Pharmacokinetic/pharmacodynamic target attainment analyses to support intravenous and oral lefamulin dose selection for the treatment of patients with community-acquired bacterial pneumonia.

OBJECTIVES: Lefamulin is a semi-synthetic intravenous (iv) and oral pleuromutilin antibiotic active against community-acquired bacterial pneumonia (CABP) pathogens. Pharmacokinetic/pharmacodynamic (PK/PD) target attainment analyses were carried out to evaluate lefamulin 150 mg iv q12h and 600 mg orally q12h under fed and fasted conditions for the treatment of patients with CABP. METHODS: The analyses undertaken used a population PK model based on Phase 1 PK data, non-clinical PK/PD targets for efficacy and in vitro surveillance data for Streptococcus pneumoniae (SP) and Staphylococcus aureus (SA), and Monte Carlo simulation. Percentage probabilities of PK/PD target attainment by MIC on day 1 were determined using median total-drug epithelial lining fluid (ELF) and free-drug plasma AUC:MIC ratio targets associated with 1 and 2 log10 cfu reductions from baseline. RESULTS: Percentage probabilities of attaining the total-drug ELF AUC:MIC ratio target for a 1 log10 cfu reduction from baseline for SP were ≥99.2% at the MIC90 of 0.12 mg/L and 96.7%, 82.1% and 96.3% for iv and oral dosing regimens under fed and fasted conditions, respectively, at the MIC99 of 0.25 mg/L. Percentage probabilities of attaining the free-drug plasma AUC:MIC target for the same endpoint at the SP MIC99 were 100% for each regimen. For the SA MIC90 of 0.12 mg/L and AUC:MIC ratio targets for the same endpoint, percentage probabilities were 92.7%-100% for iv and oral dosing regimens. CONCLUSIONS: These data provide support for lefamulin 150 mg iv q12h and 600 mg orally q12h for the treatment of patients with CABP and suggest that doses may not need to be taken under fasted conditions.

Assessment of seizure liability of Org 306039, a 5-HT2c agonist, using hippocampal brain slice and rodent EEG telemetry.

INTRODUCTION: Evaluation of the seizure potential for a CNS-targeted pharmaceutical compound before it is administered to humans is an important part of development. The current in vitro and in vivo studies were undertaken to characterize the seizure potential of the potent and selective 5-HT2c agonist Org 306039. METHODS: Rat hippocampal slices (n=5) were prepared and Org 306039 was applied over a concentration range of 0-1000µM. Male Sprague-Dawley rats, implanted with telemetry EEG recording electrodes received either vehicle (n=4) or 100mg/kg Org 306039 (n=4) by oral gavage daily for 10days. EEG was recorded continuously for 22±1h post-dose each day. Post-dose behavior observations were conducted daily for 2h. Body temperature was measured at 1 and 2h post-dose. On Day 7, blood samples were drawn for pharmacokinetic analysis of Org 306039. RESULTS: In hippocampal slice, Org 306039 elicited a concentration-dependent increase in population spike area and number recorded from CA1 area, indicating seizure-genic potential. In telemetered rats, Org 306039 was associated with a decrease in body weight, a decrease in body temperature and the appearance of seizure-related behaviors and pre-seizure waveforms on EEG. One rat exhibited an overt seizure. Plasma concentrations of Org 306039 were similar among the 4 rats in the Org-treated group. Small group size made it difficult to determine a PK-PD relationship. DISCUSSION: These results indicate that the in vitro and in vivo models complement each other in the characterization of the seizure potential of CNS-targeted compounds such as the 5-HT2c agonist Org 306039.

Mixed uncertainty analysis of polycyclic aromatic hydrocarbon inhalation and risk assessment in ambient air of Beijing.

This article presents the application of an integrated method that estimates the dispersion of polycyclic aromatic hydrocarbons (PAHs) in air, and assesses the human health risk associated with PAHs inhalation. An uncertainty analysis method consisting of three components were applied in this study, where the three components include a bootstrapping method for analyzing the whole process associated uncertainty, an inhalation rate (IR) representation for evaluating the total PAH inhalation risk for human health, and a normally distributed absorption fraction (AF) ranging from 0% to 100% to represent the absorption capability of PAHs in human body. Using this method, an integrated process was employed to assess the health risk of the residents in Beijing, China, from inhaling PAHs in the air. The results indicate that the ambient air PAHs in Beijing is an important contributor to human health impairment, although over 68% of residents seem to be safe from daily PAH carcinogenic inhalation. In general, the accumulated daily inhalation amount is relatively higher for male and children at 10 years old of age than for female and children at 6 years old. In 1997, about 1.73% cancer sufferers in Beijing were more or less related to ambient air PAHs inhalation. At 95% confidence interval, approximately 272-309 individual cancer incidences can be attributed to PAHs pollution in the air. The probability of greater than 500 cancer occurrence is 15.3%. While the inhalation of ambient air PAHs was shown to be an important factor responsible for higher cancer occurrence in Beijing, while the contribution might not be the most significant one.

Assessment of PAH-exposure among coke oven workers.

Coke oven workers are exposed to high concentrations of polycyclic aromatic hydrocarbons. Only recently have methods been developed to try to assess the individual, biologically significant exposure. The only coke oven plant in Finland started to function in 1987, in Raahe, enabling the implementation of a cohort study among the workers to determine the usefulness of some currently available biomonitoring methods, e.g. methods of measuring PAH-DNA adducts. Urine and blood samples were taken several times from a sample of workers starting from before they worked at the plant. A questionnaire (smoking, diet, former and current occupations) was filled in by the workers at every sampling, and air samples (personal and stationary) were collected at the same time. The mean values of both benzo(a)pyrene diolepoxide (BPDE)-DNA adducts were measured by synchronous fluorescence spectrophotometry (SFS) and the antibodies to these adducts increased somewhat after the work at the plant started. However, all the adduct values were low, and no differences between the smokers and non-smokers at any time point were detected. Battery workers had slightly increased means of BPDE-DNA adducts compared to non-battery workers. Also, coke oven workers had slightly higher adduct values than age, sex and smoking matched controls.