Current Issue : October - December Volume : 2020 Issue Number : 4 Articles : 5 Articles
CKD-519 is a selective and potent cholesteryl ester transfer protein (CETP) inhibitor that\nis being developed for dyslipidemia. Even though CKD-519 has shown potent CETP inhibition,\nthe exposure of CKD-519 was highly varied, depending on food and dose. For highly variable\nexposure drugs, it is crucial to use modeling and simulation to plan proper dose selection. This study\naimed to develop population pharmacokinetic (PK) and pharmacodynamics (PD) models of CKD-519\nand to predict the proper dose of CKD-519 to achieve target levels for HDL-C and LDL-C using results\nfrom multiple dosing study of CKD-519 with a standard meal for two weeks in healthy subjects.\nThe results showed that a 3-compartment with Erlangâ??s distribution, followed by the first-order\nabsorption, adequately described CKD-519 PK, and the bioavailability, which decreased by dose and\ntime was incorporated into the model (NONMEM version 7.3). After the PK model development,\nthe CETP activity and cholesterol (HDL-C and LDL-C) levels were sequentially modeled using the\nturnover model, including the placebo eect. According to PK-PD simulation results, 200 to 400 mg\nof CKD-519 showing a 40% change in HDL-C and LDL-C from baselines was recommended for proof\nof concept studies in patients with dyslipidemia....
Despite its effcacy and toxicity being exposure-related, levofloxacin pharmacokinetics in\npatients with bone and joint infections has been poorly described to date, so the possible need for a\ndose adjustment is unknown in this population. A prospective population pharmacokinetic study\nwas conducted in 59 patients to answer this question. The final model consisted of a one-compartment\nmodel with first-order absorption and elimination. Mean parameter estimates (% interindividual\nvariability) were 0.895 h-1 for the absorption rate constant (Ka), 6.10 L/h (40%) for the apparent\nclearance (CL/F), 90.6 L (25%) for the apparent distribution volume (V/F). Age and glomerular filtration\nrate (GFR), estimated by the modification of diet in renal disease formula, were related to CL/F by\npower models, and CL/F was found to increase for increasing GFR and decreasing age. For a similar\nGFR, the simulated area under the curve (AUC) was 55% higher in 70 years-old patients compared to\n30 year-old patients. Based on this model, a 750 mg dose should provide an optimal exposure (AUC/\nminimum inhibitory concentration (MIC) -100), with the possible exception of patients older than\n60 years and with GFR <70 mL/min/m2 who may necessitate a dose reduction, and patients with\ninfections caused by bacteria with MIC close to 1 mg/L who may need an increase in the dose....
2,4,6-trihydroxy-3-geranylacetophenone (tHGA) is a bioactive compound that shows\nexcellent anti-inflammatory properties. However, its pharmacokinetics and metabolism have yet to\nbe evaluated. In this study, a sensitive LC-HRMS method was developed and validated to quantify\ntHGA in rat plasma. The method showed good linearity (0.5â??80 ng/mL). The accuracy and precision\nwere within 10%. Pharmacokinetic investigations were performed on three groups of six rats. The first\ntwo groups were given oral administrations of unformulated and liposome-encapsulated tHGA,\nrespectively, while the third group received intraperitoneal administration of liposome-encapsulated\ntHGA. The maximum concentration (Cmax), the time required to reach Cmax (tmax), elimination half-life\n(t1/2) and area under curve (AUC0â??24) values for intraperitoneal administration were 54.6 ng/mL,\n1.5 h, 6.7 h, and 193.9 ng/mL-h, respectively. For the oral administration of unformulated and\nformulated tHGA, Cmax values were 5.4 and 14.5 ng/mL, tmax values were 0.25 h for both, t1/2 values\nwere 6.9 and 6.6 h, and AUC0â??24 values were 17.6 and 40.7 ng/mL-h, respectively. The liposomal\nformulation improved the relative oral bioavailability of tHGA from 9.1% to 21.0% which was a\n2.3-fold increment. Further, a total of 12 metabolites were detected and structurally characterized.\nThe metabolites were mainly products of oxidation and glucuronide conjugation....
Pneumonia is a significant cause of death in sheep flocks. Thus, antibiotics are\nessential for the treatment of bacterial pneumonia to reduce morbidity and mortality, but few drugs\nare specifically labeled for clinical use in sheep. Many of the antimicrobial clinical prescriptions that\noccur in sheep are classified as extra-label use, with dosage, administration frequency, indications, and\ndrug withdrawal times usually being extrapolated from information reported in other species. Thus,\nthe objective of this study was to determine the disposition kinetics of tildipirosin after intravenous,\nintramuscular, and subcutaneous administration in sheep. Throughout the experiment, all ewes\nwere healthy and no adverse reactions were recorded. The apparent volume of distribution was\nhigh, indicating a wide distribution in the body, which can be attributed to a significant fraction\nof tildipirosin inside the cells, and its expected activity against intracellular bacteria. Following\nintramuscular administration, tildipirosin was rapidly absorbed even to a greater extent when\ncompared to subcutaneous administration. Most of the adsorbed tildipirosin after intramuscular and\nsubcutaneous administrations were available in the body (>70%). In brief, the excellent tolerability of\nthis formulation and the suitable disposition of tildipirosin in the body makes it an alternative for\nsheep use, in conditions where the administration of antibiotics is needed to observe desired effects\nwith the benefits of scant manipulation of animals....
Mycoplasma hyopneumoniae is the major pathogen causing enzootic pneumonia in\npigs. M. hyopneumoniae infection can lead to considerable economic losses in the pig-breeding\nindustry. Here, this study established a first-order absorption, one-compartment model to study\nthe relationship between the pharmacokinetics/pharmacodynamics (PK/PD) index of tilmicosin\nagainst M. hyopneumoniae in vitro. We simulated different drug concentrations of timicosin in the\nfluid lining the lung epithelia of pigs. The minimum inhibitory concentration (MIC) of tilmicosin\nagainst M. hyopneumoniae with an inoculum of 106 CFU/mL was 1.6 microg/mL using the microdilution\nmethod. Static timeâ??kill curves showed that if the drug concentration > 1 MIC, the antibacterial\neffect showed different degrees of inhibition. At 32 MIC, the amount of bacteria decreased by\n3.16 log10 CFU/mL, thereby achieving a mycoplasmacidal effect. The M. hyopneumoniae count was\nreduced from 3.61 to 5.11 log10 CFU/mL upon incubation for 96 h in a dynamic model with a dose\nof 40â??200 mg, thereby achieving mycoplasmacidal activity. The area under the concentration-time\ncurve over 96 h divided by the MIC (AUC0â??96 h/MIC) was the best-fit PK/PD parameters for\npredicting the antibacterial activity of tilmicosin against M. hyopneumoniae (R2 = 0.99), suggesting\nthat tilmicosin had concentration-dependent activity. The estimated value for AUC0â??96 h/MIC for\n2log10 (CFU/mL) reduction and 3log10 (CFU/mL) reduction from baseline was 70.55 h and 96.72 h.\nFour M. hyopneumoniae strains (M1â??M4) with reduced sensitivity to tilmicosin were isolated from the\nfour dose groups. The susceptibility of these strains to tylosin, erythromycin and lincomycin was also\nreduced significantly. For sequencing analyses of 23S rRNA, an acquired A2058G transition in region\nV was found only in resistant M. hyopneumoniae strains (M3, M4). In conclusion, in an in vitro model,\nthe effect of tilmicosin against M. hyopneumoniae was concentration-dependent and had a therapeutic\neffect. These results will help to design the optimal dosing regimen for tilmicosin in M. hyopneumoniae\ninfection, and minimize the emergence of resistant bacteria....
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