Pharmacokinetics of Serelaxin in Patients with Severe Renal Impairment or End-Stage Renal Disease Requiring Hemodialysis: A Single-dose, Open-label, Parallel-group Study

Serelaxin, a recombinant human relaxin-2, is currently in clinical development for treating acute heart failure. This open-label parallel-group study investigated serelaxin pharmacokinetics (PK) after a single 4-h intravenous infusion (10μg/kg) in patients with severe renal impairment (n=6) or end-stage renal disease (ESRD) requiring hemodialysis (with PK on the day of dialysis [n=6] or during dialysis-free interval [n=6]) compared with healthy subjects (n=18). In all participants, serum serelaxin concentration peaked at the end of infusion and subsequently declined with a mean terminal elimination half-life of 6.5–8.8h. Compared to healthy subjects, a moderate decrease in serelaxin systemic clearance (37%–52%) and increase in its exposure (30%–115%) were observed in all patients. During the 4-h hemodialysis in ESRD patients, serelaxin was partially removed (30%) from blood with dialysis clearance constituting approximately 52% of total systemic clearance. Anti-serelaxin antibodies were not detected in any participant, and serelaxin was well tolerated with no deaths, serious adverse events (AE), or AE-related discontinuations. The observed serelaxin PK differences in patients with severe renal impairment compared with matched healthy subjects are unlikely to pose a safety risk and do not warrant a predefined dosage adjustment in such patients

Lung Delivery of Indacaterol and Mometasone Furoate Following Inhalation of QMF149 via the Twisthaler® Device in Healthy Volunteers

QMF149 is a once-daily fixed-dose combination of the long-acting β2-agonist indacaterol and the inhaled corticosteroid mometasone furoate (MF) under development for the treatment of asthma and chronic obstructive pulmonary disease. This study evaluated the contribution of pulmonary and gastrointestinal (GI) absorption to the systemic exposure of indacaterol and MF following inhalation of QMF149 via the Twisthaler® device. This was an open-label, single-dose, four-period crossover study in 20 healthy subjects. Pharmacokinetics of indacaterol and MF were evaluated after inhalation of QMF149 (indacaterol maleate/MF) 500/400 μg via the Twisthaler® device with and without post-dose mouth rinsing, and in the presence of activated charcoal. Indacaterol alone was evaluated after inhalation of indacaterol maleate 300 μg via the Breezhaler® device. The relative bioavailability of indacaterol and MF for inhalation with vs. without activated charcoal, based on AUClast, was 0.25 (90% confidence interval [CI]: 0.18, 0.35) and 0.70 (90% CI: 0.52, 0.93), respectively. Thus, 25% of systemic exposure of indacaterol and 70% of systemic exposure of MF after inhalation via the Twisthaler® device were due to lung absorption and 75% and 30%, respectively, were due to GI absorption. Total systemic exposure of indacaterol was higher (~1.5 fold) when administered without mouth rinsing, whereas no relevant effect of mouth rinsing was seen for MF. Dose normalized AUClast for indacaterol inhaled via the Breezhaler® device was 2.3-fold higher than that for QMF149 via the Twisthaler® device. All treatments had a good safety profile and were well tolerated. Comparison with data from a similar charcoal block study of indacaterol inhaled via the Breezhaler® device showed that the Breezhaler® device was more efficient than the Twisthaler® device for lung delivery of indacaterol

Pharmacokinetics of indacaterol, glycopyrronium and mometasone furoate administered as an inhaled fixed-dose combination in Japanese and Caucasian healthy subjects

Background: A once-daily (o.d.) fixed-dose combination of indacaterol acetate (IND), glycopyrronium bromide (GLY), and mometasone furoate (MF) delivered via the Breezhaler® device (IND/GLY/MF) is being developed for treatment of asthma. This study compared steady-state pharmacokinetics of IND, GLY and MF between Japanese and Caucasian male subjects after multiple inhalations of IND/GLY/MF o.d. Methods: This was a single-center, open-label, 2-treatment crossover study with a 21-day washout period. Japanese and Caucasian subjects received IND/GLY/MF 150/50/80 μg (inhaled corticosteroid [ICS] medium-dose) or 150/50/160 μg o.d. (ICS high-dose) for 14 days in each period. Pharmacokinetics were characterized up to 24 h post-dose on Days 1 and 14. Results: In total, 16 Japanese (median age 31 years [range 20–40 years], mean weight 68.3 kg) and 17 Caucasian subjects (median age 27 years [range 21–43 years], mean weight 75.0 kg) were randomized. Geometric mean ratios (Japanese/Caucasian) [90% confidence interval (CI)] for Cmax for IND, GLY and MF at the high ICS dose on Day 14 were 1.31 [1.13, 1.51] 1.38 [1.13, 1.69] and 1.07 [0.969, 1.18], respectively. Geometric mean ratios (Japanese/Caucasian) [90% CI] for AUC0–24h on Day 14 for IND, GLY and MF at the high ICS dose were 1.17 [1.01, 1.35], 1.05 [0.920, 1.20] and 1.15 [1.05, 1.27] respectively. Similar trends were noted for all components for the medium ICS dose treatment. IND/GLY/MF was safe and well tolerated; no AEs suspected to be study drug-related were observed. Conclusion: Pharmacokinetics of IND, GLY and MF (high and medium dose) when delivered as a fixed-dose combination were comparable between Japanese and Caucasian subjects. The IND/GLY/MF combination at the administrated doses was safe and well tolerated in both ethnic groups. Trial registration: Japan Registry of Clinical Trial: jRCT2031200227, retrospectively registered on 04, December, 2020

A first-in-human, randomized, double-blind, placebo-controlled, single and multiple ascending oral dose study to assess the safety, tolerability, and pharmacokinetics of BZF961 with and without ritonavir in healthy adult volunteers

Infection with hepatitis C virus is the leading indication for liver transplantation and most common cause of infectious disease-related mortality in the United States. BZF961 is a novel inhibitor of the hepatitis C virus NS3-4A protease. This sequential, three part exploratory first-in-human study investigated the safety and pharmacokinetics of single and multiple ascending oral doses of BZF961 in healthy subjects. The first two parts were randomized, double-blind, placebo-controlled, time-lagged, single and multiple ascending oral dose segments. The third part analyzed the effect of ritonavir on BZF961 pharmacokinetics. BZF961 was generally safe and well-tolerated in single and multiple oral doses in healthy subjects. There were no deaths and no serious adverse events. The most common adverse events were nausea and other gastrointestinal symptoms. Co-administration of ritonavir with BZF961 was well tolerated and increased BZF961 exposure by up to 60-fold, as well as reduced the overall exposure variability

Pharmacokinetics of glycopyrronium following repeated once-daily inhalation in healthy Chinese subjects

Glycopyrronium is a once-daily long-acting muscarinic antagonist (LAMA) for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). This study assessed the pharmacokinetics of inhaled glycopyrronium 50 µg once-daily for 14 days in healthy Chinese subjects. In this open-label study, 12 Chinese healthy subjects were enrolled and completed the study. Glycopyrronium in plasma was determined using validated liquid chromatography-mass spectrometry method with a lower limit of quantification (LLOQ) of 1.5 pg/mL. Plasma pharmacokinetic parameters were determined on Day 1 after first dose and on Day 14 (steady state) after last dose using non-compartmental analysis. Trough pharmacokinetic samples (Days 5, 7, 10 and 12) were collected. Safety was also assessed. Glycopyrronium was rapidly absorbed into the systemic circulation after inhalation and its plasma concentrations decreased rapidly thereafter. Median time to reach maximum concentration (Tmax) was reached within 5 minutes after inhalation (i.e., at the first post-dose time point) on both Days 1 and 14. Accumulation in the systemic exposure to glycopyrronium was observed from the time of first dose administration on Day 1 up to Day 14 and the observed accumulation ratio (Racc) values of AUC0-24h and Cmax (Day14/Day1) were 2.77 and 1.59, respectively. Mean effective half-life (T1/2,acc) was 37.7 hours. Pharmacokinetic steady state was reached after 5 days of daily dosing. One subject experienced dry mouth; otherwise glycopyrronium was well tolerated. Comparison of systemic exposure to glycopyrronium in Chinese versus the non-Chinese population did not indicate clinically relevant ethnic differences. Multiple inhaled doses of glycopyrronium were safe and well tolerate

Ethnic sensitivity study with serelaxin

Serelaxin, a recombinant form of the human relaxin-2 hormone, is currently under clinical investigation for treatment of acute heart failure. This double-blind, placebo-controlled, dose-ranging study investigated the effect of Japanese ethnicity on the pharmacokinetics (PK), pharmacodynamics (PD), and safety and tolerability of serelaxin. Japanese healthy subjects (n=32) received 10, 30, or 100 μg/kg/day of serelaxin, or placebo, administered as a 48-hour intravenous infusion. A Caucasian cohort (n=8) receiving 30 μg/kg/day open-label serelaxin was included for comparison. In all subjects, serum serelaxin concentrations increased rapidly after the start of infusion, approached steady state as early as 4 hours, and declined rapidly upon treatment cessation. Serum exposure to serelaxin increased with increasing doses. Statistical dose proportionality was shown for AUCinf over the entire dose range. A significant increase in estimated glomerular filtration rate from baseline to Day 2 (30 μg/kg/day and 100 μg/kg/day) and to Day 3 (10 μg/kg/day and 100 μg/kg/day) was observed compared with placebo. Serelaxin was well tolerated by all subjects. In conclusion, PK, PD, and safety profiles of serelaxin were generally comparable between Japanese and Caucasian subjects, suggesting that no dose adjustment will be required in Japanese subjects during routine clinical use of this agent

A Randomized, Open-label Study of the Pharmacokinetics and Safety of Oral and Intravenous Administration of Omadacycline to Healthy Subjects

Omadacycline is a first in class aminomethylcycline antibiotic with microbiological activity against Gram-positive and Gram-negative aerobes and anaerobes, and atypical bacteria that is being developed for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). The bioavailability of two oral tablet formulations relative to intravenous (IV) administration was investigated in an open-label, randomized, four-period, crossover study in healthy subjects age 18-50 years. Subjects received omadacycline 100 mg IV, 300 mg oral as different tablet formulations with different dissolution profiles, and a 300 mg as an oral solution. Plasma omadacycline concentrations were determined using a validated LC/MS/MS method. Twenty of 24 subjects completed all treatment periods. Both tablet formulations produced equivalent total exposure relative to the 100 mg IV dose with geometric mean ratios (90% confidence intervals [CI]) for AUCinf of 1.00 (0.93,1.07) and 0.96 (0.90,1.03), respectively. Absolute bioavailability of the tablets was approximately 34.5%. Intersubject variability was consistent among the oral formulations (~20-25%). Single oral and IV doses of omadacycline were well tolerated; three subjects experienced mild adverse events (dizziness, nausea, vomiting) that resolved without intervention. A 300 mg dose of the tablet formulation of omadacycline intended for use in phase 3 studies produced total exposure equivalent to that of a 100 mg IV dose