Drug–physiology interaction and its influence on the QT prolongation-mechanistic modeling study

The current study is an example of drug–disease interaction modeling where a drug induces a condition which can affect the pharmacodynamics of other concomitantly taken drugs. The electrophysiological effects of hypokaliemia and heart rate changes induced by the antiasthmatic drugs were simulated with the use of the cardiac safety simulator. Biophysically detailed model of the human cardiac physiology—ten Tusscher ventricular cardiomyocyte cell model—was employed to generate pseudo-ECG signals and QTc intervals for 44 patients from four clinical studies. Simulated and observed mean QTc values with standard deviation (SD) for each reported study point were compared and differences were analyzed with Student’s t test (α?=?0.05). The simulated results reflected the QTc interval changes measured in patients, as well as their clinically observed interindividual variability. The QTc interval changes were highly correlated with the change in plasma potassium both in clinical studies and in the simulations (Pearson’s correlation coefficient?>?0.55). The results suggest that the modeling and simulation approach could provide valuable quantitative insight into the cardiological effect of the potassium and heart rate changes caused by electrophysiologically inactive, non-cardiological drugs. This allows to simulate and predict the joint effect of several risk factors for QT prolongation, e.g., drug-dependent QT prolongation due to the ion channels inhibition and the current patient physiological conditions.     

Cost evolution of biological agents for the treatment of spondyloarthritis in a tertiary hospital: influential factors in price

Background Spending on biological agents has risen dramatically due to the high cost of the drugs and the increased prevalence of spondyloarthritis. Objective To evaluate the annual cost per patient and cost for each biological drug for treating patients with spondyloarthritis from 2009 to 2016, and to calculate factors that affect treatment cost, such as optimizing therapies by monitoring drug serum levels, the use of biosimilar-TNF inhibitors, and official discounts or negotiated rebates in biologicals acquired by the pharmacy department. Method Retrospective, observational study in a Spanish tertiary hospital. Main outcome Annual cost per patient and per drug. Factors that influenced the costs and socio-demographic parameters and disease activity. Results A total of 129, 215, and 224 patients were treated in 2009, 2013, and 2016, respectively. The annual cost per patient decreased: EUR11,604 in 2009, EUR8513 in 2013, and EUR7464 in 2016. The introduction of new drugs drives economic competition, leading to total savings per drug, with discounts reaching 5.8, 12.4, 16.7, 17.7, 13.7, and 24.8% for original infliximab, etanercept, adalimumab, ertolizumab, golimumab, and secukinumab, respectively, while rebates for biosimilar infliximab reached 31.90% in 2016. The number of patients with optimized therapies reached 47.5% in 2016, which led to cost savings of EUR798,614, in addition to savings from official discounts and rebates of EUR252,706 and savings from optimized therapies of EUR545,908 in 2016. Conclusion The cost of biological treatments declined after official discounts, negotiated rebates, and optimized therapies, leading to a significant decrease in the annual cost per patient. The greatest contribution to economic savings in biological therapy according to our study was biological therapy optimization.     

Evaluation of the effect of acetazolamide versus mannitol on cisplatin-induced nephrotoxicity,a pilot study

Background Cisplatin-induced nephrotoxicity still occurs despite the intensive hydration approach adapted to prevent its occurrence. Objective Evaluation of the effect of acetazolamide (ACTZ) on minimizing cisplatin-induced nephrotoxicity compared to mannitol when added to hydration regimen. Setting Nasser Institute Cancer Center (NICC), Cairo, Egypt. Method A total of 35 patients planned to receive cisplatin were divided into two groups: 20 patients received mannitol and 15 patients received ACTZ. Both groups received standard hydration measures as well for prevention of cisplatin-induced nephrotoxicity. Main outcome measure Patients’ kidney function was assessed using serum creatinine, creatinine clearance and blood urea nitrogen. Kidney injury was assessed using RIFLE criteria. Patients’ liver function tests and hematological parameters were also monitored. Results Patients in the mannitol group showed higher risk of developing kidney injury (30%) whereas those in the ACTZ group showed lower risk (8.9%), relative risk (RR) 0.269, 95% CI 0.108–0.815. No statistically significant difference occurred between the two groups concerning liver function tests or hematological parameters. Conclusion Use of ACTZ in addition to intensive hydration may have more beneficial effect on minimizing cisplatin-induced nephrotoxicity compared to mannitol plus intensive hydration approach. A large multicenter randomized clinical trials is recommended to confirm study results and to assess effect of ACTZ on tumor response.     

Pharmacovigilance workflow in Europe and Italy and pharmacovigilance terminology

The terminology used in pharmacovigilance can cause confusion, because there are similar terms that describe different phenomena (e.g. adverse reactions, adverse drug reactions, and side effects). Incorrect use of terminology can have negative effects on the reporting of adverse drug reactions and on the interpretation of these reports. To explain the most common terms used in pharmacovigilance, this article first describes the pharmacovigilance workflow process in the European Union and, as an example, in Italy. Then, the article reviews common pharmacovigilance terms.     

An historical overview over Pharmacovigilance

Pharmacovigilance started about 170 years ago, although it was not yet named as such at that time. It is structured activity in the professional health field, with important social and commercial implications aimed at monitoring the risk/benefit ratio of drugs, improving patient’s safety and the quality of life. In this commentary we report the milestones of pharmacovigilance up to the present day, in order to understand all the steps that have characterized the historical evolution; from the first reports, which were essentially letters or warnings sent by clinicians to publishers of important and famous scientific journals, up to today’s modern and ultra-structured electronic registries. The historical phases also help us to understand why pharmacovigilance helped us to achieve such important results for man’s health and for pharmacology itself, and to identify the challenges that await Pharmacovigilance in future years.     

Effectiveness of antibiotic therapy in pediatric patients with cat scratch disease

Background Appropriate antibiotic treatment of cat scratch disease (CSD) in pediatrics is not well established. Objective The purpose of this study was to evaluate the response rates of antibiotic therapy in pediatrics with CSD. Methods The electronic medical records of a cohort of pediatric patients with confirmed diagnosis of CSD (2006–2016) were reviewed, retrospectively. Data collection included patient demographics, clinical and laboratory results, antibiotic treatment and follow-up evaluations. Results One hundred and seventy-five patients (aged 7.4?±?4.4 years) had confirmed CSD. Azithromycin and trimethoprim/sulfamethoxazole (TMP/SMX) were the largest groups with documented effectiveness at follow-up visits. Resolution and improvement of CSD was observed in 51.4% and 61.5% of patients with azithromycin and TMP/SMX, respectively among those with follow-up assessment. The effectiveness of azithromycin and TMP/SMX was comparable (p?=?0.56). Conclusion Azithromycin and TMP/SMX were most frequently prescribed antibiotics. Azithromycin appeared to be an appropriate option for the treatment of CSD. TMP/SMX may be considered as an alternative antibiotic when azithromycin cannot be used.     

Population pharmacokinetics of theophylline in adult Chinese patients with asthma and chronic obstructive pulmonary disease

Background Theophylline has a narrow therapeutic range and large interindividual variability in blood levels, so a thorough understanding of its pharmacokinetic characteristics is essential. Population pharmacokinetic (PPK) approaches could achieve it and many PPK studies of theophylline have been reported in infants. However, none was conducted in Chinese adults and none has explored the effect of CYP1A2 genotypes on the PPK characteristics of theophylline in adults. Objective To evaluate the PPK characteristics of theophylline and to assess the possible influence of covariates, including CYP1A2 genotypes, on theophylline clearance in Chinese adult patients. Setting The study is conducted at the department of respiration in Zhujiang Hospital, Guangzhou, China. Methods Theophylline concentrations were obtained from eligible patients and were measured by high performance liquid chromatography. The polymorphisms of ??3860G?>?A, ??163C?>?A, C5347T (CYP1A2*1B) and G-3113A were genotyped using a direct sequencing method. Then, CYP1A2 genotypes, age, fat-free mass (FFM) and other covariates were used to develop a PPK model by NONMEM software. Bootstrap analysis was used to asses the accuracy and prediction of the PPK model. Main outcome measure The concentration and clearance of theophylline. Results A total of 134 theophylline concentrations from 95 patients were obtained. The final model was as follows: CL/F(L/h)?=?4.530?×?(FFM/56.1)^0.75 ×?0.713^CYP1A2*1B, the inter-individual variability in clearance/bioavailability (CL/F) was 44.0%, and the residual variability was 9.8%. The final model was proved to be reliable by bootstrap analysis. Conclusion Theophylline clearance was significantly associated with FFM and CYP1A2*1B genotypes in Chinese adult patients.