A Physiologically Based Pharmacokinetic Model to Predict Systemic Ondansetron Concentration in Liver Cirrhosis Patients.

INTRODUCTION: Ondansetron is a drug that is routinely prescribed for the management of nausea and vomiting associated with cancer, radiation therapy, and surgical operations. It is mainly metabolized in the liver, and it might accumulate in patients with hepatic impairment and lead to unwanted adverse events. METHODS: A physiologically based pharmacokinetic (PBPK) model was developed to predict the exposure of ondansetron in healthy and liver cirrhosis populations. The population-based PBPK simulator PK-Sim was utilized for simulating ondansetron exposure in healthy and liver cirrhosis populations. RESULTS: The developed model successfully described the pharmacokinetics of ondansetron in healthy and liver cirrhosis populations. The predicted area under the curve, maximum systemic concentration, and clearance were within the allowed twofold range. The exposure of ondansetron in the population of Child-Pugh class C has doubled in comparison to Child-Pugh class A. The dose has to be adjusted for liver cirrhosis patients to ensure comparable exposure to a healthy population. CONCLUSION: In this study, the developed PBPK model has described the pharmacokinetics of ondansetron successfully. The PBPK model has been successfully evaluated to be used as a tool for dose adjustments in liver cirrhosis patients.

Physiologically-based pharmacokinetic modeling for single and multiple dosing regimens of ceftriaxone in healthy and chronic kidney disease populations: a tool for model-informed precision dosing.

Introduction: Ceftriaxone is one of commonly prescribed beta-lactam antibiotics with several label and off-label clinical indications. A high fraction of administered dose of ceftriaxone is excreted renally in an unchanged form, and it may accumulate significantly in patients with impaired renal functions, which may lead to toxicity. Methods: In this study, we employed a physiologically-based pharmacokinetic (PBPK) modeling, as a tool for precision dosing, to predict the biological exposure of ceftriaxone in a virtually-constructed healthy and chronic kidney disease patient populations, with subsequent dosing optimizations. We started developing the model by integrating the physicochemical properties of the drug with biological system information in a PBPK software platform. A PBPK model in an adult healthy population was developed and evaluated visually and numerically with respect to experimental pharmacokinetic data. The model performance was evaluated based on the fold error criteria of the predicted and reported values for different pharmacokinetic parameters. Then, the model was applied to predict drug exposure in CKD patient populations with various degrees of severity. Results: The developed PBPK model was able to precisely describe the pharmacokinetic behavior of ceftriaxone in adult healthy population and in mild, moderate, and severe CKD patient populations. Decreasing the dose by approximately 25% in mild and 50% in moderate to severe renal disease provided a comparable exposure to the healthy population. Based on the simulation of multiple dosing regimens in severe CKD population, it has been found that accumulation of 2 g every 24 h is lower than the accumulation of 1 g every 12 h dosing regimen. Discussion: In this study, the observed concentration time profiles and pharmacokinetic parameters for ceftriaxone were successfully reproduced by the developed PBPK model and it has been shown that PBPK modeling can be used as a tool for precision dosing to suggest treatment regimens in population with renal impairment.

Development and Evaluation of a Physiologically Based Pharmacokinetic Model for Predicting Haloperidol Exposure in Healthy and Disease Populations.

The physiologically based pharmacokinetic (PBPK) approach can be used to develop mathematical models for predicting the absorption, distribution, metabolism, and elimination (ADME) of administered drugs in virtual human populations. Haloperidol is a typical antipsychotic drug with a narrow therapeutic index and is commonly used in the management of several medical conditions, including psychotic disorders. Due to the large interindividual variability among patients taking haloperidol, it is very likely for them to experience either toxic or subtherapeutic effects. We intend to develop a haloperidol PBPK model for identifying the potential sources of pharmacokinetic (PK) variability after intravenous and oral administration by using the population-based simulator, PK-Sim. The model was initially developed and evaluated to predict the PK of haloperidol and its reduced metabolite in adult healthy population after intravenous and oral administration. After evaluating the developed PBPK model in healthy adults, it was used to predict haloperidol-rifampicin drug-drug interaction and was extended to tuberculosis patients. The model evaluation was performed using visual assessments, prediction error, and mean fold error of the ratio of the observed-to-predicted values of the PK parameters. The predicted PK values were in good agreement with the corresponding reported values. The effects of the pathophysiological changes and enzyme induction associated with tuberculosis and its treatment, respectively, on haloperidol PK, have been predicted precisely. For all clinical scenarios that were evaluated, the predicted values were within the acceptable two-fold error range.

pH-Responsive Nanocomposite Based Hydrogels for the Controlled Delivery of Ticagrelor; In Vitro and In Vivo Approaches.

BACKGROUND: Ticagrelor (TG), an antiplatelet drug is employed to treat patients with acute coronary syndrome, but its inadequate oral bioavailability due to poor solubility and low permeability restricts its effectiveness. PURPOSE: This contemporary work was aimed to design a novel pH-sensitive nanocomposite hydrogel (NCH) formulation incorporating thiolated chitosan (TCH) based nanoparticles (NPs) of Ticagrelor (TG), to enhance its oral bioavailability for effectively inhibiting platelet aggregation. METHODS: NCHs were prepared by free radical polymerization technique, using variable concentrations of chitosan (CH) as biodegradable polymer, acrylic acid (AA) as a monomer, N,N-methylene bisacrylamide (MBAA) as cross-linker, and potassium persulphate (KPS) as initiator. RESULTS: The optimum hydrogel formulation was selected for fabricating NCHs, considering porosity, sol-gel fraction, swelling studies, drug loading capacity, and TG's in vitro release as determining factors. Outcomes of the studies have shown that the extent of hydrogel swelling and drug release was comparatively greater at higher pH (7.4). Moreover, an amplifying trend was observed for drug loading and hydrogel swelling by increasing AA content, while it declined by increasing MBAA. The NCHs were evaluated by various physicochemical techniques and the selected formulation was subjected to in vivo bioavailability studies, confirming enhancement of bioavailability as indicated by prolonged half-life and multifold increase in area under the curve (AUC) as compared to pure TG. CONCLUSION: The results suggest that NCHs demonstrated a pH-responsive, controlled behavior along with enhanced bioavailability. Thus NCHs can be effectively utilized as efficient delivery systems for oral delivery of TG to reduce the risk of myocardial infarction.

Synthesis and Evaluation of Thiol-Conjugated Poloxamer and Its Pharmaceutical Applications.

The current study was designed to convert the poloxamer (PLX) into thiolated poloxamer (TPLX), followed by its physicochemical, biocompatibilities studies, and applications as a pharmaceutical excipient in the development of tacrolimus (TCM)-containing compressed tablets. Thiolation was accomplished by using thiourea as a thiol donor and hydrochloric acid (HCl) as a catalyst in the reaction. Both PLX and TPLX were evaluated for surface morphology based on SEM, the crystalline or amorphous nature of the particles, thiol contents, micromeritics, FTIR, and biocompatibility studies in albino rats. Furthermore, the polymers were used in the development of compressed tablets. Later, they were also characterized for thickness, diameter, hardness, weight variation, swelling index, disintegration time, mucoadhesion, and in vitro drug release. The outcomes of the study showed that the thiolation process was accomplished successfully, which was confirmed by FTIR, where a characteristic peak was noticed at 2695.9968 cm-1 in the FTIR scan of TPLX. Furthermore, the considerable concentration of the thiol constituents (20.625 µg/g of the polymer), which was present on the polymeric backbone, also strengthened the claim of successful thiolation. A mucoadhesion test illustrated the comparatively better mucoadhesion strength of TPLX compared to PLX. The in vitro drug release study exhibited that the TPLX-based formulation showed a more rapid (p < 0.05) release of the drug in 1 h compared to the PLX-based formulation. The in vivo toxicity studies confirmed that both PLX and TPLX were safe when they were administered to the albino rats. Conclusively, the thiolation of PLX made not only the polymer more mucoadhesive but also capable of improving the dissolution profile of TCM.

Development and evaluation of physiologically based pharmacokinetic drug-disease models for predicting captopril pharmacokinetics in chronic diseases.

The advancement in the processing speeds of computing machines has facilitated the development of complex physiologically based pharmacokinetic (PBPK) models. These PBPK models can incorporate disease-specific data and could be used to predict pharmacokinetics (PK) of administered drugs in different chronic conditions. The present study aimed to develop and evaluate PBPK drug-disease models for captopril after incorporating relevant pathophysiological changes occurring in adult chronic kidney disease (CKD) and chronic heart failure (CHF) populations. The population-based PBPK simulator Simcyp was used as a modeling and simulation platform. The visual predictive checks and mean observed/predicted ratios (ratio(Obs/pred)) of the PK parameters were used for model evaluation. The developed disease models were successful in predicting captopril PK in all three stages of CKD (mild, moderate, and severe) and CHF, as the observed and predicted PK profiles and the ratio(obs/pred) for the PK parameters were in close agreement. The developed captopril PBPK models can assist in tailoring captopril dosages in patients with different disease severity (CKD and CHF).

Assessing Barriers Faced by Surgeons While Providing Surgical Care During the COVID-19 Pandemic in Pakistan: An Online Cross-Sectional Study.

BACKGROUND: The COVID-19 pandemic is not only affecting public health, but it is also impairing the specialized surgical care services in the hospitals. The present study aimed to assess the barriers faced by the surgeons while performing surgical procedures during the COVID-19 pandemic. METHODS: A cross-sectional, web-based survey was conducted from September 10 to October 14, 2020. The study population consisted of surgeons practicing in Kpk, Pakistan. Descriptive statistics and binary logistic regression analysis were used to analyze the data. RESULTS: A total of 292, out of 543, surgeons participated in the study (response rate: 59.6%). The younger surgeons (25-30 years) considered the lack of policies and practices regarding exposure to COVID-19 patients as a significant barrier to their practice. The surgeons practicing in private hospitals considered themselves at a higher risk while providing surgical care to the COVID-19 patients. The non-cooperation of the patients was the main barrier in delivering surgical care services. CONCLUSION AND RECOMMENDATION: The current study highlighted the barriers to the surgeons while providing surgical care to patients in the current pandemic. The most pronounced barriers to the surgeons were the lack of policies regarding exposure to COVID-19 and practice and non-cooperation of the patient. To address these barriers, it is recommended that health regulatory agencies of Pakistan should implement strict infection control practices to ensure the safety of surgeons and allied healthcare staff during the COVID-19 pandemic.

Knowledge, Attitude, and Practices Toward COVID-19 in Primary Healthcare Providers: A Cross-Sectional Study from Three Tertiary Care Hospitals of Peshawar, Pakistan.

An online cross-sectional study was carried out to evaluate the knowledge, attitude, and practice about coronavirus disease 2019 (COVID-19) among primary health care providers (PHPs) at three tertiary care hospital, Peshawar, Pakistan. Data was collected via email and online social media platforms. Statistical package for social science (SPSS) version 25.0 was used for data analysis. Among the total participants (n = 114), 74 (66.7%) were male and 37 (33.3%) were female. The mean scores for knowledge, attitude and practice were 12.7 ± 0.89, 8.9 ± 4.1 and 7.3 ± 1.2, respectively. Most of the participants knew the term COVID-19 and its mode of transmission (90%), signs and symptoms (84%) and risk factors (72%) associated with it. Most of the participants agreed that COVID-19 can be transmitted through coughing and sneezing (74.3%) and 84.6% were in favor that COVID-19 can be prevented by adopting preventive measures. Around 68.8% of the participants disagreed with the use of antibiotics in the prevention of COVID-19. Ninety percent of the respondents were avoiding close contact with the people having cough and flu-like symptoms. Most PHPs had good knowledge, positive attitude and reasonable practices regarding COVID-19. Moreover, focused training programs for PHPs at the Government level can further improve their understanding of risks and preventive strategies related to COVID-19, which will help them to provide appropriate care to their patients as well as to protect themselves from this infection.

Knowledge, attitude, preventive practices and perceived barriers to screening about colorectal cancer among university students of newly merged district, Kpk, Pakistan - A cross-sectional study.

INTRODUCTION: Colorectal cancer is the third most common type of cancer in the world and in Pakistan it ranks at fifth position. The present study was conducted to evaluate the knowledge, attitude, preventive practices and perceived barriers to screening about colorectal cancer among university students. METHOD: A cross-sectional study was conducted after developing a self-administered questionnaire among the university students of newly merged districts of Kpk, Pakistan. RESULT: A total of 302 students (232 male and 70 female) participated in the study. The knowledge score of the participants regarding the risk factors and warning signs of colorectal cancer was 59.9% and 40%. More than 90% of the participants were of the view that colorectal cancer diagnosis at initial stages can improve treatment and around 80% were in favor of undergoing regular physical examination to avoid colorectal cancer. Only 37.7% of the participants had intentionally collected information about colorectal cancer. The percentage of participants who intentionally participated in educational activities related to colorectal cancer was 33.1%. Furthermore, only 24.4% of the participant had ever taken part in colorectal cancer screening. The barriers toward colorectal cancer screening were fear of finding colorectal cancer and the anxiety of screening procedures. However, around 32% of the participants had no knowledge about colorectal cancer screening. CONCLUSION: In view of the findings of this study, it can be suggested that community awareness programs that are focused towards screening of colorectal cancer may be initiated in the newly merged districts of Kpk, Pakistan. The implementation of such colorectal cancer screening program can help in its early detection and can potentially lower the associated mortality and morbidity risk with this disease.

Development and Evaluation of Physiologically Based Pharmacokinetic Drug-Disease Models for Predicting Rifampicin Exposure in Tuberculosis and Cirrhosis Populations.

The physiologically based pharmacokinetic (PBPK) approach facilitates the construction of novel drug-disease models by allowing incorporation of relevant pathophysiological changes. The aim of the present work was to explore and identify the differences in rifampicin pharmacokinetics (PK) after the application of its single dose in healthy and diseased populations by using PBPK drug-disease models. The Simcyp® simulator was used as a platform for modeling and simulation. The model development process was initiated by predicting rifampicin PK in healthy population after intravenous (i.v) and oral administration. Subsequent to successful evaluation in healthy population, the pathophysiological changes in tuberculosis and cirrhosis population were incorporated into the developed model for predicting rifampicin PK in these populations. The model evaluation was performed by using visual predictive checks and the comparison of mean observed/predicted ratios (ratio(Obs/pred)) of the PK parameters. The predicted PK parameters in the healthy population were in adequate harmony with the reported clinical data. The incorporation of pathophysiological changes in albumin concentration in the tuberculosis population revealed improved prediction of clearance. The developed PBPK drug-disease models have efficiently described rifampicin PK in tuberculosis and cirrhosis populations after administering single drug dose, as the ratio(Obs/pred) for all the PK parameters were within a two-fold error range. The mechanistic nature of the developed PBPK models may facilitate their extension to other diseases and drugs.