Simultaneous quantification of plasma levels of 12 antimicrobial agents including carbapenem,anti-methicillin-resistant Staphylococcus aureus agent,quinolone and azole used in intensive care unit using UHPLC-MS/MS method

ObjectivesCritically ill patients in intensive care unit (ICU) are susceptible to infectious diseases, thus empirical therapy is recommended. However, the therapeutic effect in ICU patients is difficult to predict due to fluctuation in pharmacokinetics because of various factors. This problem can be solved by developing personalized medicine through therapeutic drug monitoring. However, when different measurement systems are used for various drugs, measurements are complicated and time consuming in clinical practice. In this study, we aimed to develop an assay using ultra-high performance liquid chromatography coupled with tandem mass spectrometry for simultaneous quantification of 12 antimicrobial agents commonly used in ICU: doripenem, meropenem, linezolid, tedizolid, daptomycin, ciprofloxacin, levofloxacin, pazufloxacin, fluconazole, voriconazole, voriconazole N-oxide which is a major metabolite of voriconazole, and posaconazole.Design & methodsPlasma protein was precipitated by adding acetonitrile and 50% MeOH containing standard and labeled IS. The analytes were separated with an ACQUITY UHPLC CSH C18 column, under a gradient mobile phase consisting of water and acetonitrile containing 0.1% formic acid and 2 mM ammonium formate.ResultsThe method fulfilled the criteria of US Food and Drug Administration for assay validation. The recovery rate was more than 84.8%. Matrix effect ranged from 79.1% to 119.3%. All the calibration curves showed good linearity (back calculation of calibrators: relative error ≤ 15%) over wide concentration ranges, which allowed determination of C_max and C_trough. Clinical applicability of the novel method was confirmed.ConclusionsWe have developed an assay for simultaneous quantification of 12 antimicrobial agents using a small sample volume of 50 μL with a short assay time of 7 min. Our novel method may contribute to simultaneous calculation of pharmacokinetic and pharmacodynamic parameters.     

Altered pharmacokinetics of combined oral contraceptives in obesity — multistudy assessment

Objective

The objective was to evaluate the pharmacokinetics (PKs) of levonorgestrel (LNG)-containing combined oral contraceptives (COCs) in obese women.

Clinical audit of gentamicin use by Bayesian pharmacokinetic approach in critically ill children

IntroductionCritically ill children tend to have altered gentamicin pharmacokinetics (PK); and so we carried out an audit of gentamicin use using the estimated peak concentrations (C_max), trough concentrations (C_min) and area-under-the-concentration-time curve (AUCs) by Bayesian approach.MethodsCritically ill children with at least one serum gentamicin concentrations available were recruited. We used multiple models Bayesian adaptive control to estimate C_max, and AUC_0-t following each dose. Pediatric risk, injury, failure, loss, end stage renal disease (pRIFLE) criteria was used to identify the incidence of acute kidney injury (AKI).ResultsSeventy-three children (961 doses and 143 concentrations) were analysed. AUC_0-24 was observed to be higher in earlier age groups with a steady decline in older children. Similar changes were observed in C_max, C_min and AUC_0-24 at steady state. Significantly higher proportions of children in the other age groups were estimated to have C_max between 5 and 10 mg/L compared to neonates. Neonates had a higher risk of C_max above 10 mg/L. Patients with augmented renal clearance exhibited lower AUC_0-24 and reduced proportion achieving the target AUC_0-24 levels. Nearly one-third of children were observed to meet the pRIFLE criteria for AKI.ConclusionWe observed higher initial doses and peak concentrations of gentamicin in neonates and infants compared to older age groups in critically ill children. Uniformity in the paediatric-specific standard treatment guidelines for gentamicin is the need of the hour.     

Pharmacokinetics of genistein distribution in blood and retinas of diabetic and non-diabetic rats

Genistein, a natural tyrosine kinase inhibitor, may act as an intraocular antiangiogenic agent. Its therapeutical use, however, is limited by its nonlinear pharmacokinetics. We aimed to determine genistein's kinetics and retinal tissue distributions in normal and diabetic rats. We developed an isocratic, reverse-phase C18 HPLC system to measure genistein concentration in blood and retinas of streptozotocin (65 mg/kg IV)-diabetic and non-diabetic rats receiving two types of genistein-rich diet (150 and 300 mg/kg) for ten days. Genistein's decay exhibited a two-compartmental open model. Half-lives of distribution and elimination were 2.09 and 71.79 min, with no difference between groups. Genistein steady-state concentration in blood for 150 and 300 mg/kg diet did not differ between diabetic (0.259 ± 0.07 and 0.26 ± 0.06 μg/ml) and non-diabetic rats (0.192 ± 0.05 and 0.183 ± 0.09 μg/ml). In retina, genistein concentration was significantly higher in diabetic rats (1.05 ± 0.47 and 0.997 ± 0.47 μg/gm wt. vs. 0.087 ± 0.11 and 0.314 ± 0.18 μg/gm wt., p < 0.05). The study determined that increasing genistein dose did not change its bioavailability, perhaps due to the poor aqueous solubility. The retina's increased genistein could be due to increased permeability of blood-retinal barrier that occurs early in diabetes.     

Specificity of pharmacokinetic modeling of nanomedicines

Nanomedicines have been developed for more than four decades to optimize the pharmacokinetics (PK) of drugs, especially absorption, distribution, and stability in vivo. Unfortunately, only a few drug products have reached the market. One reason among others is the lack of proper PK modeling and evaluation, which impedes the optimization of these promising drug delivery systems. In this review, we discuss the specificity of nanomedicines and propose key parameters to take into account for future accurate PK evaluation of nanomedicine. We believe that this could help these innovative drug products to reach to market and change the fate of many diseases.     

Rationale for the administration of systemic 5-FU in combination with heated intraperitonal oxaliplatin

Background

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) with oxaliplatin (OX) is the standard of care for selected patients with peritoneal carcinomatosis of colorectal origin. Because 5-FU is mandatory to improve efficacy of OX when used by systemic route, several teams now empirically combine intravenous (IV) 5-FU with HIPEC OX, but this practice has yet to be supported by preclinical data. Using a murine model, we studied the impact of IV 5-FU on peritoneal absorption of HIPEC OX.

Clinical pharmacokinetics of antimicrobial drugs in cystic fibrosis.

The disposition of many drugs in cystic fibrosis is abnormal compared with healthy individuals. In general, changes include an increased volume of distribution expressed in liters per kg bodyweight for highly hydrophilic drugs such as aminoglycosides, and, to a lesser extent, for penicillins and cephalosporins, together with an increased total body clearance. The main reason for the increased volume of distribution is the increased amount of lean tissue per kg bodyweight, since patients with CF are generally undernourished and have a paucity of adipose tissue. The reason for the increased renal clearance is less clear. Increased glomerular filtration and tubular secretion have been observed. Protein binding generally is unaltered in CF. The fluorquinolones and vancomycin show no altered pharmacokinetics in CF although gastro-intestinal absorption may be delayed for fluorquinolones. Sulphamethoxazole shows increased clearance due to an increased acetylation and, in the case of trimethoprim, renal clearance is increased compared with healthy individuals. As a consequence, drugs that show increased clearance, will lead to reduced serum concentrations and smaller AUCs and therefore CF patients require larger doses per kg bodyweight.