Changes in Rosuvastatin Pharmacokinetics During Postnatal Ontogenesis in Rats

Purpose: Statin therapy should be considered in children with familial hypercholesterolemia and sustained high LDL-C levels. There are no data on rosuvastatin exposure in patients <6 years and efficacy/safety can only be derived from case reports. Our aim was to examine developmental changes in pharmacokinetics of rosuvastatin in rats in vivo as a basis for clinical development of formulations for patients < 6 years. Methods: Rosuvastatin pharmacokinetics was examined in rats aged 1, 4, 7, 10, 14, 21, 28, 35 and 42 days (from birth to sexual maturity). After intraperitoneal dose of 5 mg/kg, blood samples to determine serum rosuvastatin levels were taken at 0.5, 3 and 5 hours. Pharmacokinetic parameters (Vd, CL, AUClast, AUC0-∞) were calculated using pharmacokinecic simulations. Results: Both rosuvastatin CL and Vd started to increase systematically between 2 - 3 weeks of age, which was reflected by decreased total drug exposure. The AUC was up to 13 times higher in the age groups ≤14 days compared with the value at 42 days. Conclusions: Based on interspecies scaling, a dose reduction could be a feasible way, how to develop appropriate dosing schedule and formulations for children aged 2 - 6 years. However, confirmation in clinical development studies will be needed.

Pharmacotherapy of Different Tuberculosis Patients its Analysis and Outcomes: A Retrospective Cohort Study

This study aim was to evaluate the prescribed therapies and to identify various drug-related problems as well as their causes in different TB patients admitted at the Pulmonology Department, Northwest General Hospital and Research Centre, Hayatabad, Peshawar, Pakistan. A 5-month retrospective study was conducted in which a total of 525 patients’ medical records were collected using predesigned standard data collection proforma. Among them, 25 patients having incomplete medical records were excluded and the rest of 500 cases were involved and analyzed accordingly. In all these cases, the causative agent was Mycobacterium tuberculosis. Overall 14 drugs of 133 different therapeutic classes were used in which the most frequently prescribed drugs to these patients were Anti-Tuberculosis drugs (100%), Antibiotic (100%), Multivitamins (78%), GIT drugs (55%) and Antihistamines (55%) followed by other drugs listed in the present study. Out of 500 cases, a total of 179 (35.8%) patients were identified had Drug-related problems, among them 23 (4.6%) cases were in untreated condition, in 12 (2.4%) cases drugs without indication problems were found, in 43 (8.6%) cases there were adverse drug reactions problems noted, in 75 (15%) cases total drug interactions problems were identified, while in 26 (5.2%) cases polypharmacy problems were found. The prescribed pharmacotherapy in all 500 cases meets with the standard pharmacotherapy. However, the discrepancies observed in the present study were due to lack of proper knowledge about the pharmacology of the drugs, overburden on doctors and proper lack of patient counseling. To better understand the proper management and reduction of these problems other health care professionals and proper clinical pharmacists are required to cooperate for the sake of improving the outcomes of the pharmacotherapy.

DDRE-23. PRECLINICAL EVALUATION OF BRAIN PENETRATION PROPERTIES OF NEW FIRST-IN-CLASS LYSINE-SPECIFIC DEMETHYLASE 1 (LSD1) INHIBITOR, SP-2577

BACKGROUND Lysine specific demethylase 1 (LSD1) is a histone demethylase implicated in the maintenance of pluripotency and proliferation gene programs that give rise to a number of cancers. SP-2577 is a first-in-class selective and reversible inhibitor of LSD1. Here, we evaluated the ability of SP-2577 to cross blood-brain barrier in mouse brain. METHODS Fifteen BALB/c mice were treated with 50 mg/kg SP-2577 twice daily intraperitoneally for 4 days. At 2, 6, and 12 hours after the last treatment dose was delivered, plasma and brain samples were collected for analysis of SP-2577 bound and unbound fractions (5 mice/time point). An LC–MS/MS method was developed to measure the drug levels in mouse plasma and brain. The unbound fractions of SP-2577 in plasma and brain tissue were determined using equilibrium dialysis. RESULTS Total plasma levels of SP-2577 at the 2, 6, and 12-hour time points following the last dose were 1353 nM, 1209 nM, and 560 nM, accordingly. Total drug levels in brain measured at the same time points were 276 nM, 183 nM, and 168 nM. SP-2577 is highly bound to plasma proteins and brain tissue components with an average plasma unbound fraction value of 0.009. Unbound levels of SP-2577 were undetectable in brain tissue, potentially due to instability of the drug in brain homogenates. The total brain-to-plasma ratio (Kp) was determined as 0.032 (range, 0.027–0.046) in mice. CONCLUSION SP-2577 is well tolerated in mice and achieves reasonable total drug levels in mouse brain, yet is highly-bound to plasma proteins and brain components. Taken together, these data indicate that SP-2577 cannot reach pharmacologically-relevant drug concentrations across the mouse blood-brain barrier.

A hidden web of policy influence: The pharmaceutical industry’s engagement with UK’s All-Party Parliamentary Groups

Our objective was to examine conflicts of interest between the UK’s health-focused All-Party Parliamentary Groups (APPGs) and the pharmaceutical industry between 2012 and 2018. APPGs are informal cross-party groups revolving around a particular topic run by and for Members of the UK’s Houses of Commons and Lords. They facilitate engagement between parliamentarians and external organisations, disseminate knowledge, and generate debate through meetings, publications, and events. We identified APPGs focusing on physical or mental health, wellbeing, health care, or treatment and extracted details of their payments from external donors disclosed on the Register for All-Party Parliamentary Groups. We identified all donors which were pharmaceutical companies and pharmaceutical industry-funded patient organisations. We established that sixteen of 146 (11%) health-related APPGs had conflicts of interest indicated by reporting payments from thirty-five pharmaceutical companies worth £1,211,345.81 (16.6% of the £7,283,414.90 received by all health-related APPGs). Two APPGs (Health and Cancer) received more than half of the total value provided by drug companies. Fifty APPGs also had received payments from patient organisations with conflicts of interest, indicated by reporting 304 payments worth £986,054.94 from 57 (of 84) patient organisations which had received £27,883,556.3 from pharmaceutical companies across the same period. In total, drug companies and drug industry-funded patient organisations provided a combined total of £2,197,400.75 (30.2% of all funding received by health-related APPGs) and 468 (of 1,177–39.7%) payments to 58 (of 146–39.7%) health-related APPGs, with the APPG for Cancer receiving the most funding. In conclusion, we found evidence of conflicts of interests through APPGs receiving substantial income from pharmaceutical companies. Policy influence exerted by the pharmaceutical industry needs to be examined holistically, with an emphasis on relationships between actors potentially playing part in its lobbying campaigns. We also suggest ways of improving transparency of payment reporting by APPGs and pharmaceutical companies.

Penetration Driving Force of Metformin Hydrochloride via Paracellular Pathway in Relation to its Pharmacodynamic Effect

Background: Penetration enhancement of metformin hydrochloride via its molecular dispersion in sorbitan monostearate microparticles is reported. Metformin dispersion in sorbitan monostearate as a carrier was thought to be the basic philosophy to maximize its entrapment in the matrix for maximum penetration effect.Methods: Drug dispersion in sorbitan monostearate with different theoretical drug contents (TDC) were prepared. Results: All products showed excellent micromeritics and actual drug content (ADC) increased by increasing TDC. These two features are essential for industry concerning processing and cost. The partition coefficient of the drug products showed huge improvement. This indicates the drug entrapment should be in the polar part of sorbitan monostearate as a special image. The drug entrapment process was also reflected in the drug release process due to the insolubility of the matrix in the dissolution medium. The drug permeation profiles from the different drug-sorbitan monostearate products are overlapped and its permeation parameters (permeation coefficient, total drug permeation percent & drug absorption enhancement percent) are nearly equal. The results of the permeation study by using modified non-everted sac suggested the main driving force for 11 improving the drug paracellular pathway is its dispersion in sorbitan monostearate (special image) and is independent of ADC. Pharmacodynamic of the drug products showed a significant improvement than that from the drug alone at p ˂ 0.05. ANOVA test indicated the insignificant pharmacodynamic difference between the low, middle, and high ADC of the products. There is an excellent point-to-point correlation between the drug permeation percent and the drug pharmacodynamic percent. The total amount of the drug permeation percent is equal to the mean of the total drug pharmacodynamic percent. Conclusion: The results concluded that the drug permeation driving force via the paracellular pathway is its entrapment in sorbitan monostearate as a special image and it does not depend on ADC. This entrapment mechanism improved the drug pharmacodynamic effect. The technique is simple and the products are easy to process due to having an excellent micromeritics property.

FORMULATION AND EVALUATION OF MODIFIED DISINTEGRATING SUSTAINED RELEASE TABLETS OF DICLOFENAC SODIUM

Oral drug delivery is the largest and the oldest segment of the total drug delivery market. It is the fastest growing and most preferred route for drug administration. In oral drug delivery, the sustained release (SR) tablets maintains the desired drug concentration for prolong period of time, reduced 'see- saw' fluctuation, reduced total dose, improved efficiency in treatment. But many patients like paediatric, geriatric and also patients may have difficulty in swallowing (Dysphagia) find it difficult to swallow tablets and thus do not comply with prescription. This problem is overcome by formulating and developing modified disintegrating sustained release tablets. In this case, first microspheres of the drug are formulated by using any suitable technique. And then optimized microspheres formulation is further formulated in to the fast disintegrating tablets (FDT) by using superdisintegrants. So that after taking such a tablets, the tablet only disintegrates into the mouth then microspheres are separated and ingestion of such microspheres starts releasing drug for prolonged period of time. This concept fulfills both the advantages of sustained release and fast disintegrating tablets.

Evaluating the availability of essential drugs for hypertension, diabetes and asthma in rural Rwanda, 2018

SETTING: Hypertension, diabetes mellitus and asthma are on the rise in developing countries, including Rwanda; there is thus a need to ensure uninterrupted drug availability.OBJECTIVES: To assess 1) the frequency and duration of drug stock-outs; 2) lead time duration 3) monthly stock levels; and 4) drug quantities requested vs. quantity delivered for captopril, metformin and inhaled salbutamol between January and December 2018 Kirehe District, Rwanda.DESIGN: This was a cross-sectional study using secondary programme data.RESULTS: The median annual stock-outs for captopril, metformin and inhaled salbutamol were respectively 4 (IQR 3–4), 3 (IQR 2–3) and 4 (IQR 4–5) at rural health facilities (RHCs); no stock-outs occurred at the district hospital. For all three drugs, the median lead time was 7.5 days (IQR 5.5–11.5) at the hospital vs. 5 days (IQR 3–6) in RHCs. Stock status for captopril was below the 4-week minimum stock level for 2/12 months at the hospital vs. 7/12 months at the RHCs, while metformin and inhaled salbutamol were below the 4-week minimum stock levels for respectively 1/12 and 4/12 months at both hospital and RHCs. Total drug quantities delivered were less than the combined total quantities requested in respectively 8/12, 5/12 and 8/12 months for captopril, metformin and inhaled salbutamol.CONCLUSION: There is a need to regularly and effectively monitor drug stock levels and ensure timely and sufficient stock replenishment to avert stock-outs.

A Machine Learning Algorithm to Predict Hyperglycemic Cases Induced by PD-1/PD-L1 Inhibitors in the Real World (Preprint)

BACKGROUND Diabetes mellitus and cancer are amongst the leading causes of deaths worldwide; hyperglycemia plays a major contributory role in neoplastic transformation risk. Support Vector Machine (SVM) is a type of supervised learning method which analyzes data and recognizes patterns, mainly used for statistical classification and regression. OBJECTIVE From reported adverse events of PD-1 or PD-L1 (programmed death 1 or ligand 1) inhibitors in post-marketing monitoring, we aimed to construct an effective machine learning algorithm to predict the probability of hyperglycemic adverse reaction from PD-1/PD-L1 inhibitors treated patients efficiently and rapidly. METHODS Raw data was downloaded from US Food and Drug Administration Adverse Event Reporting System (FDA FAERS). Signal of relationship between drug and adverse reaction based on disproportionality analysis and Bayesian analysis. A multivariate pattern classification of SVM was used to construct classifier to separate adverse hyperglycemic reaction patients. A 10-fold-3-time cross validation for model setup within training data (80% data) output best parameter values in SVM within R software. The model was validated in each testing data (20% data) and two total drug data, with exactly predictor parameter variables: gamma and nu. RESULTS Total 95918 case files were downloaded from 7 relevant drugs (cemiplimab, avelumab, durvalumab, atezolizumab, pembrolizumab, ipilimumab, nivolumab). The number-type/number-optimization method was selected to optimize model. Both gamma and nu values correlated with case number showed high adjusted r2 in curve regressions (both r2 >0.95). Indexes of accuracy, F1 score, kappa and sensitivity were greatly improved from the prediction model in training data and two total drug data. CONCLUSIONS The SVM prediction model established here can non-invasively and precisely predict occurrence of hyperglycemic adverse drug reaction (ADR) in PD-1/PD-L1 inhibitors treated patients. Such information is vital to overcome ADR and to improve outcomes by distinguish high hyperglycemia-risk patients, and this machine learning algorithm can eventually add value onto clinical decision making. CLINICALTRIAL N/A

How Risky Is That Risk Sharing Agreement? Mean-Variance Tradeoffs and Unintended Consequences of Six Common Risk Sharing Agreements

Background. Pharmaceutical risk sharing agreements (RSAs) are commonly used to manage uncertainties in costs and/or clinical benefits when new drugs are added to a formulary. However, existing mathematical models of RSAs ignore the impact of RSAs on clinical and financial risk. Methods. We develop a model in which the number of patients, total drug consumption per patient, and incremental health benefits per patient are uncertain at the time of the introduction of a new drug. We use the model to evaluate the impact of six common RSAs on total drug costs and total net monetary benefit (NMB). Results. We show that, relative to not having an RSA in place, each RSA reduces expected total drug costs and increases expected total NMB. Each RSA also improves two measures of risk by reducing the probability that total drug costs exceed any threshold and reducing the probability of obtaining negative NMB. However, the effects on variance in both NMB and total drug costs are mixed. In some cases, relative to not having an RSA in place, implementing an RSA can increase variability in total drug costs or total NMB. We also show that, for some RSAs, when their parameters are adjusted so that they have the same impact on expected total drug cost, they can be rank-ordered in terms of their impact on variance in drug costs. Conclusions. Although all RSAs reduce expected total drug costs and increase expected total NMB, some RSAs may actually have the undesirable effect of increasing risk. Payers and formulary managers should be aware of these mean-variance tradeoffs and the potentially unintended results of RSAs when designing and negotiating RSAs.