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

Assessing the binding interaction of polystyrene sulfonate with amitriptyline in healthy volunteers: a cross-over design — The BIND study

Purpose: Polystyrene sulfonate is used for binding potassium in patients with chronic kidney disease (CKD). Because of its binding properties, it can potentially bind other medications and thereby decrease their bioavailability and effectiveness. Amitriptyline, often used by CKD patients for neuropathic pain, shows significant binding to polystyrene sulfonate in vitro. The purpose of this study was to determine the effect of polystyrene sulfonate on the exposure of amitriptyline in vivo when taken concomitantly in healthy volunteers. Methods: We performed a prospective cross-over study in nine healthy volunteers. Participants were 18 years of age or older, did not use any medication, and had no known allergy to amitriptyline or polystyrene sulfonate. Participants visited Deventer Teaching Hospital twice. Once they received a single dose of amitriptyline 50 mg and once they received a single dose of both polystyrene sulfonate 15 g and amitriptyline 50 mg taken concomitantly, with a wash out period of at least 1 week. After intake of the medication, six blood samples were collected, at 2, 3, 4, 5, 6, and 8 h. Blood samples were analysed to determine maximum concentration (Cmax) and area under the curve 0–8 h after intake (AUC0–8 h). Difference in Cmax and AUC0–8 h was analysed with a paired T-test or Wilcoxon signed rank test, depending on normality of the data. A p-value < 0.05 was considered statistically significant. Results: Of the nine participants included, eight participants completed both visits to the hospital. Mean maximum concentration (Cmax) of amitriptyline was 35.61 µg l−1 (95% CI 27.90–43.33 µg l−1) when taken alone, compared to 9.25 µg l−1 (95% CI 6.59–11.92 µg l−1) when taken with polystyrene sulfonate (p < 0.001). Mean AUC0–8 h of amitriptyline was 168.20 µg × h l−1 (95% CI 139.95–196.45 µg × h l−1) when taken alone and 45.78 µg × h l−1 (95% CI 30.20–61.36 µg × h l−1) when taken with polystyrene sulfonate (p < 0.0001). Conclusion: These results show a significant decrease in exposure of amitriptyline of approximately 75% when taken concomitantly with polystyrene sulfonate, thereby probably compromising therapy efficacy. Patients using both amitriptyline and polystyrene sulfonate should be informed to separate intake of these medications. Trial registration: NL8539 (17 April 2020)

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

BackgroundWe previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in similar to 80% of cases.MethodsWe report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.ResultsNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P=1.1x10(-4)) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70[95%CI 1.3-8.2], P=2.1x10(-4)). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR=19.65[95%CI 2.1-2635.4], P=3.4x10(-3)), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR=4.40[9%CI 2.3-8.4], P=7.7x10(-8)). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P=1.68x10(-5)).ConclusionsRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old