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The Journal of Antimicrobial... Jul 2024Optimal antibiotic dosing for Staphylococcus aureus bloodstream infections (BSI) is still controversial. One reason is inter-individual variation in pharmacokinetics,...
BACKGROUND
Optimal antibiotic dosing for Staphylococcus aureus bloodstream infections (BSI) is still controversial. One reason is inter-individual variation in pharmacokinetics, which may be influenced by various patient-related factors, particularly in critically ill patients.
OBJECTIVES
To describe the population pharmacokinetics (PopPK) of the antibiotic flucloxacillin in patients with S. aureus BSI. Subsequently, we sought to translate the model into a user-friendly app for generating a priori and a posteriori time-concentration curves and dose recommendations to optimize dosing regimens.
METHODS
Total and unbound flucloxacillin concentrations were included from 49 patients from a prospective cohort study conducted during clinical routine, including non-critically ill and critically ill individuals who received intermittent bolus applications. These data were analysed using non-linear mixed-effects modelling.
RESULTS
Most patients (98%) were treated with 2 g of flucloxacillin every 4 h. We developed a joint model that simultaneously described total and unbound concentrations. The model included an allometric effect of glomerular filtration rate on clearance and albumin on the albumin dissociation constant. The latter was especially important, as in our population the unbound fraction was higher at 11.5% (16.7% for critically ill patients) compared with reported values of approximately 5%. Based on our joint model, we developed a web-based app for optimizing dosing regimens of flucloxacillin.
CONCLUSIONS
By utilizing data from clinical routine, we were able to create a predictive PopPK model of flucloxacillin and identify influential covariates. The web-based app is currently being validated in a clinical trial.
PubMed: 38946285
DOI: 10.1093/jac/dkae207 -
Mymensingh Medical Journal : MMJ Jul 2024Among patients with chronic kidney disease stage-5 who are treated with dialysis, the urea clearance during hemodialysis is a determinant of the mortality. Decreased... (Observational Study)
Observational Study
Among patients with chronic kidney disease stage-5 who are treated with dialysis, the urea clearance during hemodialysis is a determinant of the mortality. Decreased serum albumin, serum calcium but increased phosphorus is associated with reduction of URR and mortality in these patients. This study was to compare two groups Urea Reduction Ratio (URR) and different type of biochemical parameters. URR was aimed to target according to Kidney Disease Outcomes Quality Initiative (KDOQI) guideline. This study was an observational study was carried out in the department of Nephrology. Serum Albumin, serum calcium, phosphate, hemoglobin and pre dialysis urea, post dialysis urea were measured from blood sample. URR was calculated by = (1- postdialysis urea/predialysis urea) × 100. Among the patients who under went hemodialysis, 17.31% patients URR was more than 65.0% and Mean±SD of URR was 67.21±1.9%. On the other hand, 82.68% patients URR was less than 65.0% and Mean±SD of URR was 57.4±5.2%. Most of the Biochemical parameters in this study were significantly different between two groups. Where as, there was no significant difference in Age, Sex, Body Mass Index (BMI). The URR is an accurate indicator, can help determination of adequate dialysis. This study aimed to find out the mean value of the urea reduction ratio and the association of biochemical parameters among End Stage Renal Disease (ESRD) patients on maintenance hemodialysis.
Topics: Humans; Renal Dialysis; Urea; Female; Male; Bangladesh; Middle Aged; Adult; Kidney Failure, Chronic; Aged
PubMed: 38944713
DOI: No ID Found -
In Vivo (Athens, Greece) 2024We evaluated the usefulness of prophylactic mini-tracheostomy (PMT) and perioperative administration of tazobactam/piperacillin (TAZ/PIPC) in high-risk patients after...
BACKGROUND/AIM
We evaluated the usefulness of prophylactic mini-tracheostomy (PMT) and perioperative administration of tazobactam/piperacillin (TAZ/PIPC) in high-risk patients after esophagectomy.
PATIENTS AND METHODS
We retrospectively studied 89 consecutive high-risk patients who underwent esophagectomy for esophageal cancer between January 2013 and December 2021. We defined patients with two or more of the following factors as high risk: age ≥70 years, performance status ≥1, respiratory dysfunction, liver dysfunction, cardiac dysfunction, renal dysfunction, diabetes mellitus, albumin <3.5 g/dl, and Brinkman index >600. Standard management was administered to the first 50 patients (standard group). PMT and TAZ/PIPC were administered to the next 39 patients (combination group). Patient characteristics and short-term outcomes were compared before and after propensity-score matching.
RESULTS
Before propensity-score matching, 24-hour urine creatinine clearance, retrosternal route, 3-field lymph node dissection, and open abdominal approach were more common, postoperative pneumonia (13% vs. 36%, p=0.045) and complications of grade ≥3b (2.6% vs. 22%, p=0.01) were less frequent, and the postoperative hospital stay was shorter (median: 23 vs. 28 days, p=0.022) in the combination group than in the standard group. In propensity-score matching, patient characteristics, except for 24-h creatinine clearance and reconstructive route, were matched for 23 paired patients. Postoperative pneumonia (8.7% vs. 39%, p=0.035) and complications of grade ≥3b (0% vs. 26%, p=0.022) were less frequent and postoperative hospital stay was shorter (median: 22 vs. 25 days, p=0.021) in the combination group than in the standard group.
CONCLUSION
PMT with TAZ/PIPC can potentially prevent postoperative pneumonia in high-risk patients after esophagectomy.
Topics: Humans; Male; Female; Aged; Esophagectomy; Esophageal Neoplasms; Pneumonia; Piperacillin, Tazobactam Drug Combination; Middle Aged; Postoperative Complications; Anti-Bacterial Agents; Retrospective Studies; Risk Factors
PubMed: 38936906
DOI: 10.21873/invivo.13630 -
International Journal of Pharmaceutics Jun 2024A challenge in development of peptide and protein therapeutics is rapid elimination from the body, necessitating frequent dosing that may lead to toxicities and/or poor...
A challenge in development of peptide and protein therapeutics is rapid elimination from the body, necessitating frequent dosing that may lead to toxicities and/or poor patient compliance. To solve this issue, there has been great investment into half-life extension of rapidly eliminated drugs using approaches such as albumin binding, fusion to albumin or Fc, or conjugation to polyethylene glycol. Despite clinical successes of half-life extension products, no clear relationship has been drawn between properties of drugs and the pharmacokinetic parameters of their half-life extended analogues. In this study, non-compartmentally derived pharmacokinetic parameters (half-life, clearance, volume of distribution) were collected for 186 half-life extended drugs and their unmodified parent molecules. Statistical testing and regression analysis was performed to evaluate relationships between pharmacokinetic parameters and a matrix of variables. Multivariate linear regression models were developed for each of the three pharmacokinetic parameters and model predictions were in good agreement with observed data with r values for each parameter being: half-life: 0.879, clearance: 0.820, volume of distribution: 0.937. Significant predictors for each parameter included the corresponding pharmacokinetic parameter of the parent drug and descriptors related to molecular weight. This model represents a useful tool for prediction of the potential benefits of half-life extension.
PubMed: 38917959
DOI: 10.1016/j.ijpharm.2024.124382 -
Japanese Journal of Radiology Jun 2024To evaluate the predictive ability of combining Technetium-99m-galactosyl human serum albumin (Tc‑GSA) single-photon emission computed tomography (SPECT)/computed...
Predictability of combining Technetium-99m-galactosyl human serum albumin single-photon emission computed tomography/computed tomography and indocyanine green clearance test for posthepatectomy liver failure.
PURPOSE
To evaluate the predictive ability of combining Technetium-99m-galactosyl human serum albumin (Tc‑GSA) single-photon emission computed tomography (SPECT)/computed tomography (CT) volume and plasma clearance rate of indocyanine green (ICGK) for posthepatectomy liver failure (PHLF).
MATERIALS AND METHODS
Fifty patients who underwent Tc-GSA scintigraphy as a preoperative examination for segmentectomy or more from July 2021 to June 2023 were evaluated prospectively. Patients were divided into two groups according to the presence or absence of posthepatectomy liver failure (PHLF). Total functional liver volume (t-FLV) and remnant FLV (r-FLV) were measured from Tc-GSA SPECT/CT image. Future liver remnant ICGK (ICGK-F) was calculated by ICGK and remnant liver volume from CT. Area under the curve (AUC) of ICGK-F, r-FLV, r-FLV/t-FLV, ICGK × r-FLV, ICGK × r-FLV/t-FLV was calculated to evaluate predictive ability of each parameter for PHLF.
RESULTS
PHLF was occurred in 7 patients. AUC of ICGK × r-FLV was significantly higher than that of ICGK-F (0.99; 95% confidence interval [CI]: 0.96-1 vs 0.82; 95%CI: 0.64-0.96; p = 0.036). There was no significant difference between the AUC of r-FLV, r-FLV/t-FLV, ICGK × r-FLV/t-FLV and that of ICGK-F, respectively.
CONCLUSION
The combination of Tc‑GSA SPECT/CT volume and ICGK can predict PHLF more accurately than ICGK-F.
PubMed: 38913284
DOI: 10.1007/s11604-024-01613-4 -
Cancer Chemotherapy and Pharmacology Jun 2024High-dose methotrexate (HDMTX) is integral in treating hematologic malignancies but carries risks of severe toxicities due to prolonged MTX exposure. However, knowledge...
PURPOSE
High-dose methotrexate (HDMTX) is integral in treating hematologic malignancies but carries risks of severe toxicities due to prolonged MTX exposure. However, knowledge of delayed MTX excretion is primarily derived from pediatric and adolescent cohorts, with the reported predictors being presented as rough dichotomous values. This study aimed to identify risk factors for delayed MTX excretion exclusively in adult patients with hematologic malignancies and develop a more applicable predictive nomogram based on continuous clinical and laboratory variables.
METHODS
517 HDMTX cycles in 194 patients were retrospectively analyzed. Delayed MTX excretion was defined as either MTX concentration ≥ 1.0 µmol/L at 48 h or ≥ 0.1 µmol/L at 72 h after HDMTX initiation. Multivariate logistic regression analysis was used to construct the nomogram internally validated with the bootstrap method.
RESULTS
Delayed MTX excretion was observed in 24.0% of cycles. Six significant predictors were identified: relapsed/refractory disease (Odds ratio [OR] 2.03), fewer HDMTX cycles (OR 0.771), treatment intent (OR 2.13), lower albumin (OR 0.563) and creatinine clearance levels (OR 0.993), and increased γ-glutamyl transpeptidase levels (OR 1.004, all P < 0.05). These were incorporated into a web-based nomogram as continuous variables with good prediction accuracy (area under the curve, 0.73) and without significant overfitting. Delayed MTX excretion increased risks of developing acute kidney injury, even solely at the 72 h timepoint (OR 2.57, P = 0.025), without providing any benefit of clinical outcomes.
CONCLUSION
This study comprehensively characterized MTX elimination failure following HDMTX in adult patients and could pave the way for individualized risk prediction.
PubMed: 38902559
DOI: 10.1007/s00280-024-04687-z -
Bioorganic & Medicinal Chemistry Letters Sep 2024For small-molecule drugs, lipidation via a cleavable linkage can extend half-life in circulation through interaction with albumin. Here we modified the cysteinylprolyl...
For small-molecule drugs, lipidation via a cleavable linkage can extend half-life in circulation through interaction with albumin. Here we modified the cysteinylprolyl ester (CPE) system used in peptide thioester synthesis, which normally requires basic conditions, for use as an self-immolative linker and release device for a lipid-gemcitabine conjugate. To improve release under physiological conditions for medical application, a methyl group at the α-position of cysteine on the CPE unit was incorporated in anticipation of the Thorpe-Ingold effect. As a result, Ac-Gly-(α-Me)Cys(SH)-Pro-gemcitabine 11 drastically promoted the release of gemcitabine in comparison with Ac-Gly-Cys(SH)-Pro-gemcitabine 10. Furthermore, in the presence of bovine serum albumin and/or 2-mercaptoethanesulfonic acid, the gentle and continuous release of gemcitabine from the lipid-gemcitabine conjugate 16 was achieved. In addition to gemcitabine, this method could allow high clearance drugs, including nucleic acid and prostacyclin derivatives, to maintain their biological activity long enough to become effective.
Topics: Gemcitabine; Deoxycytidine; Lipids; Esters; Drug Liberation; Cysteine; Humans; Molecular Structure; Serum Albumin, Bovine; Animals
PubMed: 38879090
DOI: 10.1016/j.bmcl.2024.129850 -
Chembiochem : a European Journal of... Jun 2024With the increasing use of polyethylene glycol (PEG) based proteins and drug delivery systems, anti-PEG antibodies have commonly been detected among the population,...
With the increasing use of polyethylene glycol (PEG) based proteins and drug delivery systems, anti-PEG antibodies have commonly been detected among the population, causing the accelerated blood clearance and hypersensitivity reactions, poses potential risks to the clinical efficacy and safety of PEGylated drugs. Therefore, vigilant monitoring of anti-PEG antibodies is crucial for both research and clinical guidance regarding PEGylated drugs. The enzyme-linked immunosorbent assay (ELISA) is a common method for detecting anti-PEG antibodies. However, diverse coating methods, blocking solutions and washing solutions have been employed across different studies, and unsuitable use of Tween 20 as the surfactant even caused biased results. In this study, we established the optimal substrate coating conditions, and investigated the influence of various surfactants and blocking solutions on the detection accuracy. The findings revealed that incorporating 1% bovine serum albumin into the serum dilution in the absence of surfactants will result the credible outcomes of anti-PEG antibody detection.
PubMed: 38867605
DOI: 10.1002/cbic.202400316 -
Clinical Pharmacology and Therapeutics Jun 2024Data from phase IIb/III and phase III studies were used to characterize the population pharmacokinetics of risankizumab and its exposure-response relationships for...
Data from phase IIb/III and phase III studies were used to characterize the population pharmacokinetics of risankizumab and its exposure-response relationships for efficacy and safety in ulcerative colitis (UC) patients. A two-compartment model with first-order absorption and elimination accurately described risankizumab pharmacokinetics. Although certain covariates, namely, body weight, serum albumin, fecal calprotectin, sex, corticosteroid use, advanced therapy inadequate response, and pancolitis, were statistically correlated with risankizumab clearance, their impact on exposure was not clinically meaningful for efficacy or safety. Phase II exposure-response analyses demonstrated that the 1,200 mg intravenous (IV) induction dose at Weeks 0, 4, and 8 achieved near maximal response for all efficacy end points, with suboptimal efficacy from the 600 mg and little added benefit from the 1,800 mg regimens, justifying 1,200 mg IV as the induction dose in the phase III study. Phase III exposure-response analyses for efficacy during induction showed statistically significant exposure-response relationships at Week 12 following 1,200 mg IV at Weeks 0, 4, and 8, in line with phase IIb results. Exposure-response analyses for maintenance demonstrated modest improvement in Week 52 efficacy when increasing the subcutaneous dose from 180 mg to 360 mg with largely overlapping confidence intervals. Exposure-response analyses for safety indicated no apparent exposure-dependent safety events over the induction or maintenance treatment. Based on these results, the recommended dosing regimen for risankizumab in UC patients is 1,200 mg IV at Weeks 0, 4, and 8, followed by 180 mg or 360 mg subcutaneously at Week 12 and every 8 weeks thereafter.
PubMed: 38863178
DOI: 10.1002/cpt.3330 -
International Journal of Nanomedicine 2024The commercial docetaxel (DTX) formulation causes severe side effects due to polysorbate 80 and ethanol. Novel surfactant-free nanoparticle (NP) systems are needed to...
Crafting Docetaxel-Loaded Albumin Nanoparticles Through a Novel Thermal-Driven Self-Assembly/Microfluidic Combination Technology: Formulation, Process Optimization, Stability, and Bioavailability.
BACKGROUND
The commercial docetaxel (DTX) formulation causes severe side effects due to polysorbate 80 and ethanol. Novel surfactant-free nanoparticle (NP) systems are needed to improve bioavailability and reduce side effects. However, controlling the particle size and stability of NPs and improving the batch-to-batch variation are the major challenges.
METHODS
DTX-loaded bovine serum albumin nanoparticles (DTX-BSA-NPs) were prepared by a novel thermal-driven self-assembly/microfluidic technology. Single-factor analysis and orthogonal test were conducted to obtain the optimal formulation of DTX-BSA-NPs in terms of particle size, encapsulation efficiency (EE), and drug loading (DL). The effects of oil/water flow rate and pump pressure on the particle size, EE, and DL were investigated to optimize the preparation process of DTX-BSA-NPs. The drug release, physicochemical properties, stability, and pharmacokinetics of NPs were evaluated.
RESULTS
The optimized DTX-BSA-NPs were uniform, with a particle size of 118.30 nm, EE of 89.04%, and DL of 8.27%. They showed a sustained release of 70% over 96 hours and an increased stability. There were some interactions between the drug and excipients in DTX-BSA-NPs. The half-life, mean residence time, and area under the curve (AUC) of DTX-BSA-NPs increased, but plasma clearance decreased when compared with DTX.
CONCLUSION
The thermal-driven self-assembly/microfluidic combination method effectively produces BSA-based NPs that improve the bioavailability and stability of DTX, offering a promising alternative to traditional formulations.
Topics: Docetaxel; Animals; Serum Albumin, Bovine; Nanoparticles; Biological Availability; Particle Size; Drug Stability; Taxoids; Antineoplastic Agents; Drug Liberation; Drug Carriers; Rats, Sprague-Dawley; Male; Drug Compounding; Rats
PubMed: 38846644
DOI: 10.2147/IJN.S457482