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Background There is little information on the pharmacokinetics and pharmacodynamics of sacubitril/valsartan (SV) in patients undergoing peritoneal dialysis (PD) complicated with hypertension or heart failure (HF). This study was designed to evaluate the pharmacokinetics and pharmacodynamics of SV in PD patients with complications of hypertension or HF. Methods This was an open-label and cross-sectional study investigating PD patients diagnosed with hypertension or New York Heart Association Class II–IV HF. The concentrations of valsartan, sacubitril and sacubitrilat (LBQ657) were measured by ultra-performance liquid chromatography tandem mass spectrometry in plasma, urine and peritoneal dialysate samples. Pharmacodynamics were evaluated by comparing changes in mean sitting systolic blood pressure (msSBP), mean sitting diastolic blood pressure (msDBP), mean sitting heart rate, N-terminal-pro B-type natriuretic peptide (NT-proBNP) and left ventricular ejection fraction (LVEF). Results Forty patients with PD were enrolled including 27 (67.5%) patients with hypertension, 4 (10%) patients with HF and 9 (22.5%) patients with both hypertension and HF. This study included three treatment cohorts: 50 mg twice daily (BID), 100 mg once daily and 100 mg BID. The plasma maximum drug concentrations in the 100 mg BID group were 1995 ± 1499 ng/mL for valsartan, 171 ± 148 ng/mL for sacubitril and 13 686 ± 7418 ng/mL for LBQ657. The 24-h recovery rate of LBQ657 was 3.77% in urine and 2.23% in peritoneal dialysate. After taking SV, msSBP and msDBP decreased by 19.25 ± 10.32 mmHg and 10.10 ± 8.00 mmHg from baseline, respectively. NT-proBNP decreased by 1436.50 (0.00–18 198.00) from baseline, while LVEF increased by 5.00 (–0.25 to 9.25) from baseline after SV treatment. Conclusions PD and residual renal function contributed only to a minor degree to the elimination of LBQ657. Additionally, a dose of 100 mg BID SV is safe and effective in patients with PD with complications of hypertension or HF. [ABSTRACT FROM AUTHOR]

Background: Nerve growth factor (NGF), the first-discovered member of the neurotrophin family, has long been regarded as a potential drug to combat acute and chronic neurodegenerative processes. However, the pharmacokinetic profile of NGF is poorly described. Objectives: The aim of this study was to investigate the safety, tolerability, pharmacokinetics, and immunogenicity of a novel recombinant human NGF (rhNGF) in healthy Chinese subjects. Method: The study randomized 48 and 36 subjects to receive (i) single-ascending dose (SAD group; 7.5, 15, 30, 45, 60, 75 μg or placebo) and (ii) multiple-ascending dose (MAD group; 15, 30, 45 μg, or placebo) rhNGF intramuscular injections, respectively. In the SAD group, all participants received rhNGF or placebo only once. In the MAD group, participants were randomly assigned to receive multiple doses of rhNGF or placebo once a day for 7 consecutive days. Adverse events (AEs) and anti-drug antibodies (ADAs) were monitored throughout the study. Recombinant human NGF serum concentrations were determined using a highly sensitive enzyme-linked immunosorbent assay. Results: All AEs were mild, except for some injection-site pain and fibromyalgia, which were experienced as moderate AEs. Only one moderate AE was observed in the 15 μg cohort throughout the study and resolved within 24 hours of stopping dosing. Many participants (10% in 30 μg, 50% in 45 μg, and 50% in 60 μg in the SAD group; 10% in 15 μg, 30% in 30 μg, and 30% in 45 μg in the MAD group) experienced moderate fibromyalgia. However, all moderate fibromyalgia were resolved by the end of the subject's participation in the study. No severe AEs or clinically significant abnormalities were reported. All subjects in the 75 μg cohort experienced positive ADA in the SAD group, and one subject in the 30 μg dose and four subjects in the 45 μg dose also experienced positive ADA in the MAD group. Recombinant human nerve growth factor was absorbed (median Tmax, 4.0–5.3 h) and eliminated biexponentially (mean t1/2, 4.53–6.09 h) with a moderate speed. The Cmax and AUC increased in an approximately dose-proportional manner over the dose range of 7.5–45 μg, and at doses higher than 45 μg these parameters increased more than dose proportionally. There was no obvious accumulation after 7 days of daily dosing of rhNGF. Conclusion: The favorable safety and tolerability and predictable pharmacokinetic profile of rhNGF in healthy Chinese subjects support its continuing clinical development for the treatment of nerve injury and neurodegenerative diseases. The AEs and immunogenicity of rhNGF will continue to be monitored in future clinical trials. Trial Registration: This study was registered with Chinadrugtrials.org.cn (ChiCTR2100042094) on January 13th, 2021. [ABSTRACT FROM AUTHOR]

The first-line anti-rheumatic drug methotrexate (MTX) is used in the combination. Because of the unpredictable adverse reactions, optimization of relevant regimens is necessary and meaningful. This study aimed to study the possible interaction between Securidaca inappendiculate Hassk. Derived xanthones and MTX. We established adjuvant-induced arthritis (AIA) model, which was treated with MTX and MTX + xanthone-rich fraction (XRF). The clinical efficacy was evaluated by histopathological examination, and LC-MS was used to monitor the blood concentration of MTX. Western blotting and immunohistochemistry were used to detect protein expression. In vitro, we assessed the activity of related transporters by cellular uptake assay based on HEK-293T cells. Compared with MTX-treated rats, inflammation in the immunized rats in the MTX + XRF group was obvious, indicating that XRF antagonized the anti-rheumatic effect of MTX. Meanwhile, XRF reduced liver and kidney injuries caused by MTX in addition to MTX. Results from immunohistochemical and nappendiculat assays suggested that XRF may reduce uptake of MTX by down-regulating reduced folate carrier 1 (RFC1). This study indicated that XRF could reduce the plasma concentration of MTX by inhibiting the expression of RFC1, antagonize the therapeutic effect of MTX on AIA rats, and reduce its oral bioavailability. The combination of S. inappendiculate and MTX should be further optimized to achieve the goal of increasing efficiency and reducing toxicity. [ABSTRACT FROM AUTHOR]

The main objective of the study was to evaluate the bioequivalence of two rosuvastatin calcium tablets in healthy Chinese subjects under fasted and fed conditions. The study was carried out using a randomized, open‐label, two‐formulation, two‐sequence, two‐period, single‐dose crossover design, with a washout period of 7 days. Both the fasted study and fed study enrolled 28 subjects. In each study period, the subjects were administrated a single oral dose of the test product or reference product of rosuvastatin 10 mg. Blood samples were collected from pre‐dose to 72 hours after administration with 16 time points in total. Bioequivalence evaluation was performed using ln‐transformed pharmacokinetic parameters of rosuvastatin, including Cmax, AUC0–t, and AUC0–∞. In the present study, 95% confidence intervals (CIs) of test/reference geometric mean ratios (GMRs) of Cmax, AUC0–t, and AUC0–∞ under the fasted and fed conditions were all within the acceptance range of 80%–125%. Additionally, only one subject experienced one adverse event (AE). High‐fat meals reduced the Cmax, AUC0–t, and AUC0–∞, but had no significant effects on the λz, t1/2, or Tmax of rosuvastatin. In the current study, the test product was bioequivalent to the reference product, and a single dose of rosuvastatin (10 mg) was well‐tolerated. Food decreased the systemic exposure of rosuvastatin without the effects on the Tmax or elimination rate. [ABSTRACT FROM AUTHOR]

Background and Objective: Erenumab is the first-in-class, selective, and competitive human monoclonal antibody antagonist of the calcitonin gene-related peptide (CGRP) receptor that has been shown to be effective and well-tolerated in the preventive therapy of episodic and chronic migraine. The pharmacokinetics of erenumab may be affected by differences in race and ethnicity, which can lead to suboptimal outcomes. The present study was conducted to assess the single-dose pharmacokinetics and safety of erenumab in healthy Chinese subjects. Methods: This was an open-label, randomized, parallel group, non-confirmatory, single-dose study in healthy Chinese subjects. A total of 24 healthy Chinese subjects of both sexes aged between 14 and 45 years were administered a single subcutaneous injection of erenumab 70 mg or 140 mg. The serum concentration of erenumab was quantified using a validated enzyme-linked immunosorbent assay method and pharmacokinetic parameters were determined using non-compartmental models. Safety was also assessed. Results: A total of 55 subjects were screened for eligibility and 25 subjects were randomized to receive study treatments (12 subjects to the 70-mg erenumab group and 13 subjects to the 140-mg erenumab group). Erenumab was absorbed slowly with maximum serum concentration (Cmax) occurring 3–11 days after administration. The mean Cmax and area under the serum concentration versus time curve from time 0 to infinity with extrapolation of the terminal phase (AUC0-∞) were 9.20 µg/mL and 296 day·µg/mL for the 70 mg dose group, and 15.6 µg/mL and 569 day·µg/mL for the 140 mg dose group, respectively. Serum concentrations of erenumab exhibited low to high variability, with variable coefficients ranging from 17.1 to 72.2% for the 70-mg dose and 32.5 to 88.5% for the 140-mg dose. All adverse events were mild or moderate in intensity, and all resolved without intervention. Conclusions: Erenumab was safe and well tolerated after a single subcutaneous injection in healthy Chinese subjects. The systemic exposure in Chinese subjects in terms of AUC0-∞ was 70% higher than that in White subjects as previously reported. Chinese Clinical Trial Registry no.: ChiCTR2000032435. [ABSTRACT FROM AUTHOR]

This correction notice is for an article titled "Pharmacokinetics and Safety of Erenumab after a Single Subcutaneous Injection Dose in Healthy Chinese Subjects." The correction addresses mistakes in the original article, specifically regarding the comparison of systemic exposure in Chinese and White subjects. The corrected details clarify that the comparison was based on a study of limited sample size and should not be generalized to the broader population. Other factors such as safety, efficacy, and variability of exposure should also be considered for ethnic comparison. The correction also acknowledges the contribution of the China NIBR team to the study. [Extracted from the article]

Intravenous ibuprofen, a nonsteroidal anti-inflammatory drug, is widely used as an antipyretic and analgesic in adults and children. This study was designed to evaluate ethnic differences by comparing the pharmacokinetics of intravenous ibuprofen in Caucasian and Chinese populations using physiologically based pharmacokinetics (PBPK) modeling and simulation. A PBPK model for intravenous ibuprofen was developed in adults and children utilizing the Simcyp Simulator. The model was tested and verified against published literature and unpublished data obtained from the Caucasian adult population, Caucasian pediatric population and Chinese adult population. The developed PBPK model could adequately pilot the pharmacokinetics of intravenous ibuprofen, and the major observed values were within the 90% prediction interval in both adults and children. Both folding errors of the maximum peak concentration (C max) and area under the concentration–time curve (AUC) were 1.5-fold less in the Caucasian and Chinese populations. In addition, no significant differences in weight-normalized C max and AUC were observed between the Caucasian and Chinese adult populations. Moreover, there were no obvious pharmacokinetic differences between the Caucasian and Chinese pediatric populations with intravenous infusion (10 minutes) of 10 mg/kg by age group. This study indicates that the pharmacokinetic profile and the parameters of intravenous ibuprofen are analogous in Caucasian and Chinese populations, either adults or children. In addition, this study provides effective evidence that the dosing scheme of intravenous ibuprofen in Chinese children can remain the same as the regimen that the original company (Caldolor®) provided. [Display omitted] [ABSTRACT FROM AUTHOR]

• Unidirectional inversion of ibuprofen enantiomers in Chinese neonates is unclear. • High-throughput UHPLC-MS/MS method to determine ibuprofen enantiomers. • Unexpected pharmacokinetics profile of rac -ibuprofen in Chinese preterm neonates with PDA. Persistent patent ductus arteriosus (PDA) is generally observed in preterm neonates. Oral ibuprofen is the standard treatment for closing PDA in China. To investigate the chiral pharmacokinetics of ibuprofen enantiomers in Chinese premature infants with PDA, a simple, fast, and sensitive analytical enantioselective technology was developed with ultra-performance liquid chromatography (UPLC) – tandem mass spectrometry (MS/MS). Chromatographic separation of (R)-ibuprofen and (S)-ibuprofen was accomplished on a Lux® 3 µm Cellulose-3 (150 mm × 2.0 mm, 3 μm) at a flow rate of 0.2 mL/min within 6 min. UPLC separation was achieved by isocratic elution with a mobile phase consisting of formic acid:water (75:1000000, v/v) and acetonitrile:methanol (1:1, v/v). Only 50 µL of plasma samples were pre-treated with acetonitrile precipitation. Ibuprofen-d 3 was used as an internal standard. The standard curves of both enantiomers were linear over a concentration range of 0.0500 μg/mL to 50.00 μg/mL. The method has been validated for selectivity, carryover effect, lower limit of quantification, precision, accuracy, matrix effect, extraction recovery, dilution integrity, and stability based on the existing guidelines of the National Medical Products Administration, the United States Food and Drug Administration, and the European Medicines Agency. This method has been successfully applied to investigate the pharmacokinetics of ibuprofen enantiomers in 9 preterm infants with PDA. Our results showed that a high chiral inversion ratio of (R)- to (S)-ibuprofen exists in Chinese preterm neonates. Further studies should be conducted to monitor drug concentration following oral administration of ibuprofen and to consider the effect of individual variations and ethnic differences in metabolizing enantiomers of ibuprofen in premature neonates with PDA. [ABSTRACT FROM AUTHOR]

• A UPLC–MS/MS method for quantitative analysis of valsartan, sacubitril and its major metabolite in human plasma, urine and peritoneal dialysis fluid were developed and validated. • This is the first report on a UPLC–MS/MS method for the simultaneous determination of valsartan, sacubitril and LBQ657 concentration in peritoneal dialysis fluid. • This method allowed to better characterize the pharmacokinetic of sacubitril/ valsartan in peritoneal dialysis patients with end-stage renal disease and provided evidence that peritoneal dialysis had an effect on the clearance of sacubitril/valsartan. Sacubitril/valsartan was indicated for the treatment of heart failure and hypertension in patients with end-stage renal disease on peritoneal dialysis therapy. Herein, a rapid, sensitive and robust method based on ultra-liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) was developed and validated for the determination of the concentrations of valsartan, sacubitril and its major metabolite LBQ657 in plasma, urine and peritoneal dialysis fluid. Samples were extracted from various biological fluids using protein precipitation. Extracts were subjected to UPLC–MS/MS with electrospray ionization in positive-ion mode. The developed method was fully validated over a concentration range of 8.00–8000 ng/mL for valsartan, 2.00–2000 ng/mL for sacubitril and 30.0–30,000 ng/mL for LBQ657 in plasma, 2.00–1000 ng/mL for valsartan, 1.00–500 ng/mL for sacubitril and 20.0–10000 ng/mL for LBQ657 in urine, and 0.200–100 ng/mL for valsartan, 0.0400–20.0 ng/mL for sacubitril and 2.00–1000 ng/mL for LBQ657 in peritoneal dialysis fluid. The intra- and inter-day precisions for all analytes in various matrices were less than 12.3%, and the intra- and inter-day accuracies results were all between 88.0% and 109.2%. All analytes were stable for at least 8 h at room temperature (25°C), five freeze–thaw cycles, and 37 days at −40°C and −80°C in plasma, urine and peritoneal dialysis fluid. In conclusion, this developed method is reliable, sensitive and specific for determining the concentrations of valsartan, sacubitril and LBQ657 in plasma, urine and peritoneal dialysis fluid. The assay was available to pilot the pharmacokinetics study of sacubitril/valsartan in patients with end-stage renal disease on peritoneal dialysis, and it could provide evidence that peritoneal dialysis had an effect on the clearance of sacubitril/valsartan. [ABSTRACT FROM AUTHOR]

Mitomycin C (MTC) was incorporated to a micelle system preparing from a polymer named deoxycholic acid chitosan-grafted poly(ethylene glycol) methyl ether (mPEG-CS-DA). mPEG-CS-DA was synthesized and characterized by 1H nuclear magnetic resonance (1H-NMR) and Fourier transform infrared spectroscopy. mPEG-CS-DA formed a core-shell micellar structure with a critical micelle concentration of 6.57 µg/mL. The mPEG-CS-DA micelles were spherical with a hydrodynamic diameter of about 231 nm. After poly(ethylene glycol)ylation of deoxycholic acid chitosan (CS-DA), the encapsulation efficiency and drug loading efficiency increased from 50.62% to 56.42% and from 20.51% to 24.13%, respectively. The mPEG-CS-DA micelles possessed a higher drug release rate than the CS-DA micelles. For pharmacokinetics, the area under the curve (AUC) of the mPEG-CS-DA micelles was 1.5 times higher than that of MTC injection, and these micelles can enhance the bioavailability of MTC. mPEG-CS-DA micelles reduced the distribution of MTC in almost all normal tissues and had the potential to improve the kidney toxicity caused by MTC injection. [ABSTRACT FROM AUTHOR]

SY-007 is an interfering peptide designed to disrupt the cell death signaling of phosphatase and tensin homolog deleted on chromosome ten (PTEN) nuclear translocation during ischemic stroke. Preclinical studies indicated that rats treated with 1.5 mg/kg SY-007 in the middle cerebral artery occlusion (MACO) model had significantly reduced stroke lesion size even when administered 6 h after the stroke onset. The aim of this study was to evaluate the safety, tolerability, and pharmacokinetics of ascending doses of SY-007 administered intravenously in healthy Chinese subjects. A total of 78 healthy Chinese subjects were enrolled in the single ascending dose study (1–60 mg) and received a 15-min intravenous infusion SY-007 or placebo. Plasma concentrations of SY-007 were measured by a validated liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters were determined using non-compartmental and compartment analyses. A model based on target-mediated drug disposition was applied. Model evaluation was performed through visual predictive checks and bootstrap analysis. Across doses of 1–60 mg, SY-007 was well tolerated. All adverse events (AEs) were mild or moderate in intensity, and all resolved without intervention. After infusion, SY-007 plasma concentrations decreased quickly with the mean terminal half-life was shorter than 0.78 h. The area under the concentration-time curve increased with a greater than dose-dependent manner from 1 to 30 mg and resulted in a dose-dependent increased from 30 to 60 mg. The nonlinear phenomenon was well described by a simplified target-mediated drug disposition (TMDD) model. Intravenous dosing of SY-007 appears to be safe up to a dose of 60 mg. Nonlinear pharmacokinetics was observed across the evaluated doses and TMDD might be the primary reason. The effective dose of SY-007 for neuroprotective effect in patients with ischemic stroke is expected to be 10–30 mg and was recommended for the later multiple ascending dose study of SY-007. Clinicaltrials.gov: NCT04111523. [Display omitted] [ABSTRACT FROM AUTHOR]

TAVO101 is a humanized anti‐human thymic stromal lymphopoietin (TSLP) monoclonal antibody under clinical development for the treatment of atopic dermatitis (AD) and other allergic inflammatory conditions. The crystallizable fragment region of the antibody was engineered for half‐life extension and attenuated effector functions. This Phase 1, double‐blinded, randomized, placebo‐controlled study assessed the safety, tolerability, pharmacokinetics, and immunogenicity of TAVO101 in healthy adult subjects in seven ascending dose cohorts. Subjects received a single intravenous administration of TAVO101 or placebo with a 195‐day follow‐up. TAVO101 was safe and well tolerated. The incidences and severities of treatment‐emergent adverse events were mostly mild and comparable between the active and placebo groups, with no trends of dose relationship. There were no severe adverse events, deaths, or treatment‐related withdrawals. TAVO101 exhibited a linear pharmacokinetic profile, low clearance, and a median elimination half‐life of 67 days in healthy subjects. All TAVO101‐treated subjects tested negative for anti‐drug antibodies. To support development in AD, TAVO101 was studied in an oxazolone‐induced AD model in hTSLP transgenic mice and demonstrated efficacy. This long‐acting anti‐TSLP antibody has the potential for stronger and sustained allergic inflammatory disease control. The results from this study warranted further clinical development of TAVO101 in patients. [ABSTRACT FROM AUTHOR]

The main objective of the present research was to evaluate the flexible nano-vesicles for transdermal delivery of osthole. The nano-vesicles were formulated, characterized and evaluated for their physicochemical properties, in vitro skin permeation and in vivo plasma concentration. The encapsulation efficiency of osthole in ethosome and transfersome was measured to be 83.3 ± 4.8% and 80.9 ± 3.6%, respectively. In vitro studies showed that osthole ethosome provided an enhanced transdermal flux of 6.98 ± 1.6 μg/cm 2 /h and a decreased lag time of 2.45 h across porcine ear skin. Moreover, ethosome also showed increased skin deposition of the drug over transfersome (1.5-fold) and saturated solution of osthole in 35% ethanol (2.1-fold). Data from in vivo pharmacokinetic studies showed that AUC and C max of the osthole loaded-ethosome were remarkably increasing compared with the other formulations. Thus, osthole ethosome was considered as an effective delivery system for the drug. [ABSTRACT FROM AUTHOR]