Cmax Values Research Articles

Pharmacokinetic and Ocular Toxicity Evaluation of Latanoprost Ophthalmic Solution, 0.005%, with Preservative Level Reduced to Below the Limit of Quantitation.

Purpose: The systemic and ocular pharmacokinetics (PK), and ocular toxicity of benzalkonium chloride (BAK)-free TearClear latanoprost ophthalmic solution, 0.005% formulation (TC-002) were evaluated. TC-002 is designed to selectively capture BAK at the time of drug administration; therefore, the dose delivered to the eye contains no quantifiable level of preservative. Methods: The systemic and ocular PK of TC-002 were compared to a BAK containing reference listed drug (RLD, Xalatan™) over a 24-h period, after a single topical ocular dose to 1 eye of male Dutch Belted (DB) rabbits (n = 3/timepoint). Latanoprost acid concentrations were measured in plasma and ocular tissues. The ocular toxicity was evaluated in a separate study and included toxicokinetic evaluation of TC-002 after once daily topical ocular dosing into each eye of DB rabbits (n = 8/group) for at least 28 days. Toxicity endpoints included ophthalmic and clinical evaluations, necropsy, and microscopic evaluation of ocular tissues. Results: Average ratios of Cmax values for TC-002/RLD ranged from 0.6 to 1.6, and Cmax and area under the concentration-time curve of last observed concentration (AUClast) exposures to latanoprost acid were similar (<2-fold) between the 2 treatments. In the 28-day study, the Tmax was achieved in both groups in <0.5 h. There were no abnormal ocular findings. Conclusions: TC-002 with no quantifiable preservative or BAK-containing RLD exhibited similar ocular and systemic PK profiles. TC-002 was well tolerated and comparable to RLD. TC-002 retains the safety and PK characteristics of RLD without the added concern of long-term exposure of the eye to preservatives.

Pharmacokinetics in Penguins Compared to Other Avian Species: A Review of Enrofloxacin and Voriconazole.

Australasia is home to unique and endangered avian species. Drug administration to this group of animal patients for prophylaxis and treatment is challenging from a number of different perspectives. A key limitation for optimal drug dosing in birds is the lack of published pharmacokinetic studies to guide dose requirements. The aim of this review was to systematically investigate published literature on pharmacokinetics in penguin species and compare that with the pharmacokinetics of other avian species with a focus on two drugs: enrofloxacin and voriconazole. The review was conducted following PRISMA guidelines. A systematic literature search was performed in Pubmed, Embase, Scopus, and Web of Science databases. A key finding is that penguin pharmacokinetics differs from other avian species, with weight-adjusted AUC and Cmax values higher than most other avian species (e.g., for enrofloxacin, the AUC in the African penguin is 85.7 μg h/mL, which is more than double the other bird species). Doses for some avian species may be successfully extrapolated from other avian species; however, it appears important to consider factors other than just body weight (e.g., clearance mechanism and drug physicochemical characteristics). Consequently, there is an important need for robust pharmacokinetic data in wildlife species to ensure optimal therapy for this special group of patients. As part of this review, we identify key aspects that should be considered when estimating dose in species for which there is limited pharmacokinetic information available.

Comparative Pharmacokinetics of Scoparone and its Metabolite Scopoletin in Normal and ANIT-induced Intrahepatic Cholestatic Rats.

Scoparone, the principal natural active ingredient of Artemisia capillaries (Yin Chen), can effectively treat cholestatic diseases, but the pharmacokinetic properties of scoparone are rarely studied in intrahepatic cholestatic rats. A sensitive and rapid LC-MS/MS method was established to detect scoparone and its metabolite of scopoletin in rat plasma and then compare their plasma pharmacokinetic differences between the normal and ANITinduced cholestasis rats. Positive ionization was used to separate scoparone and scopoletin using acetonitrile and 0.1 % formic acid water as the mobile phase on a Hypersil ODS-BP column. The calibration curves presented good linearity (R=0.9983 and 0.9989) in the concentration range of 10- 10000 ng/mL and 0.5-500 ng/mL for scoparone and scopoletin, respectively. The precision of ≤ 9.4% and the accuracy ranged from -6.4% to 6.8% were recorded over three validation runs, and the recovery was higher than 83.9%. Under different storage conditions, scoparone and scopoletin were stable. Therefore, we studied the pharmacokinetic properties of scoparone and scopoletin in rats after a single oral administration with the above method. According to the results, the pharmacokinetic parameters of AUC, t1/2, and Cmax values of scoparone in the ANIT group were increased by 106%, 75%, and 44%, respectively, while these values of scopoletin were increased by 142%, 62%, and 65%. The findings indicated that the pharmacokinetic properties of scoparone and scopoletin were significantly different between the normal and ANIT-induced cholestasis rats, which suggested that the clinical application dosage of scoparone should be adjusted according to the liver function of patients.

Liver and Plasma Concentrations of Food Chemicals after Virtual Oral Doses Extrapolated Using in silico Estimated Input Pharmacokinetic Parameters to Confirm Reported Liver Toxicity in Rats.

The estimation of health risks of chemical substances was historically investigated using animal studies; however, current research focuses on reducing the number of animal experiments. The toxicity of chemicals in fish screening systems is reportedly correlated with their hydrophobicity. The inverse relationship between absorption rates (intestinal cell permeability) and virtual hepatic/plasma pharmacokinetics of diverse chemicals has been previously evaluated by modeling oral administration in rats. In the current study, internal exposures, i.e., virtual maximum plasma concentrations (Cmax) and areas under the concentration-time curves (AUC), of 56 food chemicals with reported hepatic lowest-observed-effect levels (LOELs) of ≤1000 mg/kg/day in rats were pharmacokinetically modeled using in silico estimated input pharmacokinetic parameters. After a virtual single oral dose of 1.0 mg/kg of 56 food chemicals, the output Cmax and AUC values in rat plasma generated by modeling using the corresponding in silico estimated input parameters were not significantly correlated with the reported hepatic LOEL values. However, significant inverse relationships between hepatic/plasma concentrations of selected lipophilic food chemicals (i.e., octanol-water partition coefficient logP >1) using forward dosimetry and reported LOEL values (≤300 mg/kg/day) were observed (n = 14, r = -0.52-0.66, p ≤ 0.05). This simple modeling approach, which uses no experimental pharmacokinetic data, has the potential to play a significant role in reducing the use of animals to estimate toxicokinetics or internal exposures of lipophilic food components after oral doses. Therefore, these methods are valuable for estimating hepatic toxicity by using forward dosimetry in animal toxicity experiments.

Investigations into Annona fruit consumption as a potential source of dietary higenamine intake in the context of sports drug testing.

Higenamine is prohibited in sports as a β2 -agonist by the World Anti-Doping Agency. As a key component of a great variety of plants, including the Annonaceae family, one aim of this research project was to evaluate whether the ingestion of Annona fruit could lead to higenamine adverse analytical findings. Single-dose administration studies including three Annona species (i.e., Annona muricata, Annona cherimola, and Annona squamosa) were conducted, leading to higenamine findings below the established minimum reporting level (MRL) of 10ng/mL in urine. In consideration of cmax values (7.8ng/mL) observed for higenamine up to 24 h, a multidose administration study was also conducted, indicating cumulative effects, which can increase the risk of exceeding the applicable MRL doping after Annona fruit ingestion. In this study, however, the MRL was not exceeded at any time point. Further, the major urinary excretion of higenamine in its sulfo-conjugated form was corroborated, its stability in urine was assessed, and in the absence of reference material, higenamine sulfo-conjugates were synthesized and comprehensively characterized, suggesting the predominant presence of higenamine 7-sulfate. In addition, the option to include complementary biomarkers of diet-related higenamine intake into routine doping controls was investigated. A characteristic urinary pattern attributed to isococlaurine, reticuline, and a yet not fully characterized bismethylated higenamine glucuronide was observed after Annona ingestion but not after supplement use, providing a promising dataset of urinary biomarkers, which supports the discrimination between different sources of urinary higenamine detected in sports drug testing programs.

Development and validation of an LC-MS/MS method for simultaneous determination of EVT201 and its five metabolites in human plasma: Application to a clinical study in Chinese healthy subjects

EVT201 is a partial GABAA receptor agonist, which inhibits nervous system to treat insomnia. EVT201 can form a variety of metabolites in vivo including Ro46–1927, Ro18–5528, Ro40–9970, Ro66–9196 and Ro66–5448. This study developed a simple method to realize the simultaneous determination of EVT201 and its five metabolites by HPLC-MS/MS with an electrospray ion source (ESI). The deuterium substitute of EVT201 was chosen as the internal standard and the multiple reaction monitoring (MRM) was used for the quantification. The separation of the six compounds was accomplished with an ACE Excel 3 AQ column (50 × 2.1 mm, 3 µm, ACE). The process of protein precipitating-transferring-nitrogen blowing-reconstituting was adopted for the sample pretreatment. This method was successfully validated according to the FDA guidance. Calibration curves were linear over the concentration range of 0.100–100 ng/mL for EVT201, 0.0300–30.0 ng/mL for Ro46–1927, 0.0600–6.00 ng/mL for Ro18–5528, 0.0200–4.00 ng/mL for Ro40–9970, 0.100–20.0 ng/mL for Ro66–9196 and 0.100–20.0 ng/mL for Ro66–5448. The intra-run and inter-run precisions and accuracies were all within 14.5%. This fully validated method was successfully applied to a clinical pharmacokinetic study of EVT201 and its five metabolites in Chinese healthy subjects after the single (2.5 mg and 5 mg, N = 12) and multiple dose (2.5 mg, N = 13) administration of EVT201 capsules. The test results of 2.5 mg dose group showed that for EVT201, Ro46–1927, Ro18–5528, Ro40–9970, Ro66–9196 and Ro66–5448, the Cmax values (ng/mL) were 39.2 ± 9.2, 10.3 ± 1.4, 0.218 ± 0.044, 0.128 ± 0.051, 7.01 ± 1.51, 8.73 ± 3.69, respectively; the AUC0−t values (h·ng/mL) were 231 ± 79, 143 ± 72, 10.9 ± 2.1, 1.84 ± 0.78, 55.9 ± 18.7, 135 ± 40 respectively. For EVT201, Ro46–1927, Ro66–5528, Ro66–9196 and Ro40–5448, the results of Cmax and AUC0−t proved that the five compounds showed linear pharmacokinetic profile over the dose ranges of 2.5 mg to 5 mg. Meanwhile, it is the first report to evaluate the pharmacokinetic characteristics of Ro40–9970, Ro66–9196 and Ro66–5448 in human plasma. It provided meaningful parameters for the safety and tolerability evaluation of EVT201 capsules in human.

Discovery of Hybrid Thiouracil-Coumarin Conjugates as Potential Novel Anti-SARS-CoV-2 Agents Targeting the Virus's Polymerase "RdRp" as a Confirmed Interacting Biomolecule.

The coronavirus (COVID-19) pandemic, along with its various strains, has emerged as a global health crisis that has severely affected humankind and posed a great challenge to the public health system of affected countries. The replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mainly depends on RNA-dependent RNA polymerase (RdRp), a key enzyme that is involved in RNA synthesis. In this regard, we designed, synthesized, and characterized hybrid thiouracil and coumarin conjugates (HTCAs) by ether linkage, which were found to have anti-SARS-CoV-2 properties. Our in vitro real-time quantitative reverse transcription PCR (RT-qPCR) results confirmed that compounds such as 5d, 5e, 5f, and 5i inhibited the replication of SARS-CoV-2 with EC50 values of 14.3 ± 0.14, 6.59 ± 0.28, 86.3 ± 1.45, and 124 ± 2.38 μM, respectively. Also, compound 5d displayed significant antiviral activity against human coronavirus 229E (HCoV-229E). In addition, some of the HTCAs reduced the replication of SARS-CoV-2 variants such as D614G and B.617.2. In parallel, HTCAs in uninfected Vero CCL-81 cells indicated that no cytotoxicity was noticed. Furthermore, we compared the in silico interaction of lead compounds 5d and 5e toward the cocrystal structure of Suramin and RdRp polymerase with Remdesvir triphosphate, which showed that compounds 5d, 5e, and Remdesvir triphosphate (RTP) share a common catalytical site of RdRp but not Suramin. Additionally, the in silico ADMET properties predicted for the lead HTCAs and RTP showed that the maximum therapeutic doses recommended for compounds 5d and 5e were comparable to those of RTP. Concurrently, the pharmacokinetics of 5d was characterized in male Wistar Albino rats by administering a single oral gavage at a dose of 10 mg/kg, which gave a Cmax value of 0.22 μg/mL and a terminal elimination half-life period of 73.30 h. In conclusion, we established a new chemical entity that acts as a SARS-CoV-2 viral inhibitor with minimal or no toxicity to host cells in the rodent model, encouraging us to proceed with preclinical studies.

Biopolymer-Capped Pyrazinamide-Loaded Colloidosomes: In Vitro Characterization and Bioavailability Studies.

This study aimed to prepare colloidosome particles loaded with pyrazinamide (PZA). These drug-loaded colloidosomes were prepared using an in situ gelation technique using a central composite design with a shell made of calcium carbonate (CaCO3) particles. Optimal amounts of 150 mg of CaCO3, sodium alginate (2%), and 400 mg of poly(3-hydroxybutyrate-co-3-hydroxy valerate) (PHBV) concentration resulted in the maximum drug loading and efficient release profile. Field emission scanning electron microscopy results showed spherical porous particles with a good coating of the PHBV polymer. Additionally, Fourier transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), thermogravimetric and differential thermal analysis (TGA-DTA), and X-ray diffraction (XRD) analysis showed good compatibility between the drug and excipients. The pharmacokinetic studies demonstrated that the drug-loaded colloidosomes resulted in 4.26 times higher plasma drug concentrations with Cmax values of 32.386 ± 2.744 mcg/mL (PZA solution) and 115.868 ± 53.581 mcg/mL (PZA-loaded colloidosomes) and AUC0-t values of 61.24 mcg-h/mL (PZA solution) and 260.9 mcg-h/mL (PZA-loaded colloidosomes), indicating that colloidosomes have the potential to be effective drug carriers for delivering PZA to the target site.

Discovery of tetrahydroisoquinolineindole derivatives as first dual PRMT5 inhibitors/hnRNP E1 upregulators: Design, synthesis and biological evaluation

Protein arginine methyltransferase 5 (PRMT5) is an epigenetics related enzyme that has been validated as an important therapeutic target for treating various types of cancer. Upregulation of tumor suppressor hnRNP E1 has also been considered as an effective antitumor therapy. In this study, a series of tetrahydroisoquinolineindole hybrids were designed and prepared, and compounds 3m and 3s4 were found to be selective inhibitors of PRMT5 and upregulators of hnRNP E1. Molecular docking studies indicated that compounds 3m occupied the substrate site of PRMT5 and formed essential interactions with amino acid residues. Furthermore, compounds 3m and 3s4 exerted antiproliferative effects against A549 cells by inducing apoptosis and inhibiting cell migration. Importantly, silencing of hnRNP E1 eliminated the antitumor effect of 3m and 3s4 on the apoptosis and migration in A549 cells, suggesting a regulatory relationship between PRMT5 and hnRNP E1. Additionally, compound 3m exhibited high metabolic stability on human liver microsomes (T1/2 = 132.4 min). In SD rats, the bioavailability of 3m was 31.4%, and its PK profiles showed satisfactory AUC and Cmax values compared to the positive control. These results suggest that compound 3m is the first class of dual PRMT5 inhibitor and hnRNP E1 upregulator that deserves further investigation as a potential anticancer agent.

Non-potable water reuse and the public health risks from protozoa and helminths: a case study from a city with a semi-arid climate.

The study estimated the risk due to Cryptosporidium, Giardia, and Ascaris, associated with non-potable water reuse in the city of Jaipur, India. The study first determined the exposure dose of Cryptosporidium, Giardia, and Ascaris based on various wastewater treatment technologies for various scenarios of reuse for six wastewater treatment plants (WWTPs) in the city. The exposure scenarios considered were (1) garden irrigation; (2) working and lounging in the garden; and (3) consumption of crops irrigated with recycled water. The estimated annual risk of infection varied between 8.57 × 10-7 and 1.0 for protozoa and helminths, respectively. The order of treatment processes, in decreasing order of annual risk of infection, was found to be: moving-bed bioreactor (MBBR) technology > activated sludge process (ASP) technology > sequencing batch reactor (SBR) technology. The estimated annual risk was found to be in this order: Ascaris > Giardia > Cryptosporidium. The study also estimated the maximum allowable concentration (Cmax) of pathogen in the effluent for a benchmark value of annual infection of risk equal to 1:10,000, the acceptable level of risk used for drinking water. The estimated Cmax values were found to be 6.54 × 10-5, 1.37 × 10-5, and 2.89 × 10-6 (oo) cysts/mL for Cryptosporidium, Giardia, and Ascaris, respectively.

Bioequivalence Study of Salbutamol 400 mg Tablet in Healthy Indonesian Volunteers by Liquid Chromatography Tandem with Mass Spectrometry

This study objective was to determine the bioequivalence of Salbutamol 4 mg Tablet manufactured by PT Kimia Farma Tbk compared to Ventolin® 2x2 mg Tablet manufactured by Glaxo Wellcome Indonesia, in healthy Indonesian volunteer. The pharmacokinetic parameters calculated in this study are AUC0-24, AUC0-inf, Cmax, Tmax, and T1/2. The study was conducted in a randomized, single-dose, open-label, two-way crossover design (2 treatments, 2 periods, and 2 sequences) under fasting state with 7 (seven) days washed-out period. The number of subjects who participated in the study were 24 volunteers ((12 males and 12 females). The participants were provided with an overview of the study and signed the informed consent form. The study participants underwent a minimum 8-hour fasting period prior to receiving both the test drug and the reference drug, and blood samples were collected at 14 specified time points: 0 hours (before drug administration), minutes-20, minutes-40, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, and 24 hours after drug administration. Plasma concentrations of the drug were determined by LCMS/MS method. The acceptance criteria for the bioequivalence test are 80.00 - 125.00% for AUC0-t and Cmax with 90% Confidence Interval (CI) with α = 5.00%. The mean SD value of AUC0-24, AUC0-inf, Cmax, Tmax, and T1/2 respectively for test drug is 84.49 ±18.99 ng.mL-1.hour; 89.66 ±21.29 ng.mL-1.hour; 13.85 ±4.25 ng/mL; 2.00 ±0.71 hour and 5.08 ±1.27 hour. The mean SD values of AUC0-24, AUC0-inf, Cmax, Tmax, and C1/2 respectively for reference drug are 88.81 ±26.50 ng.mL-1.jam; 93.78 ±27.97 ng.mL-1.jam; 13.39 ±5.39 ng/mL; 2.63 ±1.45 hour and 5.03 ±1.16 hour. Meanwhile, the geometric mean ratio of test drug to reference drug (90% confidence interval) is 96.35% (90.55- 102.53%) for AUC0-24 and 105.39% (93.62-118.65%) for Cmax. Based on the AUC0-24 and Cmax values, Salbutamol 4 mg Tablet manufactured by PT Kimia Farma Tbk is bioequivalent to Ventolin® 2x2 mg Tablet manufactured by Glaxo Wellcome Indonesia.

Bioequivalence Study of Zidovudine 100 Mg Capsule with TwoWay Crossover Design

Zidovudine is a synthetic nucleoside analogue, specifically a nucleoside reverse transcriptase inhibitor (NRTI), that inhibits the replication of retroviruses, including HIV. Study Objective: This study objective was to determine the bioequivalence of Zidovudine 100 mg capsules produced by PT Kimia Farma Tbk compared to Retrovir 100 mg capsules produced by GlaxoSmithKline Pharmaceuticals S.A, in healthy subjects Methods: The study was conducted in a randomized, single-dose, open-label, two-way crossover design (2 treatments, 2 periods, and 2 sequences) under fasting state with 7 (seven) days washed-out period between each period. The number of subjects who participated and completed the study were 31 of 32 adult male and female. One subject dropped out from 2nd period because of personal reason. The subjects received an explanation of the study and signed informed consent. Subjects fasted for a minimum of 8 hours before receiving the test drug and reference drug. Blood samples were collected 15 times at the following time points: 0 hours (before drug administration), 0.16, 0.33, 0.50, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 10 hours after drug administration. Plasma concentrations of the drug were determined by LC-MS/MS method. The pharmacokinetic parameters calculated in this study are AUC0-t, AUC0-inf, Cmax, tmax, and t½, while the statistical interval proposed was 80.00 - 125.00% for AUC0-t and Cmax with 90% Confidence Interval (CI) with α = 5.00%. Results: The main pharmacokinetic parameters of the test drug Zidovudine (BN: G2 1346 J) compared to reference drug, Retrovir (BN: JN8K) were calculated based on geometric mean ratio and 90% confidence interval (CI). The results for AUC0-t and Cmax were 101.65% (96.77- 106.83%) and 95.63% (84.09-108.76%) respectively, with intra-subject variability (%CV) for AUC0-t and Cmax were 11.49% and 30.47%. Hence, the number of 31 subjects has adequate number for required power of study. Conclusion: Based on the AUC0-t and Cmax values, Zidovudine 100 mg Capsules Produced by PT. Kimia Farma Tbk is bioequivalent to Retrovir 100 mg Capsules Produced by GlaxoSmithKline Pharmaceuticals S.A.

Pharmacokinetic Evaluation of Telmisartan and Cilnidipine Bilayer Tablet in A Rabbit Model

Hypertension is a chronic medical condition affecting a significant proportion of the global population. It is a major risk factor for cardiovascular diseases, stroke, and kidney failure. Telmisartan and cilnidipine combination are commonly used in managing hypertension due to their complementary mechanism of action. Therefore, a bilayer tablet design that enhances the pharmacokinetic profile of cilnidipine as a sustained-release drug while telmisartan act as an immediate-release drug may provide a better therapeutic option for hypertension management. We aim to evaluate the pharmacokinetic parameters of the bilayer tablet of Telmisartan and Cilnidipine. Our objective is to observe the bioavailability of the bilayer tablet in rabbit plasma. The formulation aims to achieve an immediate release effect for Telmisartan and a sustained release effect for Cilnidipine. The solubility and bioavailability of Telmisartan were enhanced by complexation with beta-cyclodextrin. To achieve our aim, we observe the drug concentration in rabbit plasma. Telmisartan is an angiotensin receptor blocker, while Cilnidipine is a calcium channel blocker. The pharmacokinetics of the drugs were evaluated in New Zealand rabbits following oral administration. Systemic drug bioavailability was assessed, and an HPLC method was developed to estimate Telmisartan and Cilnidipine's plasma concentration simultaneously. A Gemini C-18 column (250 mm X 4.6 mm X 5 microns) Phenomenex was used for peak separation. The mobile phase consisted of acetonitrile with phosphate buffer pH 3.5 v/v, with a flow rate of 1.5 ml per minute. The calibration curve analysis indicated a correlation coefficient of 0.9996 and 0.9997 for Telmisartan and Cilnidipine, respectively. The pharmacokinetics of the optimized batch, including Cmax, Tmax, and AUC values, were compared to those of the pure drug. Drug concentration was detected using a DAD detector with an excitation wavelength of 241nm. No interaction was observed between the drugs and excipients. The in-vivo study of the formulation showed higher bioavailability, indicating that the developed bilayer tablet formulation could be an effective means of delivering Telmisartan and Cilnidipine.

Comparative pharmacokinetics of six bioactive components of Shen-Wu-Yi-Shen tablets in normal and chronic renal failure rats based on UPLC-TSQ-MS/MS

Ethnopharmacological relevanceShen-Wu-Yi-Shen tablets (SWYST), a Chinese patent medicine consisting of 12 herbal medicines, was formulated by a famous TCM nephrologist, Zou Yunxiang. It is clinically used to improve the symptoms of nausea, vomiting, poor appetite, dry mouth and throat, and dry stool in patients with chronic renal failure (CRF) accompanied by qi and yin deficiency, dampness, and turbidity. SWYST can reduce urea nitrogen, blood creatinine, and urinary protein loss, and increase the endogenous creatinine clearance rate. However, little is known about its pharmacokinetics. Aim of studyTo compare the pharmacokinetics of six bioactive components after oral administration of SWYST in normal and adenine-induced CRF rats. Materials and methodsA method based on ultra-performance liquid chromatography coupled with a triple-stage quadrupole mass spectrometer (UPLC-TSQ-MS/MS) was developed and validated to determine the six bioactive compounds (albiflorin, paeoniflorin, plantagoguanidinic acid, rhein, aloe-emodin, and emodin) in rat plasma. Rat plasma samples were prepared using protein precipitation. Chromatography was performed on an Agilent Eclipse Plus C18 column (3.0 × 50 mm, 1.8 μm) using gradient elution with a mobile phase composed of acetonitrile and water containing 0.1% (v/v) formic acid, while detection was achieved by electrospray ionization MS under the multiple selective reaction monitoring modes. After SWYST administration, rat plasma was collected at different time points, and the pharmacokinetic parameters of six analytes were calculated and analyzed based on the measured plasma concentrations. ResultsThe UPLC-TSQ-MS/MS method was fully validated for its satisfactory linearity (r ≥ 0.9913), good precisions (RSD <11.5%), and accuracy (RE: -13.4∼13.1%), as well as acceptable limits in the extraction recoveries, matrix effects, and stability (RSD <15%). In normal rats, the six analytes were rapidly absorbed (Tmax ≤ 2 h), and approximately 80% of their total exposure was eliminated within 10 h. Moreover, in normal rats, the AUC0-t and Cmax of albiflorin, plantagoguanidinic acid, and rhein exhibited linear pharmacokinetics within the dose ranges, while that of paeoniflorin is non-linear. However, in CRF rats, the six analytes exhibited reduced elimination and significantly different AUC or Cmax values. These changes may reflect a decreased renal clearance rate or inhibition of drug-metabolizing enzymes and transporters in the liver and gastrointestinal tract caused by CRF. ConclusionsA sensitive UPLC-TSQ-MS/MS method was validated and used to investigate the pharmacokinetics of SWYST in normal and CRF rats. This is the first study to investigate the pharmacokinetics of SWYST, and our findings elucidate the causes of their different pharmacokinetic behaviors in CRF rats. Furthermore, the results provide useful information to guide further research on the pharmacokinetic-pharmacodynamic correlation and clinical application of SWYST.

Performance of MOS Capacitor with Different Dielectric Material Simulated Using Silvaco TCAD Tools

Metal oxide semiconductor (MOS) capacitor is a trilayer device that comprises of metal, dielectric, and semiconductor layer. The advancement of MOS technology has greatly give huge improvement to MOS devices which lead to scaling down the MOS devices. The reduction of dielectric thickness of conventional dielectric material has coming to an end, therefore as alternative new material with high mobility carrier is suggested to overcome the problem. The objectives of this work are to study the performance of MOS capacitor. Two parameters were varied, first the semiconductor material which is silicon (Si), germanium (Ge) and silicon germanium (SiGe) and second is the dielectric material that is silicon dioxide (SiO2) and silicon nitride (Si3N4). The performance of the MOS capacitor is evaluated based on the capacitance-voltage (C-V) and current-voltage (I-V) characteristics. Silvaco TCAD tool were use as as simulation tool for the method of investigation. Result shown that the performance of the MOS capacitor increased when Ge and SiGe were used as semiconductor material and Si3N4 as dielectric layer. It can see that with VT of 4.15 V for MOS with Ge and 4.28 V for MOS with SiGe. For the C-V properties Cmax value for both devices are F and F, respectively. The results show that there is around 100% increment in capacitance value when Ge is used as semiconductor layer but there is no increment or decrement in capacitance value when SiGe is used. Based on the obtained results, Ge is chosen as the best semiconductor material.

Physiologically-Based Pharmacokinetic Modeling of PAXLOVID™ with First-Order Absorption Kinetics.

PAXLOVID™ is nirmatrelvir tablets co-packaged with ritonavir tablets. Ritonavir is used as a pharmacokinetics (PK) enhancer to reduce metabolism and increase exposure of nirmatrelvir. This is the first disclosure of Paxlovid physiologically-based pharmacokinetic (PBPK) model. Nirmatrelvir PBPK model with first-order absorption kinetics was developed using in vitro, preclinical, and clinical data of nirmatrelvir in the presence and absence of ritonavir. Clearance and volume of distribution were derived from nirmatrelvir PK obtained using a spray-dried dispersion (SDD) formulation where it is considered to be dosed as an oral solution, and absorption is near complete. The fraction of nirmatrelvir metabolized by CYP3A was estimated based on in vitro and clinical ritonavir drug-drug interaction (DDI) data. First-order absorption parameters were established for both SDD and tablet formulation using clinical data. Nirmatrelvir PBPK model was verified with both single and multiple dose human PK data, as well as DDI studies. Simcyp® first-order ritonavir compound file was also verified with additional clinical data. The nirmatrelvir PBPK model described the observed PK profiles of nirmatrelvir well with predicted AUC and Cmax values within ± 20% of the observed. The ritonavir model performed well resulting in predicted values within twofold of observed. Paxlovid PBPK model developed in this study can be applied to predict PK changes in special populations, as well as model the effect of victim and perpetrator DDI. PBPK modeling continues to play a critical role in accelerating drug discovery and development of potential treatments for devastating diseases such as COVID-19. NCT05263895, NCT05129475, NCT05032950 and NCT05064800.

LC-MS/MS based quantification of steroidal biomarkers in polycystic ovary syndrome induced rats

Polycystic ovary syndrome (PCOS) is a common endocrine disorder that causes reproductive hormones imbalance, missed periods, infertility and distributed steroidogenesis. Reportedly, during PCOS, the endogenous levels of P4 (Progesterone), 17OHP4 (17-α hydroxy progesterone), and T4 (Testosterone) were significantly altered. Thus, quantification of steroid biomarkers involved in the steroidogenesis pathway of PCOS, such as P4, 17OHP4, and T4, holds significant importance. One important drawback of current methods is steroid metabolome traceability. Without adequate traceability, the findings of these techniques will be less reliable for identifying P4, 17OHP4, and T4. These methods also need a high sample size, especially for the most important biomarker that initiates steroidogenesis. To address these challenges, we require a new liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for steroid biomarker analysis. Herein the present work, using validated LC-MS/MS, PCOS biomarkers were measured and compared between normal control rats and PCOS-induced rats before and after analyte administration. The experiment utilized an isocratic separation method employing an analytical C18 column. The mobile phase consisted of acetonitrile (ACN) and aqueous 0.1% formic acid (FA) in a ratio of 90:10 (v/v). The plasma samples were processed with protein precipitation (PPT) followed by the liquid-liquid extraction (LLE) method. The lower limit of quantification (LLOQ) was 0.5 ng/mL in plasma. According to USFDA criteria, the method's systematic validation took into account linearity (r2 > 0.99), accuracy and precision of intra- and inter-batch measurements, stability, biomarker recovery (60–85%) and matrix effect (<± 15%), all of which were determined to be within range ( ± 15%). The pharmacokinetic data showed that, as compared to normal rats, PCOS-induced animals had significantly higher Cmax values for 17OHP4 and T4 (∼2 fold), while lower Cmax values for P4 (∼2 fold). The present work is novel and provides scientific information to explore systematic processes involved in steroidogenesis and boost clinical applicability for PCOS therapy.

Association between Food/UGT2B7 Polymorphisms and Pharmacokinetics/Pharmacodynamics Properties of Indapamide in Healthy Humans.

Indapamide is an effective and safe antihypertensive medication showing a beneficial effect in combination with other antihypertensive agents regarding morbidity and mortality. A comparative study was performed under fasting and fed conditions to investigate the effect of food and selected single nucleotide polymorphisms in the uridine diphosphate glucuronyl transferase (UGT2B7) gene on the pharmacokinetics and pharmacodynamics behavior of indapamide 1.5 mg sustained release. Forty-nine healthy volunteers aged 18-55 years were randomized into two groups; 25 volunteers were administered indapamide under fasting conditions and 24 under fed conditions. Genotyping of the UGT2B7 rs7438135 and rs11740316 was done before commencing the study using predesigned TaqMan assays. Results showed that food independently decreased the value of indapamide' Tmax by 5.5 h and increased the value of Cmax by 8.7 ng/mL. On the other hand, all genetic variants of both UGT2B7 SNPs had no significant impact on the values of Tmax, Cmax, and AUC0-t; however, it was found that rs11740316 variant AG was correlated with a 2.8 h lower MRTinf. Finally, BMI positively correlated with longer MRTinf. It was concluded that none of rs7438135, rs11740316, or food had a significant impact on the pharmacodynamic properties. Food had a modest impact on indapamide Cmax and Tmax values, while there were unremarkable differences in safety and efficacy.

Preclinical Pharmacokinetic Profile of Topical Ophthalmic and Intravenous Delivery of QLS-101, a Novel ATP-Sensitive Potassium Channel Opening Ocular Hypotensive Agent.

Purpose: To evaluate the pharmacokinetic profiles of the ocular hypotensive agent QLS-101, a novel ATP-sensitive potassium channel opening prodrug, and its active moiety levcromakalim, following topical ophthalmic and intravenous dosing of normotensive rabbits and dogs. Methods: Dutch belted rabbits (n = 85) and beagle dogs (n = 32) were dosed with QLS-101 (0.16-3.2 mg/eye/dose) or formulation buffer for 28 days. Pharmacokinetic profiles of QLS-101 and levcromakalim were evaluated in ocular tissues and blood by LC-MS/MS. Tolerability was assessed by clinical and ophthalmic examinations. Maximum systemic tolerated dose was evaluated in beagle dogs (n = 2) following intravenous bolus administrations of QLS-101 (0.05 to 5 mg/kg). Results: Plasma analysis following topical dosing of QLS-101 (0.8-3.2 mg/eye/dose) for 28 days indicated an elimination half-life (T1/2) of 5.50-8.82 h and a corresponding time (Tmax) range of 2-12 h in rabbits, and a T1/2 of 3.32-6.18 h with a Tmax range of 1-2 h in dogs. Maximum tissue concentration (Cmax) values ranged from 54.8-540 (day 1) to 50.5-777 ng/mL (day 28) in rabbits, and 36.5-166 (day 1) to 47.0-147 ng/mL (day 28) in dogs. Levcromakalim plasma T1/2 and Tmax were similar to QLS-101, while Cmax was consistently lower. Topical ophthalmic delivery of QLS-101 was well tolerated in both species, with sporadic mild ocular hyperemia noted in the group treated with the highest concentration (3.2 mg/eye/dose). Following topical ophthalmic dosing, QLS-101 and levcromakalim were found primarily in the cornea, sclera, and conjunctiva. Maximum tolerated dose was determined to be 3 mg/kg. Conclusions: QLS-101 was converted to its active moiety levcromakalim and showed characteristic absorption, distribution, and safety profiles of a well-tolerated prodrug.

A Bioequivalence Study of Allergostin® Compared to Administration of Kestin® in Healthy Volunteers

Relevance. International non-proprietary name (INN) Ebastin is widely used in medical practice in the treatment of urticaria and allergic rhinitis. It is an antiallergic drug, which belongs to the second generation of H1-histamine receptor blocker, it is necessary to emphasize that Ebastin is effective when taken orally. As part of the registration of trade name Allergostin, a clinical study of its bioequivalence with Kestin was conducted with the participation of 26 healthy volunteers.&#x0D; Aim. The aim of this publication is summarize results of the clinical study of the comparative pharmacokinetics and bioequivalence, safety and tolerability of Allergostin, film-coated tablets, 20 mg (NTFF POLYSAN LLC, Russia), and Kestin, film-coated tablets, 20 mg (Almiral S.A., Spain), in healthy volunteers after a single oral dose on an empty stomach.&#x0D; Materials and methods. To confirm bioequivalence, an open, randomized, two-period, cross-over study of comparative pharmacokinetics and bioequivalence of drugs with a single oral intake on an empty stomach in adult healthy male and female volunteers was conducted. During the study, blood plasma samples were taken from volunteers. Each sample was tested by using a validated high performance liquid chromatography with tandem mass spectrometry method, the concentrations of ebastine and the active metabolite carabastin were determined. Based on obtained data , pharmacokinetic and statistical analysis was carried out, 90% confidence intervals (CI) were calculated for the ratio of the geometric mean values of the pharmacokinetic parameters Cmax and AUC0-72 for carabastin.&#x0D; Results. Based on results of statistical analysis, it was shown that the pharmacokinetic parameters of the test (Allergostin) and reference (Kestin) drug are characterized by high similarity. For the estimated pharmacokinetic parameters of carabastin, 90% CI ranged from 80-125% for AUC0-t and Cmax.&#x0D; Conclusion. Thus, according to the applied criteria, the drugs are recognized as bioequivalent.