Interactions between Food and Drugs, and Nutritional Status in Renal Patients: A Narrative Review

Drugs and food interact mutually: drugs may affect the nutritional status of the body, acting on senses, appetite, resting energy expenditure, and food intake; conversely, food or one of its components may affect bioavailability and half-life, circulating plasma concentrations of drugs resulting in an increased risk of toxicity and its adverse effects, or therapeutic failure. Therefore, the knowledge of these possible interactions is fundamental for the implementation of a nutritional treatment in the presence of a pharmacological therapy. This is the case of chronic kidney disease (CKD), for which the medication burden could be a problem, and nutritional therapy plays an important role in the patient’s treatment. The aim of this paper was to review the interactions that take place between drugs and foods that can potentially be used in renal patients, and the changes in nutritional status induced by drugs. A proper definition of the amount of food/nutrient intake, an adequate definition of the timing of meal consumption, and a proper adjustment of the drug dosing schedule may avoid these interactions, safeguarding the quality of life of the patients and guaranteeing the effectiveness of drug therapy. Hence, a close collaboration between the nephrologist, the renal dietitian, and the patient is crucial. Dietitians should consider that food may interact with drugs and that drugs may affect nutritional status, in order to provide the patient with proper dietary suggestions, and to allow the maximum effectiveness and safety of drug therapy, while preserving/correcting the nutritional status.

EFFECT OF OBESITY AND ROUX-EN-Y GASTRIC SURGERY ON OMEPRAZOLE PHARMACOKINETICS

Background: The prevalence of obesity is increasing globally. Objectives: To evaluate whether gastric bypass surgery modifies the bioavailability and pharmacokinetic (PK) parameters of Omeprazole. Setting: Hospital Clínico San Carlos, Madrid, Spain. Methods: Controlled, open-label, bioavailability clinical trial in patients undergoing Roux-en-Y gastric bypass (RYGB). Healthy patients with obesity (BMI>35) were included and assessed for Omeprazole PK before RYGB and after (1 and 6 months). PK sampling was done at baseline and several times up to 12 h after drug dosing. Pre- and post-surgery parameters were compared using paired ANOVA or Wilcoxon tests, and Control vs. Cases using ANOVA or Mann Whitney tests. Given the post-surgery change in body weight, parameters were corrected by dose/body-weight. Results: Fourteen Case and 24 Control subjects were recruited, 92% were women (N= 35/38). In patients who underwent RYGB, Cmax was significantly reduced at 1 and 6 months after surgery compared with pre-surgery values (p=0.001). Regarding the AUC, the values are lower at 1 and 6 months after surgery than at baseline (p<0.001).The drug clearance was also increased in the first month after surgery. No differences were found between patients 6 months after surgery and Controls. Cmax and AUC corrected by dose/body-weight were significantly different between the baseline surgery subjects and Controls. Conclusions: Omeprazole bioavailability is reduced in patients with obesity at 1 and 6 months after RYGB. However, Omeprazole PK parameters 6 months after RYGB are similar to control subjects, and thus no dose correction is required after RYGB for a given indication.

FACTORS ASSOCIATED WITH NON-ADHERENCE TO HEPATITIS B VIRUS ANTIVIRAL THERAPY

Objective: To assess the adherence to antivirals in Hepatitis B Virus (HBV) infected patients and to determine various social and demographic factors which can have an impact on it. Study Design: Cross- sectional study. Place and Duration of Study: Department of Gastroenterology, Pak Emirates Military Hospital Rawalpindi, from Jan to Mar 2019. Methodology: Patients on oral anti-viral agents for hepatitis B virus infection were enrolled from outdoor clinics using consecutive sampling technique. Medication adherence was assessed using the 4-item Modified Morisky Score Questionnaire. Data was also collected about different variables that could potentially affect compliance, such as age, gender, education, residence, total number of pills prescribed for each day, travelling time to hospital, attendant’s company, adverse effects of treatment, presence of co-morbid conditions, patients’ knowledge regarding importance of adherence and whether they followed any particular routine in taking medicines. Results: There were 127 patients having mean age of 47.80 ± 14.54 years. Out of these, 20 (15.75%) were not adherent to treatment. Patients not following a fixed drug-dosing schedule, patients not aware of the significance of good drug compliance and residents of urban areas were more likely to have lesser compliance to treatment. Conclusion: Majority of our patients were compliant to treatment for chronic hepatitis B infection. This was more likely to be the case amongst those following a fixed drug-dosing schedule, having an awareness of significance of adherence to medication and residents of rural areas.

Numerical approaches for the rapid analysis of prophylactic efficacy against HIV with arbitrary drug-dosing schemes

Pre-exposure prophylaxis (PrEP) is an important pillar to prevent HIV transmission. Because of experimental and clinical shortcomings, mathematical models that integrate pharmacological, viral- and host factors are frequently used to quantify clinical efficacy of PrEP. Stochastic simulations of these models provides sample statistics from which the clinical efficacy is approximated. However, many stochastic simulations are needed to reduce the associated sampling error. To remedy the shortcomings of stochastic simulation, we developed a numerical method that allows predicting the efficacy of arbitrary prophylactic regimen directly from a viral dynamics model, without sampling. We apply the method to various hypothetical dolutegravir (DTG) prophylaxis scenarios. The approach is verified against state-of-the-art stochastic simulation. While the method is more accurate than stochastic simulation, it is superior in terms of computational performance. For example, a continuous 6-month prophylactic profile is computed within a few seconds on a laptop computer. The method’s computational performance, therefore, substantially expands the horizon of feasible analysis in the context of PrEP, and possibly other applications.

Multidisciplinary analysis of evolution based Abiraterone treatment for metastatic castrate resistant prostate cancer

Background We present a multidisciplinary approach to clinical trial design and analysis in a pilot study (NCT02415621) in which evolution-based mathematical models guide patient-specific dosing for Abiraterone treatment in men with castrate resistant metastatic prostate cancer. Methods Abiraterone plus prednisone were administered intermittently based on an evolutionary mathematical model. Outcomes are compared to historical controls and a matched contemporaneous cohort who met trial eligibility but received SOC dosing. Longitudinal cohort data allowed modification of pre-trial model parameter estimates. Model simulations of each patient using updated parameters critically evaluated trial design. Results Trial patients, on average, received no abiraterone during 59% of time on treatment. Median Time to Radiographic Progression (TTP) was 30.4 months compared to 14.3 months in the contemporaneous SOC group (p<0.001). All patients in the SOC group have progressed but 4 in the adaptive cohort remain on treatment at >1800 days. Longitudinal trial data found the competition coefficient ratio (αRS/αSR) of sensitive and resistant populations, a critical factor in intratumoral evolution, was 2 to 3-fold higher than pre-trial estimates. Computer simulations using the corrected parameter unexpectedly demonstrated optimal cycling can reduce the resistant cells. Longitudinal data from 4 trial patients who remain on treatment are consistent with model predictions. Modeling results predict protocol changes that will allow similar outcomes in most patients. Conclusions Administration of abiraterone using evolution-based mathematical models decreased drug dosing and increased radiographic TTP. Integration of mathematical models into trial design identifies novel insights into key treatment parameters and provides optimization strategies for follow-up investigations.

Antidepressants and Circadian Rhythm: Exploring Their Bidirectional Interaction for the Treatment of Depression

Scientific evidence that circadian rhythms affect pharmacokinetics and pharmacodynamics has highlighted the importance of drug dosing-time. Circadian oscillations alter drug absorption, distribution, metabolism, and excretion (ADME) as well as intracellular signaling systems, target molecules (e.g., receptors, transporters, and enzymes), and gene transcription. Although several antidepressant drugs are clinically available, less than 50% of depressed patients respond to first-line pharmacological treatments. Chronotherapeutic approaches to enhance the effectiveness of antidepressants are not completely known. Even so, experimental results found until this day suggest a positive influence of drug dosing-time on the efficacy of depression therapy. On the other hand, antidepressants have also demonstrated to modulate circadian rhythmicity and sleep–wake cycles. This review aims to evidence the potential of chronotherapy to improve the efficacy and/or safety of antidepressants. It includes pre-clinical and clinical studies that demonstrate the relevance of determining the most appropriate time of administration for antidepressant drugs. In parallel, their positive influence on the resynchronization of disrupted circadian rhythms is also herein discussed. It is expected that this review will promote the investigation of chronotherapy for the treatment of depression, contribute to a better understanding of the relationship between antidepressants and circadian rhythms, and consequently promote the development of new therapeutics.

Identifiability of pharmacological models for online individualization

There is a large variability between individuals in the response to anesthetic drugs, that seriously limits the achievable performance of closed-loop controlled drug dosing. Full individualization of patient models based on early clinical response data has been suggested as a means to improve performance with maintained robustness (safety). We use estimation theoretic analysis and realization theory to characterize practical identifiability of the standard pharmacological model structure from anesthetic induction phase data and conclude that such approaches are not practically feasible.

Development of the Swiss Database for dosing medicinal products in pediatrics

In daily paediatrics, drugs are commonly used off-label, as they are not approved for children. Approval is lacking because the required clinical studies were limited to adults in the past. Without clinical studies, evidence-based recommendations for drug use in children are limited. Information on off-label drug dosing in children can be found in different handbooks, databases and scientific publications but the dosing recommendations can differ considerably. To improve safety and efficacy of drugs prescribed to children and to assist the prescribers, stakeholders in Swiss paediatrics started a pilot project, supported by the Federal Office of Public Health, with the aim to create a database, providing healthcare professionals with so called “harmonised” dosage recommendations based on the latest available scientific evidence and best clinical practice. A standardised process for dosage harmonisation between paediatric experts was defined, guided and documented in an electronic tool, developed for this purpose. As proof of principle, a total of 102 dosage recommendations for 30 different drugs have been nationally harmonised in the pilot phase considering the current scientific literature and the approval of the most experienced national experts in the field.Conclusion: This approach paved the way for unified national dosage recommendations for children. Reaching the project’s milestones fulfilled the prerequisites for funding and starting regular operation of SwissPedDose in 2018. Since then, the database was extended with recommendations for 100 additional drugs. What is Known:• Prescribing off-label is a common practice among paediatricians, as many drugs are still not authorised for use in children.• Some countries developed national drug formularies providing off-label dosage recommendations. What is New:• Comparison of published dosage recommendations in known drug handbooks and online databases show substantial differences and heterogeneity, revealing the need for harmonisation.• The design of a tool for standardised harmonisation of dosage recommendations, based on information collected on currently applied dosages, latest scientific evidence and the approval of experts.