Publications by authors named "Joerg Lippert"

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 with an estimated glomerular filtration rate (eGFR) of 25 to 90 mL/min/1.73 m , a urine albumin-creatinine ratio (UACR) of 30 to 5000 mg/g, and serum potassium ≤ 4.

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Introduction: The European Sleep Apnea Database was used to identify distinguishable obstructive sleep apnoea (OSA) phenotypes and to investigate the clinical outcome during positive airway pressure (PAP) treatment.

Method: Prospective OSA patient data were recruited from 35 sleep clinics in 21 European countries. Unsupervised cluster analysis (anthropometrics, clinical variables) was performed in a random sample (n=5000).

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

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Persistent pulmonary hypertension of the newborn (PPHN) is a complication of term birth, characterized by persistent hypoxemia secondary to failure of normal postnatal reduction in pulmonary vascular resistance, with potential for short- and long-term morbidity and mortality. The primary pharmacologic goal for this condition is reduction of the neonate's elevated pulmonary vascular resistance with inhaled nitric oxide, the only approved treatment option. Various adjunctive, unapproved therapeutics have been trialed with mixed results, likely related to challenges with recruiting the full, intended patient population into clinical studies.

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Background & Aims: Decompensation is a hallmark of disease progression in cirrhotic patients. Early detection of a phase transition from compensated cirrhosis to decompensation would enable targeted therapeutic interventions potentially extending life expectancy. This study aims to (a) identify the predictors of decompensation in a large, multicentric cohort of patients with compensated cirrhosis, (b) to build a reliable prognostic score for decompensation and (c) to evaluate the score in independent cohorts.

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Background: 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 in patients with CKD and type 2 diabetes mellitus in FIDELIO-DKD, where 5734 patients were randomized 1:1 to receive either finerenone or placebo, with a median follow-up of 2.6 years. Doses of finerenone 10 or 20 mg once daily were titrated based on (serum) potassium and estimated glomerular filtration rate.

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

Methods: Nonlinear mixed-effects population pharmacokinetic models were used to analyze the pharmacokinetics in FIDELIO-DKD, sparsely sampled in all subjects receiving finerenone.

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Introduction: The acute respiratory distress syndrome (ARDS) is a highly relevant entity in critical care with mortality rates of 40%. Despite extensive scientific efforts, outcome-relevant therapeutic measures are still insufficiently practised at the bedside. Thus, there is a clear need to adhere to early diagnosis and sufficient therapy in ARDS, assuring lower mortality and multiple organ failure.

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Early indication of late-stage failure of novel candidate drugs could be facilitated by continuous integration, assessment, and transfer of knowledge acquired along pharmaceutical development programs. We here present a translational systems pharmacology workflow that combines drug cocktail probing in a specifically designed clinical study, physiologically based pharmacokinetic modeling, and Bayesian statistics to identify and transfer (patho-)physiological and drug-specific knowledge across distinct patient populations. Our work builds on two clinical investigations, one with 103 healthy volunteers and one with 79 diseased patients from which we systematically derived physiological information from pharmacokinetic data for a reference probe drug (midazolam) at the single-patient level.

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A physiologically based kidney model was developed to analyze the renal excretion and kidney exposure of hydrophilic agents, in particular contrast media, in rats. In order to study the influence of osmolality and viscosity changes, the model mechanistically represents urine concentration by water reabsorption in different segments of kidney tubules and viscosity dependent tubular fluid flow. The model was established using experimental data on the physiological steady state without administration of any contrast media or drugs.

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Active processes involved in drug metabolization and distribution mediated by enzymes, transporters, or binding partners mostly occur simultaneously in various organs. However, a quantitative description of active processes is difficult because of limited experimental accessibility of tissue-specific protein activity in vivo. In this work, we present a novel approach to estimate in vivo activity of such enzymes or transporters that have an influence on drug pharmacokinetics.

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Rivaroxaban is an oral, direct Factor Xa inhibitor approved in the European Union and several other countries for the prevention of venous thromboembolism in adult patients undergoing elective hip or knee replacement surgery and is in advanced clinical development for the treatment of thromboembolic disorders. Its mechanism of action is antithrombin independent and differs from that of other anticoagulants, such as warfarin (a vitamin K antagonist), enoxaparin (an indirect thrombin/Factor Xa inhibitor) and dabigatran (a direct thrombin inhibitor). A blood coagulation computer model has been developed, based on several published models and preclinical and clinical data.

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Today, in silico studies and trial simulations already complement experimental approaches in pharmaceutical R&D and have become indispensable tools for decision making and communication with regulatory agencies. While biology is multiscale by nature, project work, and software tools usually focus on isolated aspects of drug action, such as pharmacokinetics at the organism scale or pharmacodynamic interaction on the molecular level. We present a modeling and simulation software platform consisting of PK-Sim(®) and MoBi(®) capable of building and simulating models that integrate across biological scales.

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Natural scientists such as physicists pioneered the sharing of computing resources, which resulted in the Grid. The inter domain transfer process of this technology has been an intuitive process. Some difficulties facing the life science community can be understood using the Bozeman's "Effectiveness Model of Technology Transfer".

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