Diffusion-limited PBPK model for predicting pulmonary pharmacokinetics of florfenicol in pig.

For most bacterial lung infections, the concentration of unbound antimicrobial agent in lung interstitial fluid has been thought to be responsible for antimicrobial efficacy. In this study, a diffusion-limited physiologically based pharmacokinetic (PBPK) model was developed to predict the pulmonary pharmacokinetics of florfenicol (FF) in pigs. The model included separate compartments corresponding to blood, diffusion-limited lung, flow-limited muscle, liver, and kidney and an extra compartment representing the remaining carcass. The absorption rate constant and renal and hepatic clearance of FF were determined in vivo. Other parameters were taken from the literature or optimized based on existing pharmacokinetic data. All mathematical operations during the development of the model were performed using acslXtreme version 3.0.2.1 (Aegis Technologies Group, Inc., Huntsville, AL, USA). The model accurately predicted the concentration-time courses of FF in lung interstitial fluid, serum, and plasma following different dosing schedules, except at the dose of 15 mg/kg. When compared with the tissue residue data, the model generally underestimated the FF concentration at the injection site, whereas it gave good predictions of FF concentrations in lung, liver, and kidney at early time points. The model predictions provide a scientific basis for the dosage regimen design of FF.

Specialty pharmacist integration into an outpatient neurology clinic improves pimavanserin access.

INTRODUCTION: Access to pimavanserin, the only Parkinson disease-related psychosis treatment approved by the FDA, is restricted by insurance requirements, a limited distribution network, and high costs. Following initiation, patients require monitoring for safety and effectiveness. The primary objective of this study was to evaluate impact of specialty pharmacist (SP) integration on time to insurance approval. Additionally, we describe a pharmacist-led monitoring program. METHODS: This was a single-center, retrospective study of adults prescribed pimavanserin by the neurology clinic from June 2016 to June 2018. Patients receiving pimavanserin externally or through clinical trials were excluded. Pre- (June 2016 to December 2016) and post-SP integration (January 2017 to June 2018) periods were assessed. Proportional odds logistic regression was performed to test association of approval time with patient characteristics (age, gender, insurance type) postintegration. Interventions were categorized as clinical care, care coordination, management of adverse event, or adherence. RESULTS: We included 94 patients (32 preintegration, 62 postintegration), 80% male (n = 75) and 96% white (n = 90) with a mean age of 73 years. Median time to approval was 22 days preintegration and 3 days postintegration. Higher rates of approval (81% vs 95%) and initiation (78% vs 94%) were observed postintegration. Proportional odds logistic regression suggested patients with commercial insurance were likely to have longer time to approval compared with patients with Medicare/Medicaid (odds ratio 7.1; 95% confidence interval: 1.9, 26.7; P = .004). Most interventions were clinical (51%, n = 47) or care coordination (42%, n = 39). CONCLUSION: Median time to approval decreased postintegration. The SP performed valuable monitoring and interventions.

Chloroplast and Nuclear Genetic Diversity Explain the Limited Distribution of Endangered and Endemic Thuja sutchuenensis in China.

Narrow-ranged species face challenges from natural disasters and human activities, and to address why species distributes only in a limited region is of great significance. Here we investigated the genetic diversity, gene flow, and genetic differentiation in six wild and three cultivated populations of Thuja sutchuenensis, a species that survive only in the Daba mountain chain, using chloroplast simple sequence repeats (cpSSR) and nuclear restriction site-associated DNA sequencing (nRAD-seq). Wild T. sutchuenensis populations were from a common ancestral population at 203 ka, indicating they reached the Daba mountain chain before the start of population contraction at the Last Interglacial (LIG, ∼120-140 ka). T. sutchuenensis populations showed relatively high chloroplast but low nuclear genetic diversity. The genetic differentiation of nRAD-seq in any pairwise comparisons were low, while the cpSSR genetic differentiation values varied with pairwise comparisons of populations. High gene flow and low genetic differentiation resulted in a weak isolation-by-distance effect. The genetic diversity and differentiation of T. sutchuenensis explained its survival in the Daba mountain chain, while its narrow ecological niche from the relatively isolated and unique environment in the "refugia" limited its distribution.

A new spider fly (Diptera: Acroceridae: Ogcodinae: Ogcodes Latreille) from Chiloé Island's evergreen forest and new distributional records for other spider flies in Chile.

Ogcodes Latreille is the largest genus of Acroceridae. They exhibit a cosmopolitan distribution and parasitize several spider families. Eleven Neotropical species are currently recognized in the genus, with five of them occurring in Chile, though distribution data is limited in this group of rarely collected flies. In this work, we describe a new species, Ogcodes kunkunche sp. nov. Barahona-Segovia from the evergreen forest of Chiloé Island, provide an identification key to the Chilean species of Ogcodes, and include novel distributional data for other species of spider flies (Acrocerinae and Ogcodinae). Based in our results, we suggest that O. kunkunche sp. nov. must be incorporated in the porteri group, due to wing vein reduction. Morphological aspects within Ogcodes, and their evolutionary implications are discussed.

A Physiologically Based Pharmacokinetic Model for Ganciclovir and Its Prodrug Valganciclovir in Adults and Children.

A physiologically based pharmacokinetic (PBPK) model has been developed for ganciclovir and its prodrug valganciclovir. Initial bottom-up modeling based on physicochemical drug properties and measured in vitro inputs was verified in preclinical animal species, and then, a clinical model was verified in a stepwise fashion with pharmacokinetic data in adult, children, and neonatal patients. The final model incorporated conversion of valganciclovir to ganciclovir through esterases and permeability-limited tissue distribution of both drugs with active transport processes added in gut, liver, and kidney. A PBPK model which accounted for known age-related tissue volumes, composition and blood flows, and renal filtration clearance was able to simulate well the measured plasma exposures in adults and pediatric patients. Overall, this work illustrates the stepwise development of PBPK models which could be used to predict pharmacokinetics in infants and neonates, thereby assisting drug development in a vulnerable patient population where clinical data are challenging to obtain.