Eculizumab precision dosing algorithm for thrombotic microangiopathy in children and young adults undergoing HSCT

Transplant-associated thrombotic microangiopathy (TA-TMA) is a fatal post-transplant complication of hematopoietic stem cell transplantation (HSCT). We recently reported that survival for TA-TMA has been improved by early intervention with eculizumab, a complement C5 inhibitor, guided by pharmacokinetic/pharmacodynamic (PK/PD) model-informed precision dosing. However, patients with gastrointestinal (GI) bleeding showed poor survival even when treated with more frequent dosing. Our objective was to develop separate models in bleeding and non-bleeding TA-TMA patients and propose precision dosing algorithms. Eculizumab PK/PD were analyzed in 19 bleeding and 38 non-bleeding patients (0.5-29.9 years). A complement activation biomarker (sC5b-9) and bodyweight were identified as significant determinants of eculizumab clearance regardless of bleeding. Eculizumab clearance after the first dose was higher in bleeding patients than in non-bleeding patients (83.8 vs. 61.3 mL/h/70kg, p=0.07). The high clearance was maintained over treatment doses in bleeding patients, whereas non-bleeding patients showed a time-dependent decrease in clearance. sC5b-9 levels were highest before the first dose and decreased over time regardless of bleeding complications. A Monte Carlo Simulation analysis showed that the current dosing protocols recommended for aHUS had less than 15% probability of eculizumab target concentration attainment of >100 g/mL in non-bleeding patients. This study identified an intensified loading protocol to reach 80% target attainment. Our data clearly showed the need for individualized dosing for patients with significant bleeding, and for ongoing dose adjustments to optimize outcomes. The developed models will be incorporated into a clinical decision support for precision dosing to improve outcomes in children and young adults with TA-TMA.

Dexmedetomidine Clearance Decreases with Increasing Drug Exposure: Implications for Current Dosing Regimens and Target-controlled Infusion Models Assuming Linear Pharmacokinetics

Background Numerous pharmacokinetic models have been published aiming at more accurate and safer dosing of dexmedetomidine. The vast majority of the developed models underpredict the measured plasma concentrations with respect to the target concentration, especially at plasma concentrations higher than those used in the original studies. The aim of this article was to develop a dexmedetomidine pharmacokinetic model in healthy adults emphasizing linear versus nonlinear kinetics. Methods The data of two previously published clinical trials with stepwise increasing dexmedetomidine target-controlled infusion were pooled to build a pharmacokinetic model using the NONMEM software package (ICON Development Solutions, USA). Data from 48 healthy subjects, included in a stratified manner, were utilized to build the model. Results A three-compartment mamillary model with nonlinear elimination from the central compartment was superior to a model assuming linear pharmacokinetics. Covariates included in the final model were age, sex, and total body weight. Cardiac output did not explain between-subject or within-subject variability in dexmedetomidine clearance. The results of a simulation study based on the final model showed that at concentrations up to 2 ng · ml–1, the predicted dexmedetomidine plasma concentrations were similar between the currently available Hannivoort model assuming linear pharmacokinetics and the nonlinear model developed in this study. At higher simulated plasma concentrations, exposure increased nonlinearly with target concentration due to the decreasing dexmedetomidine clearance with increasing plasma concentrations. Simulations also show that currently approved dosing regimens in the intensive care unit may potentially lead to higher-than-expected dexmedetomidine plasma concentrations. Conclusions This study developed a nonlinear three-compartment pharmacokinetic model that accurately described dexmedetomidine plasma concentrations. Dexmedetomidine may be safely administered up to target-controlled infusion targets under 2 ng · ml–1 using the Hannivoort model, which assumed linear pharmacokinetics. Consideration should be taken during long-term administration and during an initial loading dose when following the dosing strategies of the current guidelines. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Patients with Kidney Transplant: Maximizing Mycophenolic Acid Submission with Target Dose Intervention

Background: Mycophenolate, an immunosuppressive agent choice. It is used readily in the transplantation of kidneys. Aim: To find out utilization of this drug is considered safe but the exact dosage of this drug varies according to the choice. Methods: It alters from fixed-dose to the dose optimization to the drug exposure target. It is the area under the concentration and time curve graph. This graph gives inconsistent results of concentration-controlled dosing in prospective studies. In this research paper, the evidence helping mycophenolate has been analyzed. The research includes finding out the pharmacological features, toxicities, and efficacy of this chemical ingredient. Randomized controlled trials along with dose optimization procedure and exposure have also been achieved. Results: A fixed dose of mycophenolate continuously leads to either less exposure associated with unapproved strategy or over-exposure leading to toxicity. When concentration controlled dosing is measured via pharmacokinetic measurement to target concentration intervention, mycophenolate exposure is controlled successfully and clinical benefits are visible. There is a need for agreement on practical aspects of drug-target concentration intervention in normal tacrolimus containing dosage and research to find maintenance phase subjection targets. Conclusion: More preference should be given to the effects of over suppression and under suppression in transplantation of kidney affecting short term as well as long term benefits. A single dose should be given to the mycophenolate target concentration intervention. Keywords: Mycophenolate, immunosuppressive agent, kidney transplant, target dose intervention

Migration of Cefquinome Antibiotic Residues from Milk to Dairy Products

The aim of this study was to investigate the distribution of cefquinome in different dairy products during the processing of naturally contaminated milk or spiked milk. The analysis of cefquinome residues in milk, skimmed milk, buttermilk, whey, cream, butter, curd, and cheese samples was performed using a water:acetonitrile solvent extraction and C18 dispersive solid-phase extraction (d-SPE) clean-up, followed by ultrahigh-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC–MS/MS) determination. The target concentration of cefquinome was achieved in the spiked milk (100 µg kg−1). During its processing, the antibiotic migrated primarily with the skimmed milk as opposed to cream (ratios of 3.6:1 and 2.8:1 for experiments A and B, respectively), and with the buttermilk during butter manufacture (ratios of 6.9:1 and 4.6:1), but was equal in the curd and whey during the manufacture of cheese. In the milk collected from treated animals, the measured concentration of cefquinome was considerably high (approx. 5000 µg kg−1). The results obtained from the dairy products were similar to those obtained in the spiked study (ratios of 8.2:1 and 3.1:1 for experiments A and B, respectively, during the separation of skimmed milk and cream; 6.0:1 and 5.0:1 for A and B, respectively, during the separation of buttermilk and butter). However, during cheesemaking, cefquinome migrated with the whey after cutting the curd, with ratios of 0.54:1 and 0.44:1 for experiments A and B, respectively. The difference in the migration of cefquinome between curd and whey in spiked and animal studies is probably due to the different concentration levels in the two different experiments. The results of this study showed that, in dairy products manufactured from milk containing cefquinome residues, the drug migrated primarily with the high-water-containing fractions.

Supratherapeutic Posaconazole Concentration in a Pediatric Transplant Patient With Confirmed Rhizopus Infection

There are a limited number of studies that guide dosing of posaconazole delayed-release (DR) tablets for the pediatric population. Current FDA-approved doses are only recommended for patients 13 years and older. For younger patients, providers are faced with the challenge of recommending posaconazole doses extrapolated from adult studies or choosing an alternative agent. We report on a case of a 10-year-old patient who experienced a supratherapeutic trough serum concentration and transaminitis after receiving the extrapolated adult dosage of posaconazole DR tablets (300 mg twice daily for the first day, followed by 300 mg daily) for 7 days. In the end, the patient required a smaller dose of 200 mg daily to achieve the desired trough target concentration for the treatment of a Rhizopus neck infection. Our findings highlight the need for additional studies to determine the optimal dosing of posaconazole DR tablets for children.