Aims
SAR247799 is a selective G‐protein‐biased sphingosine‐1 phosphate receptor‐1 (S1P1) agonist with potential to restore endothelial function in vascular pathologies. SAR247799, a first‐in‐class ...molecule differentiated from previous S1P1‐desensitizing molecules developed for multiple sclerosis, can activate S1P1 without desensitization and consequent lymphopenia. The aim was to characterize SAR247799 for its safety, tolerability, pharmacokinetics and pharmacodynamics (activation and desensitization).
Methods
SAR247799 was administered orally to healthy subjects in a double‐blind, randomized, placebo‐controlled study with single (2.5–37.5 mg) or 2‐week once‐daily (0.5–15 mg) doses. An open‐label single dose pilot food‐interaction arm with 10 mg SAR247799 in cross‐over design was also performed.
Results
SAR247799 was well tolerated and, at the higher end of the dose ranges, caused the expected dose‐dependent pharmacodynamics associated with S1P1 activation (heart rate reduction) and S1P1 desensitization (lymphocyte count reduction). SAR247799 demonstrated dose‐proportional increases in exposure and was eliminated with an apparent terminal half‐life of 31.2–33.1 hours. Food had a small effect on the pharmacokinetics of SAR247799. SAR247799 had a low volume of distribution (7–23 L), indicating a potential to achieve dose separation for endothelial vs cardiac S1P1 activation pharmacology. A supratherapeutic dose (10 mg) of SAR247799 produced sustained heart rate reduction over 14 days, demonstrating cardiac S1P1 activation without tachyphylaxis. Sub‐lymphocyte‐reducing doses (≤5 mg) of SAR247799, which, based on preclinical data, are projected to activate S1P1 and exhibit endothelial‐protective properties, had minimal‐to‐no heart rate reduction and displayed no marked safety findings.
Conclusion
SAR247799 is suitable for exploring the biological role of endothelial S1P1 activation without causing receptor desensitization.
Background and Objectives
Acoziborole is a novel boron-containing candidate developed as an oral drug for the treatment of human African trypanosomiasis (HAT). Results from preclinical studies ...allowed progression to Phase 1 trials. We aimed to determine the best dose regimen for all stages of HAT.
Methods
Acoziborole was assessed in 128 healthy adult males of sub-Saharan African origin living in France. The study included a single oral administration of a 20- to 1200-mg dose in a randomised double-blind study in cohorts of 8 (6 active, 2 placebo) to assess safety, tolerability, and pharmacokinetics. In three additional open cohorts of 6 participants, the effect of activated charcoal was evaluated, bioequivalence of capsules versus tablets was assessed, and safety in the 960-mg tablet cohorts was monitored.
Results
Acoziborole was well tolerated at all doses tested; no dose-related adverse events were observed. The drug appeared rapidly in plasma (at 1 h), reached
t
max
between 24 and 72 h, and remained stable for up to 96 h, after which a slow decrease was quantifiable until 14 weeks after dosing. Charcoal had little impact on the enterohepatic recirculation effect, except for the 20-mg dose. Bioequivalence between capsule and tablet formulations was demonstrated. The therapeutic single dose for administration under fasted conditions was fixed to 960 mg. The maximum administered dose was 1200 mg.
Conclusions
This study showed that acoziborole could be safely assessed in patients as a potential single-dose oral cure for both stages of
gambiense
HAT.
Trial Registration
The study was registered with ClinicalTrials.gov: NCT01533961.
Background and Objectives
Fexinidazole is a 5-nitroimidazole recently included in a clinical efficacy trial as an oral drug for the treatment of human African trypanosomiasis (HAT). Preclinical ...studies showed it acts as a pharmacologically active pro-drug with two key active metabolites: sulfoxide and sulfone (the most active metabolite). The present studies aimed to determine the best dose regimen for the treatment of stage 2 sleeping sickness patients, which could eventually also treat stage 1 patients.
Methods
Fexinidazole was assessed in 154 healthy adult male subjects of sub-Saharan African origin. Three initial first-in-human studies and two additional studies assessed a single ascending dose and multiple ascending doses (both under fasted conditions), tablet versus suspension formulation and food effect (fasted vs. high-fat meal and field-adapted food), and multiple ascending doses with a loading dose regimen under fed conditions.
Results
Fexinidazole was well-tolerated in a single dose from 100 to 3,600 mg, with quick absorption of the parent drug and rapid metabolism into sulfoxide time to maximum concentration (
t
max
) 2–5 h and sulfone (
t
max
18–24 h). The tablet formulation was approximately 25 % less bioavailable than the suspension, and food intake increased drug absorption and plasma concentrations of fexinidazole and its two metabolites by approximately 200 %. Fourteen-day multiple ascending dosing administered up to 3,600 mg/day in fasted conditions showed that fexinidazole was generally well-tolerated (mild to moderate, spontaneously reversible drug-related adverse events). Following the high-fat food effect finding, another study was conducted to evaluate the impact of a low-fat regimen closer to that of the target population, showing that the type of meal does not influence fexinidazole absorption. The last study showed that a loading dose of 1,800 mg/day for 4 days followed by a 1,200 mg/day regimen for 6 days with a normal meal provided the desired exposure of fexinidazole and its metabolites, particularly sulfone, with good tolerability. Based on preclinical evidence from a chronic infection mouse model, systemic drug concentrations obtained are expected to be clinically effective in stage 2 HAT.
Conclusions
These studies show that fexinidazole can be safely assessed in patients as a potential oral cure for both stages of HAT.
Objective
The aim of this study was to investigate the pharmacokinetic, pharmacodynamic and safety profile of the glucagon‐like peptide‐1 receptor agonist, lixisenatide, for the treatment of type 2 ...diabetes (T2D) in pediatric individuals.
Materials and Methods
In this Phase 1, multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group, ascending repeated dose study (NCT02803918), participants aged ≥10 and < 18 years were randomized 3:1 to receive once‐daily lixisenatide in 2‐week increments of 5, 10, and 20 μg (n = 18) or placebo (n = 5) for 6 weeks.
Results
Mean lixisenatide concentrations generally increased with increasing doses irrespective of anti‐drug antibody (ADA) status; however, mean lixisenatide concentrations and inter‐subject variability were higher for participants with positive ADA status. Improvements in fasting plasma glucose, post‐prandial glucose, AUC0–4.5, HbA1c, and body weight were observed with lixisenatide. Overall, the safety profile was consistent with the known profile in adults, with no unexpected side effects and no treatment‐emergent adverse events resulting in death or discontinuation. The most common events in the lixisenatide group were vomiting (11.1%) and nausea (11.1%). No symptomatic hypoglycemia was reported in either group. No clinically significant hematologic, biochemical or vital sign abnormalities were observed.
Conclusions
Mean lixisenatide concentrations generally increased with increasing dose, irrespective of ADA status. Lixisenatide was associated with improved glycemic control and a trend in body weight reduction compared with placebo. The safety and tolerability profile of repeated lixisenatide doses of up to 20 μg per day in children and adolescents with T2D was reflective of the established safety profile of lixisenatide in adults.
Aims
SAR247799 is a G‐protein‐biased sphingosine‐1 phosphate receptor‐1 (S1P1) agonist designed to activate endothelial S1P1 and provide endothelial‐protective properties, while limiting S1P1 ...desensitization and consequent lymphocyte‐count reduction associated with higher doses. The aim was to show whether S1P1 activation can promote endothelial effects in patients and, if so, select SAR247799 doses for further clinical investigation.
Methods
Type‐2 diabetes patients, enriched for endothelial dysfunction (flow‐mediated dilation, FMD <7%; n = 54), were randomized, in 2 sequential cohorts, to 28‐day once‐daily treatment with SAR247799 (1 or 5 mg in ascending cohorts), placebo or 50 mg sildenafil (positive control) in a 5:2:2 ratio per cohort. Endothelial function was assessed by brachial artery FMD. Renal function, biomarkers and lymphocytes were measured following 5‐week SAR247799 treatment (3 doses) to Zucker diabetic fatty rats and the data used to select the doses for human testing.
Results
The maximum FMD change from baseline vs placebo for all treatments was reached on day 35; mean differences vs placebo were 0.60% (95% confidence interval CI −0.34 to 1.53%; P = .203) for 1 mg SAR247799, 1.07% (95% CI 0.13 to 2.01%; P = .026) for 5 mg SAR247799 and 0.88% (95% CI −0.15 to 1.91%; P = .093) for 50 mg sildenafil. Both doses of SAR247799 were well tolerated, did not affect blood pressure, and were associated with minimal‐to‐no lymphocyte reduction and small‐to‐moderate heart rate decrease.
Conclusion
These data provide the first human evidence suggesting endothelial‐protective properties of S1P1 activation, with SAR247799 being as effective as the clinical benchmark, sildenafil. Further clinical testing of SAR247799, at sub‐lymphocyte‐reducing doses (≤5 mg), is warranted in vascular diseases associated with endothelial dysfunction.
Introduction
This study evaluated the bioequivalence of ezetimibe/rosuvastatin fixed dose combination compared to the concomitant administration of individual formulations (ezetimibe and ...rosuvastatin) in Chinese healthy subjects under fasting conditions.
Methods
This was a phase I, randomized, open-label, two-treatment, two-period, two-sequence, crossover study conducted in healthy Chinese participants under fasting conditions.
C
max
, AUC
0–
t
, and AUC
0–∞
from test and individual reference formulations were evaluated to assess bioequivalence. The safety assessments included adverse events (AEs)/treatment-emergent adverse events (TEAEs), potential clinically significant abnormalities (PCSAs) in vital signs, 12-lead electrocardiogram (12-ECG), and clinical laboratory parameters.
Results
Of the 68 subjects enrolled, 67 were treated. Systemic exposure to rosuvastatin based on
C
max
, AUC
0–
t
, and AUC
0–∞
was similar in both treatments, with respective arithmetic values 12.4 ng/ml, 117 ng·h/mL, and 120 ng·h/mL for test formulation and 12.7 ng/ml, 120 ng·h/mL, and 123 ng·h/mL for reference formulations. Similarly, systemic exposure to unconjugated ezetimibe was 4.14 ng/ml, 89.7 ng·h/mL, and 102 ng·h/mL for the test formulation and 3.80 ng/ml, 89.7 ng·h/mL, and 102 ng·h/mL for reference formulations. Systemic exposure to total ezetimibe was 70.5 ng/ml, 664 ng·h/mL, and 718 ng·h/mL for test formulation and 60.2 ng/ml, 648 ng·h/mL, and 702 ng·h/mL for reference formulations. The point estimates for rosuvastatin unconjugated ezetimibe and total ezetimibe were in the acceptable range of 0.80–1.25. No deaths or serious adverse events were reported.
Conclusions
Fixed dose combination of ezetimibe/rosuvastatin (10 mg/10 mg) achieved bioequivalence with reference to commercial tablets.
Trial Registration Number
CTR20202108.
SAR341402 (SAR-Asp) is a biosimilar/follow-on insulin to NovoLog® (NN-Asp). This non-confirmatory, randomized, open-label, 2x4 week, 2 arm crossover study in 45 T1D patients (NCT03436498) was ...designed to assess the safety of SAR-Asp and NN-Asp when used in pumps (CSII) in terms of infusion set occlusions (ISO).
The primary safety endpoint was to assess the number of patients with ISO using SAR-Asp and NN-Asp. ISO was defined as infusion set change due to failure to correct hyperglycemia (plasma glucose ≥250 mg/dL) by insulin bolus via the pump. The secondary safety endpoint was to assess the incidence of all cases of unexplained hyperglycemia events whether or not corrected by a bolus through the insulin pump with no apparent materials defects, medical, dietary, insulin dosing, or pump failure including infusion set occlusions as defined in the primary safety endpoint.
The number of patients reporting at least one ISO was: 14/43 (32.6%) patients on SAR-Asp and 12/43 (27.9%) on NN-Asp (Table 1). The number of patients with at least one unexplained hyperglycemia was 31/43 (72.1%) on SAR-Asp and 32/43 (74.4%) on NN-Asp. The total number of unexplained hyperglycemia was 329: 154 on SAR-Asp and 175 on NN-Asp.
In this study SAR-Asp and NN-Asp were well-tolerated. There was no difference in the safety profiles including ISO, hyperglycemia, hypoglycemia, hypersensitivity and injection site reactions when used in CSII.
Disclosure
J. Thrasher: Advisory Panel; Self; Lexicon Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi, Senseonics. Consultant; Self; Medtronic MiniMed, Inc. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Lexicon Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi. Speaker’s Bureau; Self; AstraZeneca, Janssen Pharmaceuticals, Inc., Sanofi. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc. S. Polsky: Consultant; Self; Jaeb Center for Health Research. Research Support; Self; Barbara Davis Center for Diabetes, Children’s Diabetes Foundation, Dexcom, Inc., Eli Lilly and Company, JDRF, Leona & Harry Helmsley Charitable Trust, National Institute of Diabetes and Digestive and Kidney Diseases, Sanofi US. L. Hovsepian: None. I.K. Nowotny: Employee; Self; Sanofi-Aventis Deutschland GmbH. Stock/Shareholder; Self; Sanofi. B. Bois De Fer: Employee; Self; IT&M Stats. Stock/Shareholder; Self; IT&M Stats. A. Bhargava: Consultant; Self; Sanofi-Aventis. Research Support; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Eli Lilly and Company, Gan & Lee Pharmaceuticals, Jaeb Center for Health Research, KOWA Research Institute, Inc, Medtronic MiniMed, Inc., Merck Research Laboratories, Mylan GmbH, Novo Nordisk Inc., Roche Diabetes Care, Sanofi, Theracos Sub, LLC. Speaker’s Bureau; Self; AstraZeneca, Eli Lilly and Company, Sanofi-Aventis. S.K. Garg: Advisory Panel; Self; Eli Lilly and Company, Roche Pharma, Sanofi-Aventis, Zealand Pharma A/S. Research Support; Self; Eli Lilly and Company, WebMD.
Funding
Sanofi
Background and Objective
The combination of rosuvastatin and ezetimibe has promising clinical benefits with a significant safety and tolerability profile. However, there is a lack of clinical data ...supporting the drug–drug interaction (DDI) in Chinese population. Thus, the aim of this study is to assess the potential pharmacokinetic DDI between rosuvastatin and ezetimibe in a Chinese population.
Methods
In this randomized, open-label, phase 1 study, 12 healthy volunteers were randomized to three treatment groups: 10 mg rosuvastatin plus 10 mg ezetimibe, 10 mg rosuvastatin alone, and 10 mg ezetimibe alone under fasting conditions. The plasma concentrations of rosuvastatin and ezetimibe were determined, and the pharmacokinetic parameters were calculated. Primary endpoints were peak plasma concentration (
C
max
), area under the curve from zero to last measurement (AUC
0–t
), and area under the curve from zero to infinity (AUC
0–∞
) that were log-transformed, and co-administration was compared with monotherapy to evaluate the DDI.
Results
The geometric mean ratios (GMRs) of rosuvastatin with 90% confidence intervals (CIs) were 0.94 (0.80–1.12) for
C
max
, 0.96 (0.85–1.08) for AUC
0–t
, and 0.96 (0.86–1.07) for AUC
0–∞
when administered in combination with ezetimibe versus administered alone. The GMRs of unconjugated ezetimibe and total ezetimibe with 90% CIs were 1.15 (1.00–1.32) and 0.93 (0.80–1.07) for
C
max
, 0.96 (0.84–1.10) and 0.95 (0.83–1.08) for AUC
0–t
, and 1.06 (0.96–1.18) and 0.94 (0.80–1.11) for AUC
0–∞
, respectively, when administered in combination with rosuvastatin versus administered alone.
Conclusion
Co-administration of rosuvastatin and ezetimibe showed no clinically significant pharmacokinetic interactions in a healthy Chinese population.
Interindividual variability of response to clopidogrel is currently a subject of much interest. We tested the hypothesis that functional variability in the platelet response to clopidogrel correlates ...with occupancy of the platelet P2Y(12) receptor by clopidogrel active metabolite. Healthy subjects were screened after seven days' treatment with clopidogrel 75 mg/day to select three clopidogrel-response groups (n = 12/group), defined as 'average' (40-60% inhibition of platelet aggregation IPA), 'low' (<10% IPA) or 'high' (>80% IPA) responders. After a two- to six-week wash-out period, subjects were randomized (double-blind) to clopidogrel 75 mg/day (n = 10/group) for 10 days, followed by clopidogrel 300 mg on day 11, or placebo (n = 2/group). IPA induced by adenosine diphosphate (ADP), and P2Y(12) receptor occupancy were measured repeatedly. The incidence of low responders was 3.7%, and low responses to clopidogrel were maintained during the randomized evaluation phase. Treatment with clopidogrel for 10 days induced a significant increase in P2Y(12) receptor occupancy in each group of responders versus placebo; receptor affinity was unchanged. This reduction correlated with IPA response (r = 0.54). The additional 300 mg dose of clopidogrel on top of 75 mg chronic treatment increased IPA and P2Y(12) receptor occupancy in all groups, but relatively more in low responders. Variability in the response to clopidogrel appears to be linked to differences in P2Y(12) receptor occupancy. An additional 300 mg dose of clopidogrel improves both IPA and P2Y(12) receptor occupancy mostly in the subset of 'low' responders.
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