Exploring co-dispensed drug use in patients on sevelamer or polystyrene sulfonate to identify potential novel binding interactions:a cross sectional in silico study: Potential novel binding interactions with resins

Background Sevelamer and polystyrene sulfonate are used for treating hyperphosphatemia and hyperkalaemia in chronic kidney disease patients. Because of their binding properties, these resins potentially bind other drugs in the gastrointestinal tract, thereby decreasing their bioavailability and clinical effectiveness. Aim The aim of this study was to explore co-dispensed drug use in patients on sevelamer or polystyrene sulfonate to identify potential novel binding interactions. Method In this in silico study, the 100 drugs most frequently co-dispensed with sevelamer/polystyrene sulfonate in the period 2000-2018 were extracted from the University Groningen IADB.nl database. Drugs dispensed to  2.0 were identified as potential interacting drug. For polystyrene sulfonate, drugs with a pKa (base) > 1.5 were identified as potential interacting drug. Results Of the top 100 drugs most frequently co-dispensed with sevelamer/polystyrene sulfonate, 22 and 27 potentially clinically relevant new interacting drugs were identified for sevelamer and polystyrene sulfonate respectively. Conclusion Several potentially relevant novel binding interactions for sevelamer and polystyrene sulfonate were identified based on dispensing data and assessment of chemical properties for which further interaction research is warranted

Enzalutamide Reduces Oxycodone Exposure in Men with Prostate Cancer

BACKGROUND AND OBJECTIVE: Up to 90% of patients with castration-resistant prostate cancer (CRPC) will develop symptomatic bone metastases requiring pain medication, with opioids being the mainstay of therapy in treating moderate and severe pain. Enzalutamide is an androgen receptor antagonist for the treatment of CRPC and a strong inducer of cytochrome P450 (CYP)3A4. Hereby, enzalutamide potentially reduces the exposure of oxycodone, an opioid metabolized by CYP3A4 and CYP2D6. Our objective was to evaluate the potential drug-drug interaction of enzalutamide and oxycodone.METHODS: A prospective, nonrandomized, open-label, two-arm parallel study was performed. All patients received a single dose of 15 mg normal-release oxycodone. Patients in the enzalutamide arm (ENZ-arm) received enzalutamide 160 mg once daily. Plasma concentrations of oxycodone and its metabolites were quantified using a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method.RESULTS: Twenty-six patients (13 ENZ-arm; 13 control arm) were enrolled in the study. Enzalutamide decreased the mean AUC 0-8 h and C max of oxycodone with, respectively, 44.7% (p &lt; 0.001) and 35.5% (p = 0.004) compared with the control arm. The AUC 0-8 h and C max of the active metabolite oxymorphone were 74.2% (p &lt; 0.001) and 56.0% (p = 0.001) lower in the ENZ-arm compared with the control arm. In contrast, AUC 0-8 h and C max of the inactive metabolites noroxycodone and noroxymorphone were significantly increased by enzalutamide. CONCLUSION: Co-administration of enzalutamide significantly reduced exposure to oxycodone and its active metabolite oxymorphone in men with prostate cancer. This should be taken into account when prescribing enzalutamide combined with oxycodone.</p

Identifying patients with metformin associated lactic acidosis in the emergency department

BackgroundMetformin associated lactic acidosis (MALA) is a serious adverse event with a high mortality rate of 30-50%. Early recognition of MALA and timely starting treatment may reduce its morbidity and mortality.ObjectiveThe aim of this study was to explore clinical parameters to identify patients with MALA in patients with suspected sepsis induced lactic acidosis in the emergency department ED.SettingA retrospective single centre study was conducted at the Deventer Teaching Hospital in the Netherlands.MethodPatients with lactate concentration > 4.0 mmol/l admitted at the ED between 2010 and 2017 with suspected sepsis or confirmed MALA and referred to the Intensive Care Unit were included. Baseline characteristics (pH, lactate, creatinine and CRP) of MALA patients were compared with patients with suspected sepsis induced lactic acidosis. Creatinine and lactate concentration were selected as potential relevant parameters.Main outcome measureSensitivity and specificity of the highest tertiles of the creatinine and the lactate concentrations separately, in combination, and both combined with metformin use, were calculated.ResultsThirteen MALA and 90 suspected sepsis induced lactic acidosis patients were included. Lactate (14.7 vs 5.9 mmol/l, p = 8.4 mmol/l, creatinine >= 256 mu mol/l had a sensitivity of 85% and a specificity of 95% for identifying MALA in suspected sepsis induced lactic acidosis patients in the ED. When combined with metformin use the specificity increased to 99%.ConclusionWhen managing lactic acidosis in the ED the diagnosis MALA should be considered in patients with a creatinine concentration >= 256 mu mol/l and lactate concentration >= 8.4 mmol/l

Dosing oxaliplatin in a haemodialysis patient with metastatic rectum cancer monitored by free platinum concentrations

WHAT IS KNOWN AND OBJECTIVE: Oxaliplatin in combination with fluorouracil and folinic acid is one of the preferred chemotherapeutic options in the treatment of metastatic rectum cancer. However, oxaliplatin is contraindicated in patients with a creatinine clearance <30 mL/min and dosing guidelines in patients on haemodialysis have not been established. CASE SUMMARY: A 77-year-old haemodialysis patient with metastatic rectum cancer was treated with FOLFOX and bevacizumab (oxaliplatin 70 mg/m2 , folinic acid 200 mg/m2 , 5-FU 340 mg/m2 bolus and 2040 mg/m2 continuous infusion during 44 hours and bevacizumab 5 mg/kg) every three weeks. Haemodialysis started immediately after infusion of oxaliplatin. The oxaliplatin dose was monitored by measuring free platinum ultrafiltrate concentrations. The AUC0-50 of free platinum plasma ultrafiltrate after cycles 1-3, respectively, was 24.3, 24.7 and 25.8 μg*h/mL. The Cmax was, respectively, 1.3, 1.3 and 2.2 μg/mL. There was no accumulation of free platinum detectable. The patient experienced no toxicity, and after 3 cycles, the CT scan showed a decrease in the liver metastases after which hemihepatectomy and metastasectomy were performed without any complications. A CT scan 6 months after the surgery showed no new liver metastases. However, lymphatic metastasis was diagnosed for which palliative treatment was started. WHAT IS NEW AND CONCLUSION: Dosing oxaliplatin in a haemodialysis patient monitored by free platinum concentrations was effective, safe and feasible in clinical practice. Further research is needed to determine the best pharmacokinetic parameter or combination of parameters and corresponding target values to further optimize the oxaliplatin dose for the individual haemodialysis patient