Clearance Values Research Articles

Meropenem Pharmacokinetics and Target Attainment in Critically Ill Patients.

This study aimed to investigate the pharmacokinetics and target attainment of meropenem and compare the effect of meropenem dosing regimens in critically ill patients. Thirty-seven critically ill patients who were administered meropenem in intensive care units were analyzed. Patients were classified according to their renal function. Pharmacokinetic parameters were assessed based on Bayesian estimation. The target attainment of 40%fT > MIC (fraction time that the free concentration exceeds the minimum inhibitory concentration) and 100%fT > MIC with the pathogen MIC of 2 mg/L and 8 mg/L were specially focused. Furthermore, the effects of standard dosing (1g meropenem, 30 min intravenous infusion every 8h) and non-standard dosing (dosage regimens except standard dosing) were compared. The results showed that the values of meropenem clearance (CL), central volume of distribution (V1), intercompartmental clearance (Q), and peripheral volume of distribution (V2) were 3.3 L/h, 9.2 L, 20.1 L/h and 12.8 L, respectively. The CL of the patients among renal function groups was significantly different (p < 0.001). The tow targets attainment for the pathogen MIC of 2 mg/L and 8 mg/L were 89%, 73%, 49% and 27%, respectively. The severe renal impairment group has higher fraction of target attainment than the other group. The standard dosing achieved the target of 40%fT > 2/8 mg/L (85.7% and 81%, respectively) and patients with severe renal impairment achieved the target fraction of 100% for 40%fT > MIC. Additionally, there was no significant difference between standard and non-standard dosing group in target attainment. Our findings indicate that renal function is an important covariate for both meropenem pharmacokinetics parameters and target attainment. The target attainment between standard and non-standard dosing group was not comparable. Therefore, therapeutic drug monitoring is indispensable in the dosing adjustment for critically ill patients if it is available.

Phase 1 study of indenoisoquinoline LMP744 in adults with relapsed solid tumors and lymphomas.

3022 Background: Indenoisoquinolines (IIQ) are non-camptothecin inhibitors of topoisomerase 1 (TOP1) that have improved characteristics over camptothecin TOP1 inhibitors. IIQs demonstrate better chemical stability, produce more persistent DNA breaks induced by trapping DNA-TOP1 cleavage complexes, induce DNA breaks at different sites than camptothecins, and are not substrates for cellular export proteins. We present data from a trial of LMP744 (NSC 706744), which was the most efficacious IIQ in a canine lymphoma trial, designed to establish the safety, efficacy, and maximum tolerated dose (MTD) of LMP744. Methods: We conducted a multicenter phase 1 trial in adult patients (pts) with dose escalations following design 3 of the Simon accelerated titration designs. LMP744 was administered intravenously daily on d1-5 in 28-day cycles (C), starting at dose level (DL) 1 (6 mg/m2/d). Responses and adverse events (AEs) were defined by RECIST 1.1 and CTCAE v4.0, respectively. Plasma concentrations were determined by LC-MS/MS with a validated assay over a range of 1-3,000 ng/mL. Paired biopsies (baseline and C1D2) were analyzed for DNA damage response markers (γH2AX, pNBS1, and Rad51) by IFA. Results: A total of 36 pts were enrolled, median age was 61 years (range 35-81), median prior lines of systemic treatment was 5 (range 2-10) and 26 pts (72%) had received prior TOP1 inhibitor therapy. One pt on DL6 (190 mg/m2/d) experienced a dose-limiting toxicity (DLT) of grade 3 hypokalemia during C1, reverting the study to a 3+3 design. MTD was established at DL6. Of 24 patients evaluable for response, 1 pt with small cell lung cancer on DL6 achieved a partial response (PR), remaining on treatment for 7C. 17 pts had stable disease (including 1 pt with an unconfirmed PR), and 6 had progressive disease. Median duration of response among pts with SD was 4.5C (range 1-28). A total of 6 pts on DL6 with colorectal cancer (n=4, all had received prior irinotecan), mesothelioma (n=1), and low-grade appendiceal mucinous neoplasm (n=1) remained on study for &gt;6C. Treatment-related grade 3/4 AEs included leukopenia (n=9), anemia (n=4), dehydration (n=2), neutropenia (n=2) and nausea (n=2). Pharmacokinetic (PK) data for the first 17 patients suggests dose-linear PK, best fit to a 2-compartment model. Approximate half-life, clearance, central and peripheral volume values were 30 h, 90 L/h, 200 L, and 2500 L, respectively. Induction of γH2AX and Rad51 was measured in the pt with PR. Conclusions: The MTD of LMP744 was established at 190 mg/m2/d on d1-5 in a 28d C. The single agent activity of LMP744 in this heavily pretreated population was limited; however, 4 colorectal cancer pts had prolonged stabilization of disease with prior progression on irinotecan. Analyses of secondary and exploratory correlatives are ongoing. Clinical trial information: NCT03030417 .

Unravelling the Hepatic Elimination Mechanisms of Colistin.

Colistin is an antibiotic which is increasingly used as a last-resort therapy in critically-ill patients with multidrug resistant Gram-negative infections. The purpose of this study was to evaluate the mechanisms underlying colistin's pharmacokinetic (PK) behavior and to characterize its hepatic metabolism. In vitro incubations were performed using colistin sulfate with rat liver microsomes (RLM) and with rat and human hepatocytes (RH and HH) in suspension. The uptake of colistin in RH/HH and thefraction of unbound colistin in HH (fu,hep) was determined. In vitro to in vivo extrapolation (IVIVE) was employed to predict the hepatic clearance (CLh) of colistin. Slow metabolism was detected in RH/HH, with intrinsic clearance (CLint) values of 9.34± 0.50 and 3.25 ± 0.27mL/min/kg, respectively. Assuming the well-stirred model for hepatic drug elimination, the predicted rat CLh was 3.64± 0.22mL/min/kg which could explain almost 70% of the reported non-renal in vivo clearance. The predicted human CLh was 91.5 ± 8.83mL/min, which was within two-fold of the reported plasma clearance in healthy volunteers. When colistin was incubated together with the multidrug resistance-associated protein (MRP/Mrp) inhibitor benzbromarone, the intracellular accumulation of colistin in RH/HH increased significantly. These findings indicate the major role of hepatic metabolism in the non-renal clearance of colistin, while MRP/Mrp-mediated efflux is involved in the hepatic disposition of colistin. Our data provide detailed quantitative insights into the hereto unknown mechanisms responsible for non-renal elimination of colistin.

Failure to predict amikacin elimination in critically ill patients with cancer based on the estimated glomerular filtration rate: applying PBPK approach in a therapeutic drug monitoring study.

The aim of this work was to integrate the Therapeutic Drug Monitoring (TDM) with the model-informed precision dosing (MIPD) approach, using Physiologically-based Pharmacokinetic/Pharmacodynamic (PBPK/PD) modelling and simulation, to explore the relationship between amikacin exposure and estimated glomerular filtration rate (GFR) in critically ill patients with cancer. In the TDM study, samples from 51 critically-ill patients with cancer treated with amikacin were analysed. Patients were stratified according to renal function based on GFR status. A full-body PBPK model with 12 organs model was developed using Simcyp V. 21, including steady-state volume of distribution of 0.21 L/kg and renal clearance of 6.9 L/h in healthy adults. PK parameters evaluated were within the 2-fold error range. During the validation step, predicted vs observed amikacin clearance values after single infusion dose in patients with normal renal function, mild and moderate renal impairment were 7.6 vs 8.1 L/h (7.5mg/kg dose); 3.8 vs 4.5 L/h (1500mg dose) and 2.2 vs 3.1 L/h (25mg/kg dose), respectively. However, predicted vs observed amikacin clearance after a single dose infusion of 1400mg in critically-ill patients with cancer were 1.46 vs 1.63 (P = 0.6406) L/h (severe), 2.83 vs 1.08 (P < 0.05) L/h (moderate), 4.23 vs 2.49 (P = 0.0625) L/h (mild) and 7.41 vs 3.36 (P < 0.05) L/h (normal renal function). This study demonstrated that estimated GFR did not predict amikacin elimination in critically-ill patients with cancer. Further studies are necessary to find amikacin PK covariates to optimize the pharmacotherapy in this population. Therefore, TDM of amikacin is imperative in cancer patients.

Effects of Ganoderma lucidum polysaccharide peptide ameliorating cyclophosphamide-induced immune dysfunctions based on metabolomics analysis.

Ganoderma lucidum polysaccharide peptide (GLPP) is one of the most abundant constituents of Ganoderma lucidum (G. lucidum), with a wide range of functional activities. The present study investigated the immunomodulatory effects of GLPP in cyclophosphamide (CTX)-induced immunosuppressive mice. The results showed that 100 mg/kg/day of GLPP administration significantly alleviated CTX-induced immune damage by improving immune organ indexes, earlap swelling rate, the index of carbon phagocytosis and clearance value, secretion of cytokines (TNF-α, IFN-γ, and IL-2), and immunoglobulin A(IgA) in the mice. Furthermore, ultra-performance liquid chromatography with mass/mass spectrometry (UPLC-MS/MS) was conducted to identify the metabolites, followed by biomarker and pathway analysis. The results showed that GLPP treatment alleviated CTX-induced alterations in the fecal metabolome profile, including arachidonic acid (AA), leukotriene D4 (LTD4), indole-3-ethanol, and formyltetrahydrofolate (CF), by reversing citric acid, malic acid, cortisol, and oleic acid. These results support the concept that GLPP exhibits immunomodulatory activity via the folate cycle, methionine cycle, TCA cycle, fatty acid biosynthesis and metabolism, glycerophospholipid metabolism, AA metabolism, and cAMP pathways. In conclusion, the results could be helpful to understand the use of GLPP to clarify the immunomodulatory mechanism and be used as immunostimulants to prevent CTX-induced side effects in the immune system.

Dose Titration of Ixazomib Maintenance Therapy in Transplant-Ineligible Multiple Myeloma: Exposure-Response Analysis of the TOURMALINE-MM4 Study.

Ixazomib has been approved in several countries as single-agent maintenance therapy in newly diagnosed multiple myeloma, in both posttransplant and transplant-ineligible settings, based on two phase III studies. In these maintenance studies, patients were initially administered 3 mg ixazomib, escalating to 4 mg if the initial dose level was well tolerated through Cycles 1-4. Here, we report the results of exposure-response analyses of TOURMALINE-MM4, wherein relationships between exposure and clinical response, dose adjustments, and selected adverse events were evaluated. Similar progression-free survival benefits were observed across the range of ixazomib exposures achieved in the study. Moreover, increased ixazomib exposures corresponded to a higher probability of maintaining complete response. Exposure was not a significant predictor (P > 0.05) of hematological adverse events (anemia, neutropenia, thrombocytopenia) and peripheral neuropathy; however, higher exposures did correlate to increased probabilities of experiencing diarrhea, vomiting, nausea, rash, and fatigue. While ixazomib exposure was not predictive of dose reductions, lower apparent clearance values (corresponding to higher systemic exposures) were correlated with a reduced likelihood of escalating to the 4 mg dose. Thus, the dose titration approach balanced patient benefit and risk; it ensured that only patients for whom the 3 mg dose was safe/tolerable escalated to the higher dose, while maximizing the fraction of patients (85%) who were able to derive additional clinical benefit at 4 mg. Collectively, these results highlight the value of safety-driven personalized dosing to maximize patient benefit/risk.

Pharmacokinetics of Enarodustat in Non-Japanese and Japanese Healthy Subjects and in Patients With End-Stage Renal Disease on Hemodialysis.

The pharmacokinetics of enarodustat were elucidated in healthy subjects and in patients with end-stage renal disease (ESRD) on hemodialysis in phase 1 studies conducted in the United States and Japan. In healthy non-Japanese and Japanese subjects, following single oral administration up to 400 mg, enarodustat was rapidly absorbed. Maximum plasma concentration and area under the plasma concentration-time curve from the time of dosing to infinity were dose-dependent, renal excretion of unchanged enarodustat was substantial (on average ≈45% of dose), and mean t1/2 of <10 hours indicated negligible accumulation with once-daily dosing. In general, with daily dosing (25, 50mg), accumulation at steady-state was ≈1.5-fold (t1/2(eff) ≈15 hours), presumably due to a decrease in renal drug excretion which is not clinically relevant in patients with ESRD. In the single- and multiple-dose studies, plasma clearance (CL/F) was lower in healthy Japanese subjects. In non-Japanese patients with ESRD on hemodialysis, following once-daily dosing (2-15mg), enarodustat was rapidly absorbed, steady-state maximum plasma concentration and area under the plasma concentration-time curve during the dosing interval were dose-dependent, and interindividual variability in the exposure parameters was low-to-moderate (coefficient of variation, 27%-39%). Steady-state CL/F was similar across doses, renal drug excretion was not significant (<10% of dose), mean t1/2 and t1/2(eff) were similar (overall, 8.97-11.6 hours), and accumulation was minimal (≈20%), demonstrating predictable pharmacokinetics. Japanese patients with ESRD on hemodialysis (15mg, single dose) exhibited similar pharmacokinetics with mean t1/2 of 11.3 hours and low interindividual variability in the exposure parameters, albeit with lower CL/F versus non-Japanese patients. Body weight-adjusted clearance values were generally similar in non-Japanese and Japanese healthy subjects and also in patients with ESRD on hemodialysis.

Pharmacokinetic studies of hyperoside-2-hydroxypropyl-β-cyclodextrin inclusion complex and ameliorated DSS-induced colitis in mice.

An inclusion complex formation with cyclodextrin is a promising method to improve the bioavailability of water-insoluble drugs. The pharmacokinetic characteristics of Hyperoside-2-hydroxypropyl-β-cyclodextrin inclusion complex in rats were evaluated. Compared with Hyperoside, the results showed that maximum plasma concentration and AUC0-t indexes of Hyperoside inclusion complex in rat plasma were increased, the value of half-life time was prolonged, and the value of apparent clearance was decreased, which proved that Hyperoside complexed with 2-hydroxypropyl-β-cyclodextrin could improve its bioavailability and increase its blood concentration. Secondly, the therapeutic effect of Hyperoside before and after complexing was further compared through the dextran sodium sulfate-induced colitis in mice. The experimental results showed that under the same dose, the Hyperoside inclusion complex had a better therapeutic effect, which could significantly increase the body weight of mice, improve the disease activity index, alleviate colon shortening, improve pathological colon changes, and have a better protective effect on colitis mice. According to 16S rDNA sequencing analyses, Hyperoside-2-hydroxypropyl-β-cyclodextrin may have an anti-inflammatory effect by increasing the abundance of beneficial bacteria (e.g. Firmicuria) and decreasing the proportion of harmful bacteria (e.g. Bacteroidetes) to balance the colon's microbiota.

Investigation of N-Acetyltransferase 2-Mediated Drug Interactions of Amifampridine: In Vitro and In Vivo Evidence of Drug Interactions with Acetaminophen.

Amifampridine is a drug used for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) and was approved by the Food and Drug Administration (FDA) of the United States (US) in 2018. It is mainly metabolized by N-acetyltransferase 2 (NAT2); however, investigations of NAT2-mediated drug interactions with amifampridine have rarely been reported. In this study, we investigated the effects of acetaminophen, a NAT2 inhibitor, on the pharmacokinetics of amifampridine using in vitro and in vivo systems. Acetaminophen strongly inhibits the formation of 3-N-acetylamifmapridine from amifampridine in the rat liver S9 fraction in a mixed inhibitory manner. When rats were pretreated with acetaminophen (100 mg/kg), the systemic exposure to amifampridine significantly increased and the ratio of the area under the plasma concentration-time curve for 3-N-acetylamifampridine to amifampridine (AUCm/AUCp) decreased, likely due to the inhibition of NAT2 by acetaminophen. The urinary excretion and the amount of amifampridine distributed to the tissues also increased after acetaminophen administration, whereas the renal clearance and tissue partition coefficient (Kp) values in most tissues remained unchanged. Collectively, co-administration of acetaminophen with amifampridine may lead to relevant drug interactions; thus, care should be taken during co-administration.

Dosage Optimization of Digoxin in Older Patients with Heart Failure and Chronic Kidney Disease: A Population Pharmacokinetic Analysis.

Renal function is an important index for digoxin dose adjustment, especially in patients with chronic kidney disease (CKD). Decreased glomerular filtration rate is common in older patients with cardiovascular disease. The aim of this study was to establish a digoxin population pharmacokinetic model in older patients with heart failure and CKD and to optimize the digoxin dose strategy. Older patients with heart failure and CKD aged > 60years from January 2020 to January 2021 and who had an estimated glomerular filtration rate (eGFR) < 90mL/min/1.73m2 or urine protein production were enrolled in this retrospective study. Population pharmacokinetic analysis and Monte Carlo simulations (n = 1000) were performed using NONMEN software. The precision and stability of the final model were analyzed by graphical and statistical methods. Overall, 269 older patients with heart failure were enrolled. A total of 306 digoxin concentrations were collected, with a median value of 0.98ng/mL (interquartile range [IQR] 0.62-1.61, range 0.04-4.24). The median age was 68years (IQR 64-71, range 60-94) and eGFR was 53.6mL/min/1.73m2 (IQR 38.1-65.2, range 11.4-89.8). A one-compartment model with first-order elimination was developed to describe the digoxin pharmacokinetics. Typical values for clearance and volume of distribution were 2.67L/h and 36.9L, respectively. Dosage simulations were stratified by eGFR and metoprolol. Doses of 62.5 and 125μg were recommended for older patients with eGFR < 60mL/min/1.73m2. A population pharmacokinetic model of digoxin in older patients with heart failure and CKD was established in this study. A novel digoxin dosage strategy was recommended in this vulnerable population.

Predicting Optimal Antimalarial Drug Combinations from a Standardized Plasmodium falciparum Humanized Mouse Model.

The development of new combinations of antimalarial drugs is urgently needed to prevent the spread of parasites resistant to drugs in clinical use and contribute to the control and eradication of malaria. In this work, we evaluated a standardized humanized mouse model of erythrocyte asexual stages of Plasmodium falciparum (PfalcHuMouse) for the selection of optimal drug combinations. First, we showed that the replication of P. falciparum was robust and highly reproducible in the PfalcHuMouse model by retrospective analysis of historical data. Second, we compared the relative value of parasite clearance from blood, parasite regrowth after suboptimal treatment (recrudescence), and cure as variables of therapeutic response to measure the contributions of partner drugs to combinations in vivo. To address the comparison, we first formalized and validated the day of recrudescence (DoR) as a new variable and found that there was a log-linear relationship with the number of viable parasites per mouse. Then, using historical data on monotherapy and two small cohorts of PfalcHuMice evaluated with ferroquine plus artefenomel or piperaquine plus artefenomel, we found that only measurements of parasite killing (i.e., cure of mice) as a function of drug exposure in blood allowed direct estimation of the individual drug contribution to efficacy by using multivariate statistical modeling and intuitive graphic displays. Overall, the analysis of parasite killing in the PfalcHuMouse model is a unique and robust experimental in vivo tool to inform the selection of optimal combinations by pharmacometric pharmacokinetic and pharmacodynamic (PK/PD) modeling.

Physiologically-based pharmacokinetic/pharmacodynamic modeling to predict tumor growth inhibition and the efficacious dose of selective estrogen receptor degraders in humans.

GDC-9545 (giredestrant) is a highly potent, nonsteroidal, oral selective estrogen receptor antagonist and degrader that is being developed as a best-in-class drug candidate for early-stage and advanced drug-resistant breast cancer. GDC-9545 was designed to improve the poor absorption and metabolism of its predecessor GDC-0927, for which development was halted due to a high pill burden. This study aimed to develop physiologically-based pharmacokinetic/pharmacodynamic (PBPK-PD) models to characterize the relationships between oral exposure of GDC-9545 and GDC-0927 and tumor regression in HCI-013 tumor-bearing mice, and to translate these PK-PD relationships to a projected human efficacious dose by integrating clinical PK data. PBPK and Simeoni tumor growth inhibition (TGI) models were developed using the animal and human Simcyp V20 Simulator (Certara) and adequately described each compound's systemic drug concentrations and antitumor activity in the dose-ranging xenograft experiments in mice. The established PK-PD relationship was translated to a human efficacious dose by substituting mouse PK for human PK. PBPK input values for human clearance were predicted using allometry and in vitro in vivo extrapolation approaches and human volume of distribution was predicted from simple allometry or tissue composition equations. The integrated human PBPK-PD model was used to simulate TGI at clinically relevant doses. Translating the murine PBPK-PD relationship to a human efficacious dose projected a much lower efficacious dose for GDC-9545 than GDC-0927. Additional sensitivity analysis of key parameters in the PK-PD model demonstrated that the lower efficacious dose of GDC-9545 is a result of improvements in clearance and absorption. The presented PBPK-PD methodology can be applied to support lead optimization and clinical development of many drug candidates in discovery or early development programs.

Mathematical Model Describing the Hardening and Failure Behaviour of Aluminium Alloys: Application in Metal Shear Cutting Process

Recent research has focused on sheet shear cutting operations. However, little research has been conducted on bar shear cutting. The main objective of the present investigation is to study bar shear cutting with numerical and experimental analysis. Bar shear cutting is an important operation because it precedes bulk metalworking processes for instance machining, extrusion and hot forging. In comparison to sheet shear cutting, bar shear cutting needs thermomechanical modelling. The variational formulation of the model is presented to predict damage mechanics in the bar shear cutting of aluminium alloys. Coupled thermomechanical modelling is required to analyse the mechanical behaviour of bulk workpieces, in which the combined effect of strain and temperature fields is considered in the shear cutting process. For this purpose, modified hardening and damage Johnson–Cook laws are developed. Numerical results for sheet and bar shear cutting operations are presented. The comparison between numerical and experimental results of shearing force/tool displacement during sheet and bar shear cutting operations proves that the use of a thermomechanical model in the case of the bar shear cutting process is crucial to accurately predict the mechanical behaviour of aluminium alloys. The analysis of the temperature field in the metal bar shows that the temperature can reach T = 388 °C on the sheared surface. The current model accurately predicts the shear cutting process and shows a strong correlation with experimental tests. Two values of clearance (c1 = 0.2 mm) and (c2 = 1.2 mm) are assumed for modeling the bar shear cutting operation. It is observed that for the low shear clearance, the burr is small, the quality of the sheared surface is better, and the fractured zone is negligible.

Develop adult extrapolation to pediatrics and pediatric dose optimization based on the physiological pharmacokinetic model of azithromycin.

Physiologically-based pharmacokinetic (PBPK) models are more frequently used for supporting pediatric dose selection in small-molecule drugs. Through literature research, drug parameters of azithromycin and clinical data from different studies were obtained. Through parameter optimization of the absorption and dissolution process, the adult intravenous model was extended to the adult oral model. The adult intravenous and oral PBPK models are precise to meet the AAFE<2 standard, and the pharmacokinetic parameters of the predicted values of the model are all within the mean standard deviation of the clinical observations. The values of plasma protein unbound fraction, renal clearance, and gastric juice pH between adults and pediatrics were changed by using the age-dependent pediatric organ maturity formula, and the adult model was extrapolated to the pediatric model. The final developed pediatric PBPK model was used to evaluate optimal dosing for children of different developmental ages. The relationship between the frist dose and age was as follows: 8.8mg/kg/day from 0.5 to 2years old, 9.2mg/kg/day from 3 to 6years old, 9.4mg/kg/day from 7 to 12years old, and 8.2mg/kg/day from 13 to 18years old, taken in half for 2-5days. Simultaneously, the simulated exposures achieved with the dosing regimen proposed were comparable to adult plasma exposures for treatment of community-acquired pneumonia. A reasonable azithromycin pharmacokinetic-pharmacodynamic model for adults and pediatrics has been established, which can be demonstrated by the use of literature pediatric data to develop pediatric PBPK models, expanding the scope of this powerful modeling tool.

Clearance and blockage effects on hydrodynamic performance of hybrid hydrokinetic turbine

Hydrokinetic turbines are prominent solutions for providing electricity by utilizing the kinetic energy of flowing water streams. Various sites parameters such as flow velocity, channel dimensions and placement of turbine rotor across the water channel are the decisive factors to effectively harness the hydrokinetic energy. In current research, hybrid rotor is investigated considering different values of clearance and blockage ratio (by varying the channel dimensions). A hybrid rotor having the two conventional rotors (Savonius and Darrieus) is analyzed under different flow parameters such as flow velocity and tip speed ratio. To visualize the flow behavior across the turbine vicinity, flow contours have been analyzed and discussed. For the considered range of parameters, hybrid hydrokinetic rotor yields its maximum hydrodynamic performance corresponding to 0.55 value of clearance ratio. The maximum power coefficient as 0.122 occurs corresponding to 26.32% blockage ratio at 0.98 value of tip speed ratio (TSR).

Novel Benzylamine Derivatives: Synthesis, Anti-Mycobacterium Tuberculosis Evaluation and Predicted ADMET Properties

Background: Tuberculosis (TB), a disease caused by the bacillus bacteria Mycobacterium tuberculosis is one of the major contributors of ill health in the world. TB is ranked in the top 10 causes of death globally and it is the leading killer associated with a single infectious agent. According to the World Health Organization (WHO), global number of deaths associated with TB have been slowly declining with 1.3 million in reported 2016 and 2017, and 1.2 million reported in 2018 and 2019. Objective: The synthesis, characterisation, biological evaluations, and the prediction of ADMET properties of the novel benzylamine derivatives. Methods: Commercially available reagents and solvents were purchased from Sigma Aldrich and Merck (South Africa). All chemicals were used as received, unless otherwise stated. The synthesised crude compounds were purified by flash silica gel column chromatography (5 – 30% ethyl acetate in hexane). The successful formation and purity of the synthesised compounds was confirmed by NMR, HRMS and melting point. Results: The respective organic compounds were synthesised by treating 3-ethoxysalcyladehyde, 5-bromo-3-ethoxysalcyladehyde, 5-chloro-3-ethoxysalcyladehyde with various aromatic amines and the products were obtained in good to excellent yields. The 1H and 13C NMR spectra of all the products showed the appearance of the methylene signals ranging from 3.88 – 4.68 ppm and 42.25 – 52.57 ppm respectively. Additionally, most compounds showed anti-Mycobacterium tuberculosis activity that ranged between 20 and 28 µM. Conclusion: A total of 36 compounds were synthesised and successfully biologically evaluated against Mycobacterium tuberculosis (Mtb) H37RV strain. All compounds showed activity against Mtb at concentrations of &gt; 20 µM &lt; 28 µM with the exception of compound one that was active against Mtb at higher concentration (MIC90 &gt; 125 µM).

PERANCANGAN 3D PRINTING CARTESIAN BERBASIS FUSED DEPOSITION MODELLING DENGAN UKURAN 200 X 200 X 200 mm

The technology of adding manufacturing or 3D printing is one of the main issues in the concept of technology 4.0. The construction design of the 3D printing machine and the deflection of its construction significantly affect the accuracy of the dimension and shape the printed product. The study aims to obtain a construction design of a cartesian type 3 D printing machine based on fused deformation modelling, and to verify the maximum value of the deflection of the machine axis. The study method used VDI222, calculation analysis, and Finite Element Analysis (FEA) simulation using CAE Solidworks software to verify the strength and deflection of the machine design construction. The study results show the construction design of 3D printing machine has been obtained according to the requirement. The verified maximum deflection value is 0.036 mm, hence the maximum error in the dimensions and shape of the printed product for each layer will still be within the standard tolerance. In addition, its maximum deflection value is verified within the radial clearance value of each determined machine axis bearing.

Clearance as an Early Indicator of Efficacy for Therapeutic Monoclonal Antibodies: Circumventing Dose Selection Challenges in Oncology.

The designs of first-in-human (FIH) studies in oncology (e.g., 3+3 dose escalation design) usually do not provide a sufficient sample size to determine the dose-response relationship for efficacy. This study aimed to assess the feasibility of using monoclonal antibody (mAb) clearance as a biomarker for efficacy to facilitate the identification of potentially efficacious doses across cancer types and drug targets. We performed electronic searches of the Drugs@FDA website, the European Medicines Agency website, and PubMed to identify reports of FIH trials of approved mAbs in oncology. The clearance, half-life, and overall response rate (ORR) data for the mAbs at different dose levels were extracted. Twenty-five approved mAbs were included in this study. As expected, due to the small sample sizes in FIH studies, there was no clear dose-response for ORR. However, we found a clear negative association between mAb clearance and ORR across tumors/drug targets, and a clear negative dose-clearance relationship, with clearance decreasing and saturated at high dose levels. The approved mAb doses (1-25 mg/kg) are approximately 2-fold the saturation doses (1-10 mg/kg). The associated clearance values at the approved doses vary across different cancers and drug targets (0.17-1.56 L/day), while tend to be similar within a disease/drug target. Anti-CD20 mAbs for B-cell lymphomas show a higher clearance (~ 1 L/day) than other cancers and targets (e.g., ~0.3 L/day for anti-PD-1). Clearance of mAbs can be a tumor/drug target-agnostic biomarker for potential anti-tumor activity as clearance decreases with increasing ORR. Our findings shed important insights into target clearance values that may lead to desired efficacy for different cancers and drug targets, which can be used to guide dose selection for the future development of mAbs during FIH oncology studies.

Population PK/PD modelling of meropenem in preterm newborns based on therapeutic drug monitoring data.

Background: Preterm neonates rarely participate in clinical trials, this leads to lack of adequate information on pharmacokinetics for most drugs in this population. Meropenem is used in neonates to treat severe infections, and absence of evidence-based rationale for optimal dosing could result in mismanagement. Aim: The objective of the study was to determine the population pharmacokinetic (PK) parameters of meropenem in preterm infants from therapeutic drug monitoring (TDM) data in real clinical settings and to evaluate pharmacodynamics (PD) indices as well as covariates affecting pharmacokinetics. Materials and methods: Demographic, clinical and TDM data of 66 preterm newborns were included in PK/PD analysis. The NPAG program from the Pmetrics was used for modelling based on peak-trough TDM strategy and one-compartment PK model. Totally, 132 samples were assayed by high-performance liquid chromatography. Meropenem empirical dosage regimens (40-120mg/kg/day) were administered by 1-3-h IV infusion 2-3 times a day. Regression analysis was used to evaluate covariates (gestation age (GA), postnatal age (PNA), postconceptual age (PCA), body weight (BW), creatinine clearance, etc.) influenced on PK parameters. Results: The mean ± SD (median) values for constant rate of elimination (Kel) and volume of distribution (V) of meropenem were estimated as 0.31 ± 0.13 (0.3) 1/h and 1.2 ± 0.4 (1.2) L with interindividual variability (CV) of 42 and 33%, respectively. The median values for total clearance (CL) and elimination half-life (T1/2) were calculated as 0.22L/h/kg and 2.33h with CV = 38.0 and 30.9%. Results of the predictive performance demonstrated that the population model by itself gives poor prediction, while the individualized Bayesian posterior models give much improved quality of prediction. The univariate regression analysis revealed that creatinine clearance, BW and PCA influenced significantly T1/2, meropenem V was mostly correlated with BW and PCA. But not all observed PK variability can be explained by these regression models. Conclusion: A model-based approach in conjunction with TDM data could help to personalize meropenem dosage regimen. The estimated population PK model can be used as Bayesian prior information to estimate individual PK parameter values in the preterm newborns and to obtain predictions of desired PK/PD target once the patient's TDM concentration(s) becomes available.

In Vitro Pharmacokinetic Behavior of Antiviral 3-Amidinophenylalanine Derivatives in Rat, Dog and Monkey Hepatocytes

Type II transmembrane serine proteases represent pharmacological targets for blocking entry and spread of influenza or coronaviruses. In this study, the depletion rates of the 3-amidinophenylalanine (3-APhA)-derived matriptase/TMPRSS2 inhibitors MI-463, MI-472, MI-485 or MI-1900 were determined by LC-MS/MS measurements over a period of 300 min using suspensions of rat, dog and cynomolgus monkey primary hepatocytes. From these in vitro pharmacokinetic (PK) experiments, intrinsic clearance values (Clint) were evaluated, and in vivo pharmacokinetic parameters (hepatic clearance, hepatic extraction ratio and bioavailability) were predicted. It was found that rat hepatocytes were the most active in the metabolism of 3-APhA derivatives (Clint 31.9-37.8 mL/min/kg), whereas dog and monkey cells displayed somewhat lower clearance of these compounds (Clint 6.6-26.7 mL/min/kg). These data support elucidation of important PK properties of anti-TMPRSS2/anti-matriptase 3-APhAs using mammalian hepatocyte models and thus contribute to the optimization of lead compounds.