Aerosolized lancovutide in adolescents (≥12 years) and adults with cystic fibrosis – a randomized trial

BackgroundLancovutide activates a chloride channel (TMEM-16A) other than the cystic fibrosis (CF) transmembrane conductance regulator protein and could benefit CF patients.MethodsIn this randomized, multi-center, double-blind, placebo-controlled, parallel-group trial 161 patients ≥12 years with a confirmed diagnosis of CF were randomized to either placebo (saline) or active drug in 3 different dosing schemes of 2.5mg inhaled lancovutide (once daily, every other day or twice a week) for eight weeks. The primary endpoint was the change in the forced expiratory volume in 1 second (FEV1) percent predicted. Secondary endpoints included further lung function parameters (FEV1 (absolute), functional vital capacity percent predicted, forced expiratory flow percent predicted, pulse oximetry), quality of life assessment, pulmonary exacerbations, hospitalization due to pulmonary exacerbations, time to first pulmonary exacerbation, duration of anti-inflammatory, mucolytic or antibiotic treatment, and safety.ResultsThere was no significant difference in the change in FEV1 percent predicted, quality of life, other lung function parameters, pulmonary exacerbations or requirement of additional treatment between groups. Overall, the inhalation of lancovutide was safe although a higher rate of adverse events, especially related to the respiratory system, occurred as compared to placebo.ConclusionsLancovutide did not improve FEV1 percent predicted when compared to placebo (NCT00671736).     

First‐in‐human development of a pharmacodynamic biomarker for PAC1 receptor antagonists using intradermal injections of maxadilan

Maxadilan, a potent vasodilator peptide, selectively activates the PAC₁ receptor, a promising target for migraine therapy. Therefore, maxadilan has been suggested as a tool to study the pharmacodynamics (PDs) of PAC₁ receptor antagonists. The objectives of this first‐in‐human study were to: (1) determine the safety, tolerability, dose response, and time course of the dermal blood flow (DBF) changes after intradermal (i.d.) injections of maxadilan in the human forearm, and (2) assess the inter‐arm and inter‐period reproducibility of this response. This was a single‐center, open‐label study in healthy subjects, comprising three parts: (1) dose–response (n = 25), (2) response duration (n = 10), and (3) reproducibility (n = 15). DBF measurements were performed using laser Doppler imaging (LDI) up to 60 min postinjection, or up to 5 days for the response duration assessments. To assess reproducibility, the intraclass correlation coefficient (ICC) and sample sizes were calculated. The i.d. maxadilan (0.001, 0.01, 0.1, 0.9, 3, and 10 ng) produced a well‐tolerated, dose‐dependent increase in DBF, with a half‐maximal effective concentration fitted at 0.0098 ng. The DBF response to 0.9 ng maxadilan was quantifiable with LDI up to 72 h postinjection. The inter‐period reproducibility of the DBF response was better upon 0.9 ng (ICC > 0.6) compared to 0.01 ng (ICC < 0.4) maxadilan. However, irrespective of the study design or maxadilan dose, a sample size of 11 subjects is sufficient to detect a 30% difference in DBF response with 80% power. In conclusion, intradermal maxadilan provides a safe, well‐tolerated, and reproducible PD biomarker for PAC₁ receptor antagonists in vivo in humans.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Selective target engagement biomarkers have proven to be successful in guiding go/no‐go decisions in early clinical drug development. Recently, the PAC₁‐receptor gained interest as novel target for anti‐migraine drugs. Intradermal injections of maxadilan, a selective and potent PAC₁ receptor agonist, have been proposed as a pharmacodynamic (PD) biomarker tool to assess PAC₁ receptor activation.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study evaluated the safety and applicability of intradermal maxadilan injection in humans by characterizing the induced vascular changes in terms of safety, dose response, and reproducibility.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Intradermal injection of maxadilan induces a robust, dose‐dependent increase in dermal blood flow with low variability. Hence, it can be used in the early clinical drug development of PAC₁ receptor antagonists.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Implementation of this novel PD biomarker will support the early clinical development of PAC₁ receptor antagonists, thereby reducing the costs and time invested to translate promising results in rodent pain models to human conditions.     

Population pharmacokinetics of digoxin in Korean patients

AIM: Digoxin possesses a narrow therapeutic index and shows a large inter-patient pharmacokinetic variability. The purpose of this study was to develop a population model for the pharmacokinetics of digoxin in Korean patients. METHODS: Plasma concentrations of digoxin after multiple administration at varying dosing schedules in Korean patients were used for population modeling. Data analysis was performed with the P-Pharm software. The data were best fitted by a one-compartment model. The effect of demographic and clinical factors like sex, age, weight, disease state, and renal function on the pharmacokinetic parameters of digoxin was investigated. RESULTS: The study indicated that the clearance of digoxin was influenced by creatinine clearance, while body weight and creatinine clearance were the covariates for its volume of distribution. The population mean estimates for CL and V were 4.4 l/h and 535 l, respectively. Absorption rate constant was lower in females and in the presence of concomitant drug treatment. CONCLUSION: A population pharmacokinetic model for the digoxin pharmacokinetics in a section of Korean patients was developed. The relationships between the pharmacokinetic parameters and the demographic data and the patient-specific covariates were established.     

Challenges in ethics, safety, best practices, and oversight regarding HIT vendors, their customers, and patients: a report of an AMIA special task force

The current commercial health information technology (HIT) arena encompasses a number of competing firms that provide electronic health applications to hospitals, clinical practices, and other healthcare-related entities. Such applications collect, store, and analyze patient information. Some vendors incorporate contract language whereby purchasers of HIT systems, such as hospitals and clinics, must indemnify vendors for malpractice or personal injury claims, even if those events are not caused or fostered by the purchasers. Some vendors require contract clauses that force HIT system purchasers to adopt vendor-defined policies that prevent the disclosure of errors, bugs, design flaws, and other HIT-software-related hazards. To address this issue, the AMIA Board of Directors appointed a Task Force to provide an analysis and insights. Task Force findings and recommendations include: patient safety should trump all other values; corporate concerns about liability and intellectual property ownership may be valid but should not over-ride all other considerations; transparency and a commitment to patient safety should govern vendor contracts; institutions are duty-bound to provide ethics education to purchasers and users, and should commit publicly to standards of corporate conduct; and vendors, system purchasers, and users should encourage and assist in each others'' efforts to adopt best practices. Finally, the HIT community should re-examine whether and how regulation of electronic health applications could foster improved care, public health, and patient safety.     

Blood omega-3 and trans fatty acids in middle-aged acute coronary syndrome patients

We tested the hypothesis that lower blood omega-3 (omega-3) fatty acids (FAs) and/or higher trans FAs are associated with the risk of an acute coronary syndrome (ACS). Higher levels of omega-3 FA have been associated with decreased risk of sudden cardiac death. However, their association with ACS risk is unclear. Although higher self-reported intakes of trans FAs have been linked to increased coronary risk, the association between blood levels of trans FA and ACS risk is also unknown. We analyzed the FA composition of whole blood from 94 subjects with ACS and 94 age-, gender-, and race-matched controls. Omega-3 and trans FA associations with ACS were assessed using multivariable models after adjusting for smoking status, alcohol use, diabetes, body mass index, serum lipids, and history of myocardial infarction or revascularization. Subjects' mean age was 47 years, 54% were men, and 80% were Caucasian. Whole blood long-chain omega-3 FA (eicosapentaenoic acid [EPA] plus docosahexaenoic acid [DHA]) content was 29% lower in patients than in controls (1.7 +/- 0.9% vs 2.4 +/- 1.4%, p <0.001), whereas trans FA content was not different (2.1 +/- 0.7% vs 2.0 +/- 0.9%, p = NS). The multivariable-adjusted odds for case status was 0.67 (95% confidence interval 0.46 to 0.98) for a 1 SD increase in blood EPA + DHA. The inclusion of trans FAs in the EPA + DHA model did not alter this association. In conclusion, low blood EPA + DHA content is an independent predictor of increased risk for ACS, but higher blood trans FA content is not. Blood EPA + DHA may serve as a new, modifiable risk factor for ACS.