Purpose: We assessed the differential effect of clarithromycin, a strong inhibitor of cytochrome P450 (CYP) 3A4 and P-glycoprotein, on the pharmacokinetics of a regular dose of edoxaban and on a microdose cocktail of factor Xa inhibitors (FXaI). Concurrently, CYP3A activity was determined with a midazolam microdose. Methods: In an open-label fixed-sequence trial in 12 healthy volunteers, the pharmacokinetics of a microdosed FXaI cocktail (μ-FXaI; 25 μg apixaban, 50 μg edoxaban, and 25 μg rivaroxaban) and of 60 mg edoxaban before and during clarithromycin (2 x 500 mg/d) dosed to steady-state was evaluated. Plasma concentrations of study drugs were quantified using validated ultra-performance liquid chromatography–tandem mass spectrometry methods. Results: Therapeutic clarithromycin doses increased the exposure of a therapeutic 60 mg dose of edoxaban with a geometric mean ratio (GMR) of the area under the plasma concentration-time curve (AUC) of 1.53 (90 % CI: 1.37–1.70; p < 0.0001). Clarithromycin also increased the GMR (90% CI) of the exposure of microdosed FXaI apixaban to 1.38 (1.26–1.51), edoxaban to 2.03 (1.84–2.24), and rivaroxaban to 1.44 (1.27–1.63). AUC changes observed for the therapeutic edoxaban dose were significantly smaller than those observed with the microdose (p < 0.001). Conclusion: Clarithromycin increases FXaI exposure. However, the magnitude of this drug interaction is not expected to be clinically relevant. The edoxaban microdose overestimates the extent of the drug interaction with the therapeutic dose, whereas AUC ratios for apixaban and rivaroxaban were comparable to the interaction with therapeutic doses as reported in the literature. Trial Registration: EudraCT Number: 2018-002490-22

Background: Little is known about heparin‐induced thrombocytopenia (HIT), a pro‐thrombotic, potentially life‐threatening immune‐mediated reaction to heparin exposure, in conservative and interventional cardiovascular medicine.Hypothesis: The 4T score, validated for prediction of HIT in surgical patients before, is also suitable for assessing HIT probability in cardiovascular patients with unclear thrombocytopenia.Methods: A total of 403 consecutive patients from our Department of Cardiology, Angiology and Pneumology in whom a HIT screening test was performed between 2009 and 2016 were identified. All 72 patients with a positive screening test were subjected to a functional confirmation test (heparin‐induced platelet activation test, HIPA), resulting in 23 patients with serologically confirmed HIT (positive screening test, positive HIPA) and 49 patients with nonconfirmed HIT (positive screening test, negative HIPA).Results: The 4TScore had a sensitivity of 82.6% and a specificity of 28.6% in our patients, suggesting that it might not sufficiently predict the clinical probability of HIT in cardiovascular patients. In both confirmed and nonconfirmed HIT, intrahospital mortality was high without a significant difference (30% in confirmed HIT vs 43% in nonconfirmed HIT). Bacteremia was more often found in patients with nonconfirmed HIT, suggesting infection as a frequent differential diagnosis of thrombocytopenia in these patients (49% vs 17%, P = 0.0185).Conclusion: HIT screening should be initiated in cardiovascular patients with unclear thrombocytopenia despite a low 4Tscore in order to distinguish patients requiring alternative anticoagulants from those with other causes such as infections. Further research is needed to specify the risk profile for HIT in cardiovascular patients.

There is increasing research interest in cholesterol-lowering therapy in older patients. The newer lipid-lowering agents (the proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors evolocumab and alirocumab; the PCSK9 synthesis inhibitor inclisiran, and the adenosine triphosphate–citrate lyase inhibitor bempedoic acid) might also provide more options for the future treatment of older patients. Data analyses of the phase III outcome trials of the PCSK9 inhibitors suggest that their clinical benefits are maintained at older ages and that there is no increased relative risk of adverse events in older patients; however, data from patients aged ≥ 75 years and particularly aged ≥ 85 years are limited, and the trials did not collect information on the frailty status of patients. Frailty is a predictor of adverse outcomes, including mortality, and might help guide therapy decisions. To date, no outcome data are available for cardiovascular endpoints for the low-density lipoprotein cholesterol-lowering drugs inclisiran and bempedoic acid. Except for the risk of gout and tendon rupture with bempedoic acid, which remains to be further characterized in larger populations, the safety profile of the novel lipid-lowering agents in older patients seems favorable. The newer lipid-lowering agents could be added to other lipid-lowering medication or used as an alternative treatment in older patients with documented statin intolerance (as is already recommended in guidelines for the PCSK9 inhibitors), such as myopathy. Especially in older patients needing high-intensity therapy despite polypharmacy or certain comedications, the absence of clinically relevant drug–drug interactions with the PCSK9 inhibitors and inclisiran might be an advantage.

Bile acids (BA) play an important role in cholesterol metabolism and possess further beneficial metabolic effects as signalling molecules. Blocking the hepatocellular uptake of BA via sodium-taurocholate co-transporting polypeptide (NTCP) with the first-in-class drug bulevirtide, we expected to observe a decrease in plasma LDL cholesterol. In this exploratory phase I clinical trial, volunteers with LDL cholesterol > 130 mg/dL but without overt atherosclerotic disease were included. Thirteen participants received bulevirtide 5 mg/d subcutaneously for 12 weeks. The primary aim was to estimate the change in LDL cholesterol after 12 weeks. Secondary endpoints included changes in total cholesterol, HDL cholesterol, lipoprotein(a), inflammatory biomarkers, and glucose after 12 weeks. In addition, cardiac magnetic resonance imaging (CMR) was performed at four time points. BA were measured as biomarkers of the inhibition of hepatocellular uptake. After 12 weeks, LDL cholesterol decreased not statistically significantly by 19.6 mg/dL [−41.8; 2.85] (Hodges–Lehmann estimator with 95% confidence interval). HDL cholesterol showed a significant increase by 5.5 mg/dL [1.00; 10.50]. Lipoprotein(a) decreased by 1.87 mg/dL [−7.65; 0]. Inflammatory biomarkers, glucose, and cardiac function were unchanged. Pre-dose total BA increased nearly five-fold (from 2026 nmol/L ± 2158 (mean ± SD) at baseline to 9922 nmol/L ± 7357 after 12 weeks of treatment). Bulevirtide was generally well tolerated, with most adverse events being administration site reactions. The exploratory nature of the trial with a limited number of participants allows the estimation of potential effects, which are crucial for future pharmacological research on bile acid metabolism in humans.

Background and Objective Voriconazole is an important broad-spectrum anti-fungal drug with nonlinear pharmacokinetics. The aim of this single centre fixed-sequence open-label drug–drug interaction trial in healthy participants (N = 17) was to determine whether microdosed probe drugs for CYP3A and CYP2C19 reliably predict voriconazole clearance (CL_VRZ). Methods At baseline, a single oral microdose of the paradigm substrates midazolam (CYP3A) and omeprazole (CYP2C19) were given to estimate their clearances (CL). Thereafter, a single oral dose of voriconazole was administered (50, 100, 200 or 400 mg), followed by the microdosed probe drugs. Results The clearances of midazolam (CL_MDZ 790–2790 mL/min at baseline; 248–1316 mL/min during voriconazole) and omeprazole (CL_OMZ 66.4–2710 mL/min at baseline; 30.1–1420 mL/min during voriconazole) were highly variable. CL_MDZ [geometric mean ratio (GMR) 0.586 at 50 mg voriconazole decreasing to GMR 0.196 at 400 mg voriconazole] and CL_OMZ (GMR 0.590 at 50 mg decreasing to GMR 0.166 at 400 mg) were reduced with higher voriconazole doses. CL_MDZ was linearly correlated with CL_VRZ (slope 1.458; adjusted R² 0.528) as was CL_OMZ (slope 0.807; adjusted R² 0.898). Multiple linear regression resulted in an adjusted R² of 0.997 for the relationship CL_VRZ ~ log CL_OMZ + log CL_MDZ using data during voriconazole treatment and an adjusted R² of 0.997 for the relationship CL_VRZ ~ log CL_OMZ + log CL_MDZ + voriconazole dose, using baseline data for CL_MDZ and CL_OMZ. Conclusion Microdosed midazolam and omeprazole accurately described and predicted total CL_VRZ Trial Registration EudraCT No: 2020-001017-20, registered on March 5th, 2020. DRKS: DRKS00022547, registered on August 6th, 2020.

Hydroxychloroquine as a weak basic compound with two amines is strongly enriched in cell compartments with low pH, suggesting that modification of gastric pH by coadministered proton pump inhibitors might reduce its solubility and absorption and thus its efficacy in patients. We addressed this question in a single-center, open-label, randomized, parallel drug-drug interaction trial in healthy adults (EudraCT No. 2020-001470-30). All participants received a single oral dose of 400-mg hydroxychloroquine, and one group additionally received 40 mg of pantoprazole once daily for 9 days dosed to steady state. Whole-blood samples were collected for 72 hours, and hydroxychloroquine was quantified by liquid chromatography–tandem mass spectrometry. Primary endpoints were whole-blood hydroxychloroquine areas under the concentration-time curve from 0 to 72 hours (AUC_0-72h) and peak concentrations (C_max). Unpaired 2-sided t-tests of the log transformed pharmacokinetic parameters were performed to compare both groups. Twenty-four participants (12 per group) were included. Hydroxychloroquine AUC_0-72h and C_max did not differ between groups without and with pantoprazole (arithmetic mean; AUC_0-72h, 7649 ng/ml • h, and 8429 ng/ml • h, P = .50; C_max, 448 ng/mL and 451.5 ng/mL, P = .96, respectively). Pantoprazole did not alter hydroxychloroquine absorption, indicating that proton pump inhibitors do not affect its bioavailability.