is a nonsteroidal selective mineralocorticoid receptor antagonist (MRA) that demonstrated efficacy in delaying the progression of chronic kidney disease (CKD) and reducing cardiovascular events patients with CKD type 2 diabetes mellitus FIDELIO-DKD, where 5734 were randomized 1:1 to receive either finerenone or placebo, median follow-up 2.6 years. Doses 10 20 mg once daily titrated based on (serum) potassium estimated glomerular filtration rate. The MRA mode action increases...

Previously, a systems pharmacology model was developed characterizing drug effects on the interrelationship between mean arterial pressure (MAP), cardiac output (CO) and total peripheral resistance (TPR). The present investigation aims to (i) extend previously by parsing CO into heart rate (HR) stroke volume (SV) (ii) evaluate if mechanism of action (MoA) new compounds can be elucidated using only HR MAP measurements.

Finerenone (BAY 94-8862) is a potent non-steroidal, selective mineralocorticoid receptor antagonist being developed for the treatment of patients with type 2 diabetes and chronic kidney disease. We present population pharmacokinetics pharmacodynamics (PD) analysis efficacy safety markers based on data from two clinical phase IIb studies: ARTS-DN (NCT01874431) Japan (NCT01968668). The finerenone were adequately characterized, estimated glomerular filtration rate (eGFR) body weight as...

Abstract Aims To perform dose–exposure–response analyses to determine the effects of finerenone doses. Materials and Methods Two randomized, double‐blind, placebo‐controlled phase 3 trials enrolling 13 026 randomized participants with type 2 diabetes (T2D) from global sites, each an estimated glomerular filtration rate (eGFR) 25 90 mL/min/1.73 m , a urine albumin‐creatinine ratio (UACR) 30 5000 mg/g, serum potassium ≤ 4.8 mmol/L were included. Interventions titrated doses 10 or 20 mg versus...

The homeostatic control of arterial BP is well understood with changes in resulting from cardiac output (CO) and/or total peripheral resistance (TPR). A mechanism-based and quantitative analysis drug effects on this interrelationship could provide a basis for the prediction BP. Hence, we aimed to develop pharmacokinetic-pharmacodynamic (PKPD) model rats that be used characterize cardiovascular drugs different mechanisms action (MoA) between BP, CO TPR.The six diverse MoA, (amlodipine,...

Finerenone reduces the risk of kidney failure in patients with chronic disease and type 2 diabetes. Changes urine albumin-to-creatinine ratio (UACR) estimated glomerular filtration rate (eGFR) are surrogates for failure. We performed dose–exposure–response analyses to determine effects finerenone on these presence absence sodium glucose co-transporter-2 inhibitors (SGLT2is) using individual patient data from FIDELIO-DKD study. Non-linear mixed-effects population...

In pharmacometric modeling, it is often important to know whether the data sufficiently rich identify parameters of a proposed model. While may be possible assess this based on results model fit, difficult disentangle identifiability issues from other fitting and numerical problems. Furthermore, can value ascertain beforehand. This paper compares four methods for parameter identifiability, namely Differential Algebra Identifiability SYstems (DAISY), sensitivity matrix method (SMM), Aliasing,...

Pharmacokinetic/pharmacodynamic (PK/PD) modeling benefits from the inclusion of covariates to enhance predictive capabilities and explain variability. This study uses simulations illustrate overadjustment bias in PK/PD when incorporating time-varying or postbaseline that are affected by treatment demonstrates use mediation analysis estimate percentage drug effect explained intermediate (time-varying covariate). Overadjustment is a term used epidemiology refer situation where introduced...

Finerenone is a nonsteroidal selective mineralocorticoid receptor antagonist that recently demonstrated efficacy in delaying chronic kidney disease progression and reducing cardiovascular events patients with type 2 diabetes FIDELIO-DKD, where 5734 were randomized 1:1 to receive either titrated finerenone doses of 10 or 20 mg once daily placebo, median follow-up 2.6 years. Nonlinear mixed-effects population pharmacokinetic models used analyze the pharmacokinetics sparsely sampled all...

Objectives The primary objective of this analysis was to characterise the steady-state pharmacokinetics (PK) ethinylestradiol (EE) and drospirenone (DRSP) in a randomised Phase III study that investigated contraceptive efficacy safety three different regimens EE 20 µg/DRSP 3 mg. Methods Non-linear mixed-effects modelling used develop population PK models for DRSP. DRSP serum concentrations were determined blood samples obtained from approximately 1100 healthy young women on two occasions...

Reboxetine is a clinically used antidepressant and racemic mixture of two enantiomers, SS- RR-reboxetine. The aim the work described in this manuscript was to determine kinetics binding RR- SS-reboxetine human noradrenaline transporter (hNET).

A complicating factor in the translational pharmacology of sphingosine 1-phosphate agonists is that they exert their pharmacological effect through respective phosphate metabolites, which are formed by enzyme kinase (S1PHK). In this investigation, we present a semimechanistic pharmacokinetic model for interconversion S1PHK substrates and phosphates rats humans with aim investigating whether characterization rate phosphorylation blood platelets constitutes basis interspecies scaling using...

Abstract Obesity has become a major public health concern worldwide. Pharmacological interventions with the glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) have shown promising results in facilitating weight loss and improving metabolic outcomes individuals obesity. Quantifying drug effects of GLP‐1RAs on energy intake (EI) body (BW) using QSP modeling approach can further increase mechanistic understanding these effects, support obesity development. An extensive literature‐based...

Cardiac and cerebrovascular events in hypertensive patients are related to specific features of the 24-hour diurnal blood pressure (BP) profile (i.e., daytime nighttime BP, nocturnal dip (ND), morning surge (MS)). This investigation aimed characterize systolic BP (SBP) with parameters that correlate directly SBP, ND, MS using nonlinear mixed effects modeling. Ambulatory SBP measurements (ABPM) 196 nontreated subjects from three ethnic groups were available. A population model was...

Sphingosine 1-phosphate (S1P) receptor agonists are associated with cardiovascular effects in humans. This study aims to develop a systems pharmacology model identify the site of action (i.e., primary hemodynamic response variable) S1P agonists, and predict, quantitative manner, novel vivo. The once-daily fingolimod (0, 0.1, 0.3, 1, 3, 10 mg/kg) siponimod (3 15 were continuously recorded spontaneously hypertensive rats Wistar-Kyoto rats. results analyzed using recently developed model, i.e....

Aims This investigation aimed to quantitatively characterize the relationship between gonadotropin‐releasing hormone agonist leuprorelin, testosterone (T) and prostate specific antigen (PSA) concentrations over time, aid identification of a target T concentration that optimises balance benefits suppression whilst reducing risk side effects related futile over‐suppression. Methods Data from single dose study investigate effect leuprorelin in 6‐month depot formulation on PSA cancer patients...

Usually limited information about the frequency of migraine episodes is derived from acute trials. However, design some studies such that they also provide relevant attack without bias associated with patient expectations treatment effect between attacks during prophylaxis Using clinical data repeated treated placebo, naratriptan 2.5 mg or sumatriptan 100 mg, we show and interictal periods can be described by a random probability distribution. Based on gamma distribution, mean interval was...

Abstract The vascular adhesion protein-1 (VAP-1) inhibitor ASP8232 reduces albuminuria in patients with type 2 diabetes and chronic kidney disease. A mechanism-based model was developed to quantify the effects of on renal markers from a placebo-controlled Phase study diabetic disease 12 weeks treatment. incorporated available pharmacokinetic, pharmacodynamic (plasma VAP-1 concentration activity), serum urine creatinine, cystatin C, albumin excretion rate, urinary albumin-to-creatinine ratio,...