Development, Optimization, and Evaluation of Carvedilol-Loaded Solid Lipid Nanoparticles for Intranasal Drug Delivery.

Carvedilol, a beta-adrenergic blocker, suffers from poor systemic availability (25%) due to first-pass metabolism. The aim of this work was to improve carvedilol bioavailability through developing carvedilol-loaded solid lipid nanoparticles (SLNs) for nasal administration. SLNs were prepared by emulsion/solvent evaporation method. A 23 factorial design was employed with lipid type (Compritol or Precirol), surfactant (1 or 2% w/v poloxamer 188), and co-surfactant (0.25 or 0.5% w/v lecithin) concentrations as independent variables, while entrapment efficiency (EE%), particle size, and amount of carvedilol permeated/unit area in 24 h (Q 24) were the dependent variables. Regression analysis was performed to identify the optimum formulation conditions. The in vivo behavior was evaluated in rabbits comparing the bioavailability of carvedilol after intravenous, nasal, and oral administration. The results revealed high drug EE% ranging from 68 to 87.62%. Carvedilol-loaded SLNs showed a spherical shape with an enriched core drug loading pattern having a particle size in the range of 66 to 352 nm. The developed SLNs exhibited significant high amounts of carvedilol permeated through the nasal mucosa as confirmed by confocal laser scanning microscopy. The in vivo pharmacokinetic study revealed that the absolute bioavailability of the optimized intranasal SLNs (50.63%) was significantly higher than oral carvedilol formulation (24.11%). Hence, we conclude that our developed SLNs represent a promising carrier for the nasal delivery of carvedilol.

Population pharmacokinetics of etomidate in neonates and infants with congenital heart disease.

BACKGROUND: Etomidate is a rapid-onset, short-acting hypnotic medication administered for the induction of anesthesia. It is currently approved by the Food and Drug Administration for use in older children and adults. Pharmacokinetic data to help guide dosing in neonates and infants are lacking. OBJECTIVE: The aim of this study was to determine the pharmacokinetics of etomidate in neonates and infants with congenital heart disease undergoing cardiac surgery. METHODS: Four neonates and 16 infants, postnatal age 0.3-11.7 months, requiring open-heart surgery received 0.3 mg/kg of etomidate administered as a single intravenous dose prior to surgery. Blood sampling for plasma etomidate concentration occurred immediately following etomidate administration until the initiation of cardiopulmonary bypass. A population pharmacokinetic approach using nonlinear mixed-effects modeling was applied to characterize etomidate pharmacokinetics. RESULTS: The pharmacokinetics of etomidate was described by a two-compartment model with first-order elimination. An allometric weight-based model was applied to scale results to a 70 kg adult. Covariates including age and cardiac physiology were not found significantly to impact etomidate pharmacokinetics. The study population was found to have a central and intercompartmental clearance of 0.624 l/min/70 kg and 0.44 l/min/70 kg, respectively; central and peripheral distribution volume of 9.47 l/70 kgand 22.8 l/70 kg, respectively. Inter-individual variability was 94-142% for all parameters and the residual variability was 29%. CONCLUSIONS: The clearance of etomidate is lower in neonates and infants with congenital heart disease compared with published values for older children without congenital heart disease. In addition, etomidate pharmacokinetics is highly variable in this pediatric cardiac population.

Association between vancomycin trough concentration and area under the concentration-time curve in neonates.

National treatment guidelines for invasive methicillin-resistant Staphylococcus aureus (MRSA) infections recommend targeting a vancomycin 24-h area under the concentration-time curve (AUC0-24)-to-MIC ratio of >400. The range of vancomycin trough concentrations that best predicts an AUC0-24 of >400 in neonates is not known. This understanding would help clarify target trough concentrations in neonates when treating MRSA. A retrospective chart review from a level III neonatal intensive care unit was performed to identify neonates treated with vancomycin over a 5-year period. Vancomycin concentrations and clinical covariates were utilized to develop a one-compartment population pharmacokinetic model and examine the relationships between trough and AUC0-24 in the study neonates. Monte Carlo simulations were performed to examine the effect of dose, postmenstrual age (PMA), and serum creatinine level on trough and AUC0-24 achievement. A total of 1,702 vancomycin concentrations from 249 neonates were available for analysis. The median (interquartile range) PMA was 39 weeks (32 to 42 weeks) and weight was 2.9 kg (1.6 to 3.7 kg). Vancomycin clearance was predicted by weight, PMA, and serum creatinine level. At a trough of 10 mg/liter, 89% of the study neonates had an AUC0-24 of >400. Monte Carlo simulations demonstrated that troughs ranging from 7 to 11 mg/liter were highly predictive of an AUC0-24 of >400 across a range of PMA, serum creatinine levels, and vancomycin doses. However, a trough of ≥10 mg/liter was not readily achieved in most simulated subgroups using routine starting doses. Higher starting doses frequently resulted in troughs of >20 mg/liter. A vancomycin trough of ∼10 mg/liter is likely adequate for most neonates with invasive MRSA infections based on considerations of the AUC0-24. Due to pharmacokinetic and clinical heterogeneity in neonates, consistently achieving this target vancomycin exposure with routine starting doses is difficult. More robust clinical dosing support tools are needed to help clinicians with dose individualization.

2,2',3,5',6-Pentachlorobiphenyl (PCB 95) and its hydroxylated metabolites are enantiomerically enriched in female mice.

Epidemiological and laboratory studies link polychlorinated biphenyls and their metabolites to adverse neurodevelopmental outcomes. Several neurotoxic PCB congeners are chiral and undergo enantiomeric enrichment in mammalian species, which may modulate PCB developmental neurotoxicity. This study measures levels and enantiomeric enrichment of PCB 95 and its hydroxylated metabolites (OH-PCBs) in adult female C57Bl/6 mice following subchronic exposure to racemic PCB 95. Tissue levels of PCB 95 and OH-PCBs increased with increasing dose. Dose-dependent enantiomeric enrichment of PCB 95 was observed in brain and other tissues. OH-PCBs also displayed enantiomeric enrichment in blood and liver, but were not detected in adipose and brain. In light of data suggesting enantioselective effects of chiral PCBs on molecular targets linked to PCB developmental neurotoxicity, our observations highlight the importance of accounting for PCB and OH-PCB enantiomeric enrichment in the assessment of PCB developmental neurotoxicity.

Pharmacokinetic analysis of continuous erythropoietin receptor activator disposition in adult sheep using a target-mediated, physiologic recirculation model and a tracer interaction methodology.

The pharmacokinetics (PK) of continuous erythropoietin receptor activator (CERA), a PEGylated erythropoietin (EPO) derivative, was studied in sheep after bone marrow (BM) busulfan ablation by using a receptor-based recirculation model and tracer interaction method (TIM) experiments. The nontracer CERA component of the TIM was analyzed using a noncompartmental approach. In contrast to EPO elimination that is linear after the BM ablation, CERA elimination remains nonlinear. After busulfan treatment, initial EPO receptors (EPOR) normalized production rate constant, EPOR degradation rate constant, and CERA-EPOR complex internalization rate constant decreased (p < 0.01), whereas no change in CERA/EPOR equilibrium dissociation constant was detected (p > 0.05). After BM ablation, noncompartmental analysis showed that CERA-PK parameters underwent 1) a decrease in plasma clearance (p < 0.01); 2) a concomitant increase in elimination half-life and mean residence time; and 3) no significant change in volume of distribution, distribution half-life, or distributional clearance (p > 0.05). These results suggest that CERA elimination is mediated through saturable hematopoietic and nonhematopoietic EPOR pathways, with possible contribution of another EPOR-independent pathway(s). Compared with the nonhematopoietic EPOR population, the hematopoietic receptors have similar affinity to CERA but are significantly more involved in CERA's in vivo elimination. The saturable nature of the nonerythropoietic, non-BM pathway(s) for CERA in contrast to EPO predicts two fundamental differences: 1) an increasing fraction of CERA is used for erythropoiesis for increasing concentrations; and 2) the clearance of CERA becomes more limited for increasing concentrations. Taken together, these differences favor a more efficacious and prolonged action for CERA.

Differential pharmacokinetic analysis of in vivo erythropoietin receptor interaction with erythropoietin and continuous erythropoietin receptor activator in sheep.

The two erythropoiesis stimulating agents (ESAs), short acting recombinant human erythropoietin (EPO) and long acting continuous erythropoietin receptor activator (CERA), have been hypothesized to share an in vivo elimination pathway that involves binding to erythropoietin receptor (EPOR) and subsequent internalization. A physiologically based recirculation model and a pharmacokinetic tracer interaction methodology (TIM) were used to compare the in vivo interaction kinetics with EPOR between the two ESAs in adult sheep. Animals treated with EPO experienced a greater EPOR up-regulation than those treated with CERA, as evidenced by an eightfold-higher initial EPOR normalized production rate constant, k(syn) /R(0) , versus a twofold-larger EPOR degradation rate constant, k(deg) . In agreement with in vitro studies, EPO had a lower in vivo equilibrium dissociation constant from EPOR than CERA (K(D) = 6 versus 88.4 pmol/l, respectively, p < 0.01). The internalization and/or degradation of the EPO-EPOR complex was faster than that of the CERA-EPOR complex (k(int) = 24 versus 2.41 h(-1) , respectively, p < 0.01). The adopted model enables a mechanism-based explanation for CERA's slower elimination and greater erythropoietic activity in vivo. As predicted by the model, the slower elimination of CERA is due to: (1) less EPOR up-regulation induced by CERA administration; (2) slower binding of CERA to EPOR; and (3) reduced internalization and/or degradation rate of surface-bound CERA. Slower CERA/EPOR complex elimination explains the greater in vivo erythropoiesis reported for CERA, despite its lower affinity to EPOR. A sensitivity analysis showed that the model parameters were reliably estimated using the TIM methodology.

Clearance of polychlorinated biphenyl atropisomers is enantioselective in female C57Bl/6 mice.

Changes in the enantiomeric composition of polychlorinated biphenyls (PCBs) can not only be used to investigate environmental and biological transport processes, but also have human health implications because of enantiospecific adverse health effects. To further understand differences in the disposition of PCB atropisomers in vivo, the present study investigates the toxicokinetics of PCB atropisomers in female C57Bl/6 mice after oral administration of a mixture of several PCBs, including racemic PCBs 91, 95, 132, 136, 149, 174, and 176. On the Chirasil-Dex column, an enrichment of the second eluting atropisomers was generally observed, whereas only the first eluting atropisomers E1-PCB 95, (-)-PCB 132, and (-)-PCB 149 had half-lives that were distinctively longer compared to the second eluting atropisomers. The bioavailability normalized clearance of first eluting atropisomers in blood was faster compared to that of second eluting atropisomers. The opposite trend was observed for the accumulation factors in adipose tissue, which is consistent with the slower clearance of the first eluting atropisomer. The only exception was PCB 174, which showed no differences in the toxicokinetic parameters of both atropisomers. Together, the differences in the toxicokinetics of PCB atropisomers point toward enantioselective biotransformation processes as the origin of PCB's enantiomeric enrichment in mammals and, possibly, humans.