Discovery and Characterization of Brigimadlin, a Novel and Highly Potent MDM2-p53 Antagonist Suitable for Intermittent Dose Schedules.

p53 is known as the guardian of the genome and is one of the most important tumor-suppressors. It is inactivated in most tumors, either via tumor protein p53 (TP53) gene mutation or copy number amplification of key negative regulators, e.g., mouse double minute 2 (MDM2). Compounds that bind to the MDM2 protein and disrupt its interaction with p53 restore p53 tumor suppressor activity, thereby promoting cell cycle arrest and apoptosis. Previous clinical experience with MDM2-p53 protein-protein interaction antagonists (MDM2-p53 antagonists) have demonstrated that thrombocytopenia and neutropenia represent on-target dose-limiting toxicities that might restrict their therapeutic utility. Dosing less frequently, while maintaining efficacious exposure, represents an approach to mitigate toxicity and improve the therapeutic window of MDM2-p53 antagonists. However, to achieve this, a molecule possessing excellent potency and ideal pharmacokinetic properties is required. Here, we present the discovery and characterization of brigimadlin (BI 907828), a novel, investigational spiro-oxindole MDM2-p53 antagonist. Brigimadlin exhibited high bioavailability and exposure, as well as dose-linear pharmacokinetics in preclinical models. Brigimadlin treatment restored p53 activity and led to apoptosis induction in preclinical models of TP53 wild-type, MDM2-amplified cancer. Oral administration of brigimadlin in an intermittent dosing schedule induced potent tumor growth inhibition in several TP53 wild-type, MDM2-amplified xenograft models. Exploratory clinical pharmacokinetic studies (NCT03449381) showed high systemic exposure and a long plasma elimination half-life in cancer patients who received oral brigimadlin. These findings support the continued clinical evaluation of brigimadlin in patients with MDM2-amplified cancers, such as dedifferentiated liposarcoma.

Exploring Sirolimus Pharmacokinetic Variability Using Data Available from the Routine Clinical Care of Renal Transplant Patients - Population Pharmacokinetic Approach.

BACKGROUND: Due to wide intra- and inter-individual pharmacokinetic variability and narrow therapeutic index of sirolimus, the therapeutic drug monitoring (TDM) of sirolimus with detailed biochemical and clinical monitoring is necessary for dose individualization in kidney transplant patients. The purpose of the study was to explore and identify factors that contribute to pharmacokinetic variability by developing and validating a population model using routine TDM data and routinely monitored biochemical and clinical parameters. METHODS: The data obtained by routine monitoring of 38 patients over a period of one year from the sirolimus treatment initiation, were collected from patients' records. Population analysis was performed using the software NONMEM®. The validity of the model was tested by the internal and external validation techniques. RESULTS: The pharmacokinetic variability was partially explained with patient's age and liver function. CL/F was found to decrease with age. According to the developed model, sirolimus CL/F decreases by, in average, 37% in patients with aspartate aminotransferase (AST) greater than 37 IU/L. The internal and external validation confirmed the satisfactory prediction of the developed model. CONCLUSIONS: The population modeling of routinely monitored data allowed quantification of the age and liver function influence on sirolimus CL/F. According to the final model, patients with compromised liver function expressed via AST values require careful monitoring and dosing adjustments. Proven good predictive performance makes this model a useful tool in everyday clinical practice.

Expectations, concerns, and needs of patients who start drugs for chronic conditions. A prospective observational study among community pharmacies in Serbia.

BACKGROUND: During the initiation of treatment of a chronic disease, patients may have varying interests, expectations, concerns, and reasons to stop treatment, influencing compliance with prescribed treatment. Thus, healthcare professionals are expected to integrate these needs into medicines management. OBJECTIVES: To determine what information is important to patients; assess predictors of patients' interests, expectations, concerns, reasons to stop therapy; evaluate drug-related problems following initiation of therapy and summarize how pharmacists resolve them during patient-pharmacist counselling. METHODS: In 2014, a four-month study was performed in Serbian community pharmacies, as part of the Pharmaceutical Care Quality Indicators Project led by the European Directorate for the Quality of Medicines & Healthcare. Seventy community pharmacists were asked to participate in the study. Pharmacists recruited adult patients who consented to participate in the study and who initiated treatment, lasting at least six months. Patients completed an open-ended questions form. After two-to-four weeks, a patient-pharmacist consultation was performed. RESULTS: Forty-four community pharmacists (response rate 62.9%) sent back the completed forms from 391 patients (response rate 67.1%). The total number of dispensed drugs was 403. In terms of drug safety, 29.4% of patients sought information, 32.5% expressed concerns, and 28.1% of patients cited it as a reason to discontinue treatment. During the first weeks of therapy, 18% of patients experienced practical problems, while 27.3% reported adverse drug reactions. CONCLUSION: Safety issues are a major focus of patients' prescribed new medicines for long-term treatment.

Elderly polypharmacy patients' needs and concerns regarding medication assessed using the structured patient-pharmacist consultation model.

OBJECTIVE: To evaluate elderly polypharmacy patients' needs and concerns regarding medication through the Structured Patient-Pharmacist Consultation (SPPC). METHODS: Older patients on chronic treatment with ≥5 medications were asked to fill in the SPPC form at home. A consultation with the community pharmacist, structured according to patient's answers, followed within 2-4 weeks. Logistic regression associated patients' individual treatment with care issues and consultation outcomes. RESULTS: Out of 440 patients, 39.5% experienced problems, and 46.1% had concerns about medication use. 122 patients reported reasons for discontinuing treatment. The main outcome of the consultation was a better understanding of medication use (75.5%). Side effects and/or non-adherence were identified in 50% of patients, and 26.6% were referred to the doctor. Atrial fibrillation, COPD, anticoagulants, benzodiazepines, and beta agonists/corticosteroids were associated with problems during medication use. Patients with diabetes improved their understanding of medication use significantly. CONCLUSION: Patients on benzodiazepines, anticoagulants, and beta agonists/corticosteroids, with atrial fibrillation and/or COPD, may have a higher potential for non-adherence. Counseling patients based on the SPPC model may be particularly useful for patients with diabetes. PRACTICE IMPLICATIONS: The SPPC model is a useful tool for counseling based on patient needs.

Evaluation of drug-related problems in older polypharmacy primary care patients.

AIMS AND OBJECTIVES: Targeting older patients with predictive factors for drug-related problems (DRPs) could make clinical medication reviews more cost-effective. The aim of this study was to identify the number, type, and potential predictive factors for DRPs in older polypharmacy patients. METHODS: Community pharmacists performed clinical medication reviews and documented DRPs, types of interventions, and their implementation in older patients. RESULTS: Three hundred eighty-eight medication reviews were analyzed, 964 DRPs (average 2.5 ± 1.9), and 1022 interventions (average 2.6 ± 2.0) were identified. The overall implementation rate of interventions was 70.1%, the highest was observed in interventions aiming to resolve the lack of therapy monitoring (86.8%). Patients with ≥12 medications had an increased risk of ≥5 DRPs (P < .001). Asthma was associated with lack of adherence (P = .002), lack of aspirin, statins, and proton pump inhibitors use with additional therapy needed (P = .002-.004). Predictive factors for drug interactions were antihypertensive medications and/or medications with narrow therapeutic index (P < .05). Lack of efficacy was associated with diabetes (P = .006). Nonsteroidal anti-inflammatory drugs were risk factors for inappropriate drug selection (P = .002). Lack of monitoring was associated with hypertension (P = .013), whereas benzodiazepines (P < .001) and aspirin (P = .021) were overused. CONCLUSION: Patients with asthma, hypertension, and diabetes and lack of statin, antithrombotic agent, and/or proton pump inhibitor use were associated with higher risks for DRPs.

Population Pharmacokinetic Approach of Immunosuppressive Therapy in Kidney Transplant Patients.

Immunosuppressive therapy is the cornerstone of successful kidney transplantation. Frequently used immunosuppressives are cyclosporine, tacrolimus, sirolimus and mycophenolic acid. These drugs have narrow therapeutic index and show high pharmacokinetic variability. In order to maintain the balance between efficacy and safety, dosing is based on measured drug concentrations. Proper identification, quantification and understanding the sources of variability in measured concentrations facilitate routine dose adjustment in clinical practice. Classical pharmacokinetic studies have limited use in transplant patients attributable to design with intense sampling in a small, relatively homogenous population, and identification of only single variability factor per study. Population approach is a powerful tool for analysing sparse data, identifying factors that influence drug pharmacokinetics and estimating variability. In this report we reviewed available population pharmacokinetic models for cyclosporine, tacrolimus, sirolimus and mycophenolic acid in adult kidney transplant patients. The major focus was to describe various demographic factors, biochemical parameters, genetic polymorphisms of metabolic enzymes and transporters and drug-drug interactions, which have been identified as an important concern of pharmacokinetic variability in kidney transplant patients.

Nonlinear mixed effects modelling approach in investigating phenobarbital pharmacokinetic interactions in epileptic patients.

PURPOSE: The present study aimed to establish population pharmacokinetic model for phenobarbital (PB), examining and quantifying the magnitude of PB interactions with other antiepileptic drugs concomitantly used and to demonstrate its use for individualization of PB dosing regimen in adult epileptic patients. METHODS: In total 205 PB concentrations were obtained during routine clinical monitoring of 136 adult epilepsy patients. PB steady state concentrations were measured by homogeneous enzyme immunoassay. Nonlinear mixed effects modelling (NONMEM) was applied for data analyses and evaluation of the final model. RESULTS: According to the final population model, significant determinant of apparent PB clearance (CL/F) was daily dose of concomitantly given valproic acid (VPA). Typical value of PB CL/F for final model was estimated at 0.314 l/h. Based on the final model, co-therapy with usual VPA dose of 1000 mg/day, resulted in PB CL/F average decrease of about 25 %, while 2000 mg/day leads to an average 50 % decrease in PB CL/F. CONCLUSIONS: Developed population PB model may be used in estimating individual CL/F for adult epileptic patients and could be applied for individualizing dosing regimen taking into account dose-dependent effect of concomitantly given VPA.

Total plasma protein effect on tacrolimus elimination in kidney transplant patients--population pharmacokinetic approach.

Data from routine therapeutic drug monitoring of 105 adult kidney transplant recipients were used for population pharmacokinetic analysis which was performed using a non-linear mixed-effects modeling. The effect of demographic and clinical factors on tacrolimus clearance was evaluated. Following the initiation of treatment with tacrolimus, the results of our study indicate a decrease of the drug clearance on day 15, 1 and 6 months after transplantation for 4.4%, 6.3% and 10.92%, respectively. Our model suggests a negative correlation between tacrolimus clearance and haematocrit. According to final model, clearance decreases with increasing of aspartate aminotransferase. Our results demonstrated that CL/F increases with patients' weight. This study reveals incensement for 10.4% in tacrolimus clearance with alteration of patients' minimal measured total protein levels to upper normal range. The findings of this study explore various factors of tacrolimus pharmacokinetic variability and point out a relationship between tacrolimus clearance and total plasma protein. Developed model demonstrates the feasibility of estimation of individual tacrolimus clearance and may allow rational individualization of tacrolimus dosing in kidney transplant patients.