Biological Activity of sym-Triazines with Acetylcholine-like Substitutions as Multitarget Modulators of Alzheimer’s Disease

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Interspecies prediction of pharmacokinetics and tissue distribution of doxorubicin by physiologically-based pharmacokinetic modeling

The aim of the study was to develop a physiologically-based pharmacokinetic (PBPK) model to describe and predict whole-body disposition of doxorubicin following intravenous administration. The PBPK model was established using previously published data in mice and included 10 tissue compartments: lungs, heart, brain, muscle, kidneys, pancreas, intestine, liver, spleen, adipose tissue, and plasma. Individual tissues were described by either perfusion-limited or permeability-limited models. All parameters were simultaneously estimated and the final model was able to describe murine data with good precision. The model was used for predicting doxorubicin disposition in rats, rabbits, dogs, and humans using interspecies scaling approaches and was qualified using plasma and tissue observed data. Reasonable prediction of the plasma pharmacokinetics and tissue distribution was achieved across all species. In conclusion, the PBPK model developed based on a rich dataset obtained from mice, was able to reasonably predict the disposition of doxorubicin in other preclinical species and humans. Applicability of the model for special populations, such as patients with hepatic impairment, was also demonstrated. The proposed model will be a valuable tool for optimization of exposure profiles of doxorubicin in human patients.     

Amikacin population pharmacokinetics among paediatric burn patients

Introduction

The objectives of this study were to (1) determine the pharmacokinetics of amikacin among children with severe burn and (2) identify influential covariates.

Methods

Population-based pharmacokinetic modelling was performed in NONMEM 7.2 for hospitalized children who received amikacin at 10–20 mg/kg divided two, three, or four times per day as part of early empiric treatment of presumed burn-related sepsis.

Results

The analysis included data from 70 patients (6 months to 17 years) with 282 amikacin serum concentrations. Amikacin's mean C_max was 33.2 ± 9.4 μg/mL and the mean C_min was 3.8 ± 4.6 μg/mL. The final covariate model estimated clearance as 5.98 L/h/70 kg (4.97–6.99, 95% CI), the volume of distribution in the central compartment as 16.7 L/70 kg (14.0–19.4, 95% CI), the volume of distribution in the peripheral compartment as 40.1 L/70 kg (15.0–80.4, 95% CI), and the inter-compartmental clearance as 3.38 L/h/70 kg (2.44–4.32, 95% CI). In multivariate analyses, current weight (P < 0.001) was a significant covariate, while age, sex, height, serum creatinine, C-reactive protein, platelet count, the extent and type of burn, and concomitant vancomycin administration did not influence amikacin pharmacokinetics.

Discussion

Children with burn featured elevated amikacin clearance when compared to healthy adult volunteers. However, peak amikacin concentrations are comparable to those attained in other critically-ill children, suggesting that elevated amikacin clearance may not result in sub-therapeutic antibacterial effects. In this study, we found that amikacin displays two-compartment pharmacokinetics, with weight exerting a strong effect upon amikacin clearance. Further pharmacodynamic studies are needed to establish the optimal dosing regimen for amikacin in paediatric burn patients.     

Protocols,practices, and needs for investigating sudden unexpected infant deaths

Understanding case identification practices, protocols, and training needs of medical examiners and coroners (MEC) may inform efforts to improve cause-of-death certification. We surveyed a U.S.-representative sample of MECs and described investigation practices and protocols used in certifying sudden unexpected infant deaths (SUID). We also identified MEC training and resource needs. Of the 377 respondents, use of the SUID Investigation Reporting Form or an equivalent was 89% for large, 87% for medium, and 52% for small jurisdictions. Routine completion of infant medical history, witness interviews, autopsy, photos or videos, and family social history for infant death investigations was ≥80%, but routine scene re-creation with a doll was 30% in small, 64% in medium, and 59% in large offices. Seventy percent of MECs reported infant death investigation training needs. Increased training and use of standardized practices may improve SUID cause-of-death certification, allowing us to better understand SUID.