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Purpose: Currently, body weight-based dosing of rifampicin is recommended. But lately, fat-free mass (FFM) was reported to be superior to body weight (BW). The present evaluation aimed to assess the influence of body mass-related covariates on rifampicin's pharmacokinetics (PK) parameters in more detail using non-linear mixed effects modeling (NLMEM). Methods: Twenty-four healthy Caucasian volunteers were enrolled in a bioequivalence study, each receiving a test and a reference tablet of 600 mg of rifampicin separated by a wash-out period of at least 9 days. Monolix version 2023R1 was used for NLMEM. Monte Carlo simulations (MCS) were performed to visualize the relationship of body size descriptors to the exposure to rifampicin. Results: A one-compartment model with nonlinear (Michaelis–Menten) elimination and zero-order absorption kinetics with a lag time best described the data. The covariate model including fat-free mass (FFM) on volume of distribution (V/F) and on maximum elimination rate (Vmax/F) lowered the objective function value (OFV) by 56.4. The second-best covariate model of sex on V/F and Vmax/F and BW on V/F reduced the OFV by 51.2. The decrease in unexplained inter-individual variability on Vmax/F in both covariate models was similar. For a given dose, MCS showed lower exposure to rifampicin with higher FFM and accordingly in males compared to females with the same BW and body height. Conclusion: Our results indicate that beyond BW, body composition as reflected by FFM could also be relevant for optimized dosing of rifampicin. This assumption needs to be studied further in patients treated with rifampicin. [ABSTRACT FROM AUTHOR]

Introduction: Noscapine is a commonly used cough suppressant, with ongoing research on its anti-inflammatory and anti-tumor properties. The drug has a pronounced pharmacokinetic variability. Objective: This evaluation aims to describe the pharmacokinetics of noscapine using a semi-mechanistic population pharmacokinetic model and to identify covariates that could explain inter-individual pharmacokinetic variability. Methods: Forty-eight healthy volunteers (30 men and 18 women, mean age 33 years) were enrolled in a randomized, two-period, two-stage, crossover bioequivalence study of noscapine in two different liquid formulations. Noscapine plasma concentrations following oral administration of noscapine 50 mg were evaluated by a non-compartmental analysis and by a population pharmacokinetic model separately. Results: Compared to the reference formulation, the test formulation exhibited ratios (with 94.12% confidence intervals) of 0.784 (0.662–0.929) and 0.827 (0.762–0.925) for peak plasma concentrations and area under the plasma concentration–time curve, respectively. Significant differences in p values (< 0.01) were both observed when comparing peak plasma concentrations and area under the plasma concentration–time curve between CYP2C9 genotype-predicted phenotypes. A three-compartmental model with zero-order absorption and first-order elimination process best described the plasma data. The introduction of a liver compartment was able to describe the profound first-pass effect of noscapine. Total body weight and the CYP2C9 genotype-predicted phenotype were both identified as significant covariates on apparent clearance, which was estimated as 958 ± 548 L/h for extensive metabolizers (CYP2C9*1/*1 and *1/*9), 531 ± 304 L/h for intermediate metabolizers with an activity score of 1.5 (CYP2C9*1/*2), and 343 ± 197 L/h for poor metabolizers and intermediate metabolizers with an activity score of 1.0 (CYP2C9*1/*3, *2/*3, and*3/*3). Conclusion: The current work is expected to facilitate the future pharmacokinetic/pharmacodynamic development of noscapine. This study was registered prior to starting at "Deutsches Register Klinischer Studien" under registration no. DRKS00017760. [ABSTRACT FROM AUTHOR]

Introduction: A medicine's acceptability is likely to have significant impact on pediatric adherence. The importance is underlined in EMA and FDA guidance on this topic where investigation of acceptability is stated as a regulatory expectation. Demonstrating acceptability can be challenging given there is no globally recognized definition and no standardized testing methodology or assessment criteria. Palatability and swallowability are generally recognized as important elements of acceptability, and this work proposes a definition of acceptability using these elements to give a composite endpoint for acceptability for pediatric subjects across all age ranges. Methods: This composite acceptability endpoint is based on validated assessment methods for swallowability and palatability in children of different age groups using different galenic placebo formulations, in line with criteria proposed by EMA for assessing acceptability in children from newborn to 18 years of age. Data from two studies investigating mini-tablets, oblong tablets, orodispersible films, and syrup were analyzed to establish the validity, expediency, and applicability of the suggested composite acceptability assessment tool. Results: The new composite endpoint is an efficient and suitable way to distinguish preferences of oral formulations: Mini-tablets and oblong tablets had significantly better acceptability than syrups and orodispersible films. Conclusion: Since the suggested acceptability criteria takes both swallowability and palatability into account as composite endpoint, it is highly sensitive to detect acceptability differences between oral formulations. It is a well-defined valid approach, which meets regulatory requirements in an appropriate and comprehensive manner and may in future serve as a pragmatic, standardized method to assess and compare acceptability of pediatric formulations with active substances. [ABSTRACT FROM AUTHOR]

Background: The presence of pulmonary hypertension (PH) severely aggravates the clinical course of heart failure with preserved ejection fraction (HFPEF) resulting in substantial morbidity and mortality. So far, neither established heart failure therapies nor pulmonary vasodilators have proven to be effective for this condition. Riociguat (Adempas®, BAY 63-2521), a stimulator of soluble guanylate cyclase, is a novel pulmonary and systemic vasodilator that has been approved for the treatment of precapillary forms of PH. With regard to postcapillary PH, the DILATE-1 study was a multicenter, double-blind, randomized, placebo-controlled single-dose study in subjects with PH associated with HFPEF. Although there was no significant change in the primary outcome measure, peak decrease in mean pulmonary artery pressure with riociguat versus placebo, riociguat significantly increased stroke volume without changing heart rate, pulmonary artery wedge pressure, transpulmonary pressure gradient or pulmonary vascular resistance. The present study is designed to test the efficacy of long-term treatment with riociguat in patients with PH associated with HFPEF. Methods/study design: The DYNAMIC study is a randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical phase IIb trial evaluating the efficacy, safety and kinetics of riociguat in PH-HFPEF patients. The drug will be given over 26 weeks to evaluate the effects of riociguat versus placebo. The primary efficacy variable will be the change from baseline in cardiac output at rest, measured by right heart catheter after 26 weeks of study drug treatment. Additional efficacy variables will be changes from baseline in further hemodynamic parameters, changes in left and right atrial area, right ventricular volume, as well as right ventricular ejection fraction measured by cardiac magnetic resonance imaging, and changes from baseline in World Health Organization (WHO) class and N-terminal prohormone B-type natriuretic peptide (NT-proBNP). The trial was registered on 25 August 2014 (EudraCT Number: 2014-003055-60; ). [ABSTRACT FROM AUTHOR]

Purpose: This phase I study was performed in volunteers of Japanese ethnicity to compare pharmacokinetic data after infusion of 6 % hydroxyethyl starch (HES) 130/0.4 with historical data of Caucasians. Methods: In an open-label, uncontrolled, single-center study, 12 healthy male Japanese volunteers received single intravenous infusions of 500 ml 6 % HES 130/0.4 (Voluven 6 %; Fresenius Kabi Deutschland, Bad Homburg, Germany) over 30 min. Results: Plasma concentration of 6 % HES 130/0.4 was highest at end of infusion (5.53 ± 0.55 mg/ml) and decreased following a biphasic manner. Total plasma clearance and rapid and slow elimination half-lives obtained by a two-compartment model were 1.14 ± 0.16 l/h, 1.12 ± 0.26 h, and 9.98 ± 2.38 h, respectively, and the volume of distribution was 4.76 ± 0.64 l. Mean area under the concentration-time curve was 26.7 ± 3.75 mg/ml h. The total amount of HES excreted into urine was 59.4 % of the applied dose. Hemodilution was observed in all 12 subjects as indicated by a decrease of hemoglobin from 15.5 ± 0.4 g/dl at baseline to 13.8 ± 0.4 g/dl after the end of infusion. Adverse events in this study refer to changes of laboratory parameters and were assessed as not clinically relevant. Conclusion: Single administration of a 500 ml solution of 6 % HES 130/0.4 was confirmed to be safe and tolerable in healthy male Japanese subjects. A rapid renal excretion was observed within 24 h after drug administration, accounting for 96 % of the total amount excreted. A comparison with pharmacokinetic data derived from Caucasians did not reveal significant differences to Japanese and confirmed the good tolerability in both ethnic groups. [ABSTRACT FROM AUTHOR]