Pharmacokinetics, safety, and tolerability of siponimod (BAF312) in subjects with severe renal impairment: A single-dose, open-label, parallel-group study

Objective To investigate the pharmacokinetics (PK), safety, and tolerability of siponimod and selected metabolites (M3 and M5) in subjects with varying degrees of renal impairment (RI) compared to demographically matched healthy subjects (HS). Methods The study enrolled subjects with severe RI (n=8) and matched HS (n=8). Subjects with moderate and mild RI were to be enrolled only if interim analysis showed ≥50% increase in maximum plasma concentration (Cmax) or area under the curve (AUC) of total and/or unbound siponimod in severe RI subjects versus HS. All subjects received single oral dose of siponimod 0.25 mg on Day 1; PK and safety were evaluated during the follow-up (~13 days). Results PK of siponimod was marginally affected in severe RI subjects versus HS: Cmax decreased by 8% and AUClast and AUCinf increased by 23% and 24%, respectively. Siponimod plasma unbound (u) fraction was 7% higher in the severe RI subjects versus HS. Cmax(u) was comparable while AUClast(u) and AUCinf(u) increased by 32% and 33%, respectively, compared to HS. M3 exposure was similar (Cmax decreased by 9%; AUClast and AUCinf increased by 11%) and M5 exposure was slightly lower (Cmax decreased by 26%; AUClast decreased by 16%) in subjects with severe renal impairment compared with matched HS. No adverse events were reported during this study. Conclusions Changes in the plasma exposure of total and unbound siponimod and metabolites M3 and M5 were not considered to be clinically relevant. Further investigation of PK in subjects with mild and moderate RI was not warranted

Evaluation of two novel tablet formulations of artemether-lumefantrine (Coartem®) for bioequivalence in a randomized, open-label, two-period study

Background: Artemether-lumefantrine (Coartem®; AL) is a standard of care for malaria treatment as an oral six-dose regimen, given twice daily over three days with one to four tablets (20/120 mg) per dose, depending on patient body weight. In order to reduce the pill burden at each dose and potentially enhance compliance, two novel fixed-dose tablet formulations (80/480 mg and 60/360 mg) have been developed and tested in this study for bioequivalence with their respective number of standard tablets. Methods. A randomized, open-label, two-period, single-dose, within formulation crossover bioequivalence study comparing artemether and lumefantrine exposure between the novel 80/480 mg tablet and four standard tablets, and the novel 60/360 mg tablet and three standard tablets, was conducted in 120 healthy subjects under fed conditions. Artemether, dihydroartemisinin, and lumefantrine were measured in plasma by HPLC/UPLC-MS/MS. Pharmacokinetic (PK) parameters were determined by non-compartmental analyses. Results: Adjusted geometric mean AUClast for artemether were 345 and 364 ng·h/mL (geometric mean ratio (GMR) 0.95; 90% CI 0.89-1.01) and for lumefantrine were 219 and 218 μg·h/mL (GMR 1.00; 90% CI 0.93-1.08) for 80/480 mg tablet versus four standard tablets, respectively. Corresponding Cmax for artemether were 96.8 and 99.7 ng/mL (GMR 0.97; 90% CI 0.89-1.06) and for lumefantrine were 8.42 and 8.71 μg/mL (GMR 0.97; 90% CI 0.89-1.05). For the 60/360 mg tablet versus three standard tablets, adjusted geometric mean AUClast for artemether were 235 and 231 ng·h/mL (GMR 1.02; 90% CI 0.94-1.10), and for lumefantrine were 160 and 180 μg·h/mL (GMR 0.89; 90% CI 0.83-0.96), respectively. Corresponding Cmax for artemether were 75.5 and 71.5 ng/mL (GMR 1.06; 90% CI 0.95-1.18), and for lumefantrine were 6.64 and 7.61 μg/mL (GMR 0.87; 90% CI 0.81-0.94), respectively. GMR for Cmax and AUClast for artemether and lumefantrine for all primary comparisons were within the bioequivalence acceptance criteria (0.80-1.25). In addition, secondary PK parameters also met bioequivalence criterion. Conclusion: Both of the novel artemether-lumefantrine tablet formulations evaluated are bioequivalent to their respective standard Coartem® tablet doses. These novel formulations are easy to administer and may improve adherence in the treatment of uncomplicated malaria caused by Plasmodium falciparum. Trial registration. Clinical trial registration number: CTRI/2011/12/002256. © 2013 Lefèvre et al.; licensee BioMed Central Ltd

The changing phase of prosthodontics: Nanotechnology

Science is presently undergoing a great evolution, taking humanity to a new era: The era of nanotechnology. Nanotechnology is the field of science and technology pertaining to the creation and use of materials or devices at nanometer scale. Nanoscale is small in size, but its potential is vast. Since 1990s, nanotechnology has been exploited for potential medical and dental applications. Nanotechnology has numerous applications in the field of nanomedicine, nanomaterials, nanorobotics, implantology, and biotechnology. Nanomaterials in dentistry can be metals, ceramics, polymers, implant modifications, and composite materials that demonstrate novel properties when compared with conventional materials due to their nanoscale features. The present article focuses on the various applications of nanotechnology in the field of dentistry, especially prosthodontics

Pharmacokinetics, Safety and Tolerability of Sacubitril/Valsartan (LCZ696) After Single-Dose Administration in Healthy Chinese Subjects

Background and Objective: Sacubitril/valsartan (LCZ696) is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) and has been recently approved in several countries for the treatment of patients with heart failure and reduced ejection fraction. This was the first study conducted to characterise the pharmacokinetics of LCZ696 analytes (pro-drug sacubitril, active neprilysin inhibitor LBQ657 and valsartan) after single-dose administration of LCZ696 in healthy Chinese subjects. Methods: In this open-label, randomised, parallel-group study, following screening and baseline evaluation, eligible healthy subjects received single oral doses of LCZ696 50, 100, 200 or 400 mg. The pharmacokinetics, safety and tolerability of LCZ696 were assessed up to 72 h after dosing. A total of 40 healthy male subjects were enrolled, and all completed the study. Results: Following oral administration, LCZ696 delivered systemic exposure to sacubitril, LBQ657 and valsartan with a median time to reach maximum plasma concentration (Tmax) ranging from 0.50 to 1.25, 2.00 to 3.00 and 1.50 to 2.50 h, respectively, over the investigated dose range. The mean terminal elimination half-life (T1/2) ranged from 0.89 to 1.35, 8.57 to 9.24 and 5.33 to 7.91 h for sacubitril, LBQ657 and valsartan, respectively. The area under the plasma concentration–time curve from time zero to the time of the last quantifiable concentration (AUC0–last), and maximum plasma concentration (Cmax) for LBQ657 increased dose proportionally over the entire dose range. Dose linear increase in the exposure was observed across the dose range for sacubitril and valsartan. LCZ696 was safe and well tolerated at all doses in this study. Adverse events of only mild intensity, which required no treatment, were reported in 6 (15 %) subjects. Conclusion: The pharmacokinetic profiles of LCZ696 analytes in Chinese subjects are similar to those reported previously in Caucasian subjects

Bioavailability of lumefantrine is significantly enhanced with a novel formulation approach, an outcome from a randomized, Open-label pharmacokinetic study in healthy volunteers

The artemether-lumefantrine combination requires food intake for the optimal absorption of lumefantrine. In an attempt to enhance the bioavailability of lumefantrine, new solid dispersion formulations (SDF) were developed, and the pharmacokinetics of two SDF variants were assessed in a randomized, open-label, sequential two-part study in healthy volunteers. In part 1, the relative bioavailability of the two SDF variants was compared with that of the conventional formulation after administration of a single dose of 480 mg under fasted conditions in three parallel cohorts. In part 2, the pharmacokinetics of lumefantrine from both SDF variants were evaluated after a single dose of 480 mg under fed conditions and a single dose of 960 mg under fasted conditions. The bioavailability of lumefantrine from SDF variant 1 and variant 2 increased up to 48-fold and 24-fold, respectively, relative to that of the conventional formulation. Both variants demonstrated a positive food effect and a less than proportional increase in exposure between the 480-mg and 960-mg doses. Most adverse events (AEs) were mild to moderate in severity and not suspected to be related to the study drug. All five drug-related AEs occurred in subjects taking SDF variant 2. No clinically significant treatment-emergent changes in vital signs, electrocardiograms, or laboratory blood assessments were noted. The solid dispersion formulation enhances the lumefantrine bioavailability to a significant extent, and SDF variant 1 is superior to SDF variant 2