Effects of Sport Climbing on Multiple Sclerosis.

Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease of the central nervous system (CNS) with different types of disease courses (relapsing-remitting, secondary-progressive, primary progressive) that leads to physical as well as mental disability. The symptoms comprise paresis or/and paralysis, ataxia, bladder dysfunction, visual problems as well as effects on cognition. There is limited data regarding the possible effects of sport climbing respectively therapeutic climbing on patients with MS.

Post-prostatectomy radiotherapy adversely affects urinary continence irrespective of radiotherapy regime.

Purpose: To investigate the influence of different postoperative radiotherapy (RT) regimes on post-prostatectomy continence and QoL.

Methods: Men after prostatectomy (RP) and RT were assigned in adjuvant (ART), early salvage (ESRT) and salvage radiotherapy (SRT) groups depending on time of initiation, indication and pre-RT-PSA (≤/>0.5 ng/ml).

Good Practices in Model-Informed Drug Discovery and Development: Practice, Application, and Documentation.

This document was developed to enable greater consistency in the practice, application, and documentation of Model-Informed Drug Discovery and Development (MID3) across the pharmaceutical industry. A collection of "good practice" recommendations are assembled here in order to minimize the heterogeneity in both the quality and content of MID3 implementation and documentation. The three major objectives of this white paper are to: i) inform company decision makers how the strategic integration of MID3 can benefit R&D efficiency; ii) provide MID3 analysts with sufficient material to enhance the planning, rigor, and consistency of the application of MID3; and iii) provide regulatory authorities with substrate to develop MID3 related and/or MID3 enabled guidelines.

Early combined parenteral and enteral nutrition for pancreaticoduodenectomy - Retrospective cohort analysis.

Background: Suggested guidelines for nutritional support after pancreaticoduodenectomy are still controversial. Recent evidence suggests that combining enteral nutrition (EN) with parenteral nutrition (PN) improves outcome. For ten years, patients have been treated with Early Combined Parenteral and Enteral Nutrition (ECPEN) after PD.

Pharmacometrics: opportunity for reducing disease burden in the developing world: the case of Africa.

Pharmacometricians are virtually nonexistent in Africa and the developing world. The unrelenting burden of infectious diseases, which are often treated using medicines with narrow effectiveness and safety dose ranges, and the growing prevalence and recognition of non-communicable diseases represent significant threats for the patients, although affording an opportunity for advancing science. This article outlines the case for pharmacometricians to redirect their expertise to focus on the disease burden affecting the developing world.

Animal Health Modeling & Simulation Society: a new society promoting model-based approaches in veterinary pharmacology.

The Animal Health Modeling & Simulation Society (AHM&S) is a newly founded association (2012) that aims to promote the development, application, and dissemination of modeling and simulation techniques in the field of Veterinary Pharmacology and Toxicology. The association is co-chaired by Pr. Johan Gabrielsson (Europe), Pr.

Pharmacokinetic similarity of biologics: analysis using nonlinear mixed-effects modeling.

Our objective was to show, using two examples, that a pharmacokinetic (PK) similarity analysis can be performed using nonlinear mixed-effects models (NLMEM). We used two studies that compared different biosimilars: a three-way crossover trial with somatropin and a parallel-group trial with epoetin-α. For both data sets, the results of NLMEM-based analysis were compared with those of noncompartmental analysis (NCA).

Modelling the genesis and treatment of cancer: the potential role of physiologically based pharmacodynamics.

Physiologically based modelling of pharmacodynamics/toxicodynamics requires an a priori knowledge on the underlying mechanisms causing toxicity or causing the disease. In the context of cancer, the objective of the expert meeting was to discuss the molecular understanding of the disease, modelling approaches used so far to describe the process, preclinical models of cancer treatment and to evaluate modelling approaches developed based on improved knowledge. Molecular events in cancerogenesis can be detected using 'omics' technology, a tool applied in experimental carcinogenesis, but also for diagnostics and prognosis.

Incorporating physiological and biochemical mechanisms into pharmacokinetic-pharmacodynamic models: a conceptual framework.

The aim of this conceptual framework paper is to contribute to the further development of the modelling of effects of drugs or toxic agents by an approach which is based on the underlying physiology and pathology of the biological processes. In general, modelling of data has the purpose (1) to describe experimental data, (2a) to reduce the amount of data resulting from an experiment, e.g.

Population pharmacokinetics of ibandronate in Caucasian and Japanese healthy males and postmenopausal females.

Introduction: Ibandronate is a potent, nitrogen-containing bisphosphonate that is licensed as a once-monthly oral preparation and is currently in clinical development as a novel intermittent intravenous (i.v.) injection in osteoporosis.

Modelling response time profiles in the absence of drug concentrations: definition and performance evaluation of the K-PD model.

The plasma concentration-time profile of a drug is essential to explain the relationship between the administered dose and the kinetics of drug action. However, in some cases such as in pre-clinical pharmacology or phase-III clinical studies where it is not always possible to collect all the required PK information, this relationship can be difficult to establish. In these circumstances several authors have proposed simple models that can analyse and simulate the kinetics of the drug action in the absence of PK data.

Non-linear mixed effects modeling - from methodology and software development to driving implementation in drug development science.

Few scientific contributions have made significant impact unless there was a champion who had the vision to see the potential for its use in seemingly disparate areas-and who then drove active implementation. In this paper, we present a historical summary of the development of non-linear mixed effects (NLME) modeling up to the more recent extensions of this statistical methodology. The paper places strong emphasis on the pivotal role played by Lewis B.

Modelling and simulation in the development and use of anti-cancer agents: an underused tool?

To help identify the role of modelling and simulation in the development of anti-cancer agents, their main advantages and the obstacles to their rational use, an expert meeting was organized by COST B15. This manuscript presents a synthesis of views expressed at that meeting and indicates future directions. The manuscript also shows some examples where modelling and simulation have proven to be of relevant value in the drug development process for anti-cancer agents.

A semimechanistic and mechanistic population PK-PD model for biomarker response to ibandronate, a new bisphosphonate for the treatment of osteoporosis.

Aims: Ibandronate, a highly potent nitrogen-containing bisphosphonate, is the subject of an ongoing clinical development programme that aims to maximize the potential of simplified, less frequent oral and intravenous (i.v.) administration in osteoporosis.

Clinical pharmacokinetic/pharmacodynamic and physiologically based pharmacokinetic modeling in new drug development: the capecitabine experience.

Preclinical studies, along with Phase I, II, and III clinical trials demonstrate the pharmacokinetics, pharmacodynamics, safety and efficacy of a new drug under well controlled circumstances in relatively homogeneous populations. However, these types of studies generally do not answer important questions about variability in specific factors that predict pharmacokinetic and pharmacodynamic (PKPD) activity, in turn affecting safety and efficacy. Semi-physiological and clinical PKPD modeling and simulation offer the possibility of utilizing data obtained in the laboratory and the clinic to make accurate characterizations and predictions of PKPD activity in the target population, based on variability in predictive factors.

Population pharmacokinetics and concentration-effect relationships of capecitabine metabolites in colorectal cancer patients.

Aims: To assess the relationship between systemic exposure to capecitabine metabolites and parameters of efficacy and safety in patients with advanced or metastatic colorectal cancer from two phase III studies.

Methods: Concentration-effect analyses were based on data from 481 patients (248 males, 193 females; age range 27-86 years) in two phase III studies. Plasma concentration-time data for 5'-deoxy-5-fluorouridine (5'-DFUR), 5-fluorouracil (5-FU) and alpha-fluoro-beta-alanine (FBAL) were obtained from sparse blood samples collected within the time windows 0.

Population pharmacokinetic analysis of the major metabolites of capecitabine.

Capecitabine has been developed as an orally administered tumor selective fluoropyrimidine for use in the treatment of breast and colorectal cancer. The metabolic pathway for capecitabine includes 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-deoxy-5-fluorouridine (5'-DFUR), which is then converted to the pharmacologically active agent 5-fluorouracil (5-FU). A previous analysis showed that systemic exposure to 5'-DFUR and alpha-fluoro-beta-alanine (FBAL), a catabolite of 5-FU, was predictive of dose limiting toxicities.

Role of modelling and simulation in Phase I drug development.

Although the use of pharmacokinetic/pharmacodynamic modelling and simulation (M&S) in drug development has increased during the last decade, this has most notably occurred in patient studies using the population approach. The role of M&S in Phase I, although of longer history, does not presently have the same impact on drug development. However, trends such as the increased use of biomarkers and clinical trial simulation as well as adoption of the learn/confirm concept can be expected to increase the importance of modelling in Phase I.

Pharmacometrics: modelling and simulation tools to improve decision making in clinical drug development.

There is broad recognition within the pharmaceutical industry that the drug development process, especially the clinical part of it, needs considerable improvement to cope with rapid changes in research and health care environments. Modelling and simulation are mathematically founded techniques that have been used extensively and for a long time in other areas than the pharmaceutical industry (e.g.

Population pharmacokinetics of levodopa in patients with Parkinson's disease treated with tolcapone.

Objective: To use pharmacostatistical models to evaluate the overall exposure of patients with Parkinson's disease to levodopa in the presence and absence of tolcapone.

Methods: Four hundred twelve patients with Parkinson's disease with fluctuating and nonfluctuating responses to levodopa participated in three multicentered, parallel, double-blind, placebo-controlled dose-finding studies and received either placebo or tolcapone in addition to levodopa-decarboxylase inhibitor therapy. Sparse blood samples were obtained from 393 patients for levodopa and 3-O-methyldopa assay, and the data were analyzed with use of the NONMEM program.

Pharmacokinetic/pharmacodynamic modeling in drug development.

We propose a framework for considering the role of pharmacokinetic/pharmacodynamic modeling in drug development and an appraisal of its current and potential impact on that activity. After some introduction, definitions, and background information on drug development, we discuss subject-matter models that underlie pharmacokinetic/pharmacodynamic modeling and show how they determine appropriate statistical models. We discuss the broad role modeling can play in drug development, enhancing primarily the "learning" steps, i.