A Population Pharmacokinetic and Pharmacodynamic Model of CKD-519

CKD-519 is a selective and potent cholesteryl ester transfer protein (CETP) inhibitor that is being developed for dyslipidemia. Even though CKD-519 has shown potent CETP inhibition, the exposure of CKD-519 was highly varied, depending on food and dose. For highly variable exposure drugs, it is crucial to use modeling and simulation to plan proper dose selection. This study aimed to develop population pharmacokinetic (PK) and pharmacodynamics (PD) models of CKD-519 and to predict the proper dose of CKD-519 to achieve target levels for HDL-C and LDL-C using results from multiple dosing study of CKD-519 with a standard meal for two weeks in healthy subjects. The results showed that a 3-compartment with Erlang’s distribution, followed by the first-order absorption, adequately described CKD-519 PK, and the bioavailability, which decreased by dose and time was incorporated into the model (NONMEM version 7.3). After the PK model development, the CETP activity and cholesterol (HDL-C and LDL-C) levels were sequentially modeled using the turnover model, including the placebo effect. According to PK-PD simulation results, 200 to 400 mg of CKD-519 showing a 40% change in HDL-C and LDL-C from baselines was recommended for proof of concept studies in patients with dyslipidemia.

Quantitative analysis of the effect of fraction of inspired oxygen on peripheral oxygen saturation in healthy volunteers

Background The international organization for standardization (ISO) 80601-2-61 dictates that the accuracy of a pulse oximeter should be assessed by a controlled desaturation study. We aimed to characterize the relationship between the fraction of inspired oxygen (FiO 2 ) and peripheral oxygen saturation (SpO 2 ) using a turnover model by retrospectively analyzing the data obtained from previous controlled desaturation studies. We also measured the changes in biomarkers expected to be related to hypoxia (i.e., lactate, carboxyhemoglobin (COHb), and methemoglobin (MetHb)) in response to short-term exposure to hypoxia.Methods Volunteers were exposed to various levels of induced hypoxia over 70−100% arterial oxygen saturation (SaO 2 ). The study period consisted of two rounds of hypoxia and the volunteers were maintained in room air between each round. FiO 2 and SpO 2 were recorded continuously during the study period. A population pharmacodynamic analysis was performed with the NONMEM VII level 4 (ICON Development Solutions, Ellicott City, MD, USA). Lactate, COHb, and MetHb were measured using a CO-oximeter.Results In total, 2899 SpO 2 data points obtained from 20 volunteers were used to determine the pharmacodynamic characteristics. The pharmacodynamic parameters were as follows: k out = 0.942 1/min, Imax = 0.802, IC 50 = 85.3%, γ = 27.3. The changes in SpO 2 due to decreases in FiO 2 well explained by the turnover model with inhibitory function as a sigmoidal model. As SpO 2 decreased, lactate and COHb increased as a whole, and COHb showed the best correlation (Pearson’s correlation, R 2 =0.3263, P < 0.0001).Conclusion The potency of FiO 2 required to reduce SpO 2 from 100% to 70% was 14.7%. Carboxyhemoglobin has the potential to be a useful biomarker for acute hypoxia.

Factors Driving Employeesʼ Intention to Stay

This study investigates factors influencing employeesʼ intention to stay. Therefore, we developed and analyzed a retention model relating to the voluntary turnover model ( Allen et al., 2010 ). We assume that the decision processes for retention and turnover might be similar. Differences can be found in the initiating factors (the drivers for leaving and staying). We combine empirically evident retention drivers, which are weighted regarding their implementation in the organization, with process variables from the turnover model. The model is tested with a sample of 881 German employees using structural equation modeling. Results show a significant indirect effect of the retention drivers on the intention to stay. The influence is mediated by the key attitudes job satisfaction and affective commitment. A psychological contract breach influences the relationship between job satisfaction and intention to stay, but not between affective commitment and intention to stay. We integrated research from Human Resource Management (HRM) into the framework of voluntary turnover.