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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. Keywords Hydroxyethyl starch * 6% HES 130/0.4 * Pharmacokinetics * Safety * Japanese healthy male volunteers, Introduction Hydroxyethyl starch (HES) solutions are used in most parts of the world to maintain circulating blood volume (normovolemia) or to treat hypovolemia according to the individual need of the [...]

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., (© 2024. The Author(s).)

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; www.clinicaltrialsregister.eu )., Competing Interests: J. Mascherbauer has received fees and research grants from Bayer Healthcare, AOP Orphan, Actelion, Pfizer and Novartis. E. Grünig is member of the national and international advisory boards of Bayer HealthCare, Novartis, Actelion, Pfizer, GlaxoSmithKline and has received financial compensation for talks by Bayer HealthCare, Novartis, Actelion, Pfizer, United Therapeutics, Gilead and GlaxoSmithKline. M. Halank has received fees for board memberships (Actelion, Bayer and Novartis), lectures (Actelion, Bayer, GSK, Novartis, OMT and Pfizer), travel, accommodation and meeting expenses (Actelion, Bayer, GSK and Novartis) I.M. Lang is member of the speakers’ bureau of Actelion, Bayer, Astra Zeneca, Servier and is recipient of research grants from Actelion, Bayer, AOP Orphan and United Therapeutics. R. Frey is a former employee of Bayer Pharma involved in the development of riociguat and holds stocks in Bayer. D. Bonderman has received fees and research grants from Bayer Healthcare, AOP Orphan, United Therapeutics, Actelion, Pfizer and Novartis. W. Hohenforst-Schmidt, A.A. Kammerlander, I. Pretsch, R. Steringer-Mascherbauer S. Ulrich and M. Wargenau declare that they have no competing interests.