Prevalence and location of coronary artery disease in anomalous aortic origin of coronary arteries.

BACKGROUND: The prevalence and location of coronary artery disease (CAD) in anomalous aortic origin of a coronary artery (AAOCA) remain poorly documented in adults. We sought to assess the presence of CAD in proximal (or ectopic) and distal (or nonectopic) segments of AAOCA. We hypothesized that the representation of CAD may differ among the different courses of AAOCA. METHODS: The presence of CAD was analyzed on coronary angiography and/or coronary computed tomography angiography in 390 patients (median age 64 years; 73% male) with AAOCA included in the anomalous coronary arteries multicentric registry. RESULTS: AAOCA mainly involved circumflex artery (54.4%) and right coronary artery (RCA) (31.3%). All circumflex arteries had a retroaortic course; RCA mostly an interarterial course (98.4%). No CAD was found in the proximal segment of interarterial AAOCA, whereas 43.8% of retroaortic AAOCA, 28% of prepulmonic AAOCA and 20.8% subpulmonic AAOCA had CAD in their proximal segments (P < 0.001). CAD was more prevalent in proximal than in distal segments of retroaortic AAOCA (OR: 3.1, 95% CI: 1.8-5.4, P < 0.001). On multivariate analysis, a retroaortic course was associated with an increased prevalence of CAD in the proximal segment (adjusted OR 3.4, 95% CI: 1.3-10.7, P = 0.022). CONCLUSION: Increased prevalence of CAD was found in the proximal segment of retroaortic AAOCA compared to the proximal segments of other AAOCA, whereas no CAD was observed in the proximal segment of interarterial AAOCA. The mechanisms underlying these differences are not yet clearly identified.

Risk of Bronchial Complications After Lung Transplantation With Respiratory Corynebacteria. Results From a Monocenter Retrospective Cohort Study.

Corynebacterium spp. are associated with respiratory infections in immunocompromised hosts. A link with bronchial complications after lung transplantation (LTx) has been suggested. We aimed to assess the link between respiratory sampling of Corynebacterium spp. and significant bronchial complication (SBC) after LTx. We performed a single center retrospective study. Inclusion of LTx recipients with at least one respiratory Corynebacterium spp. sample (July 2014 to December 2018). Subjects were matched to unexposed LTx recipients. Primary outcome was SBC occurrence after Corynebacterium spp. isolation. Secondary outcomes were Corynebacterium spp. persistent sampling, chronic lung allograft dysfunction (CLAD) onset and all-cause mortality. Fifty-nine patients with Corynebacterium spp. sampling with 59 without isolation were included. Corynebacterium spp. identification was not associated with SBC occurrence (32.4% vs. 21.6%, p = 0.342). Previous SBC was associated with further isolation of Corynebacterium spp. (OR 3.94, 95% CI [1.72-9.05]). Previous SBC and corticosteroids pulses in the last 3 months were the only factors associated with increased risk of Corynebacterium spp. isolation in multivariate analysis. Corynebacterium spp. sampling was significantly associated with CLAD onset (27.1% vs. 6.9%, p = 0.021). Corynebacterium spp. isolation was not associated with SBC but with higher risk of CLAD. Whether CLAD evolution is affected by Corynebacterium spp. eradication remains to be investigated.

Exposure-Response Analysis of Osimertinib in Patients with Advanced Non-Small-Cell Lung Cancer.

High interindividual variability (IIV) of the clinical response to epidermal growth factor receptor (EGFR) inhibitors such as osimertinib in non-small-cell lung cancer (NSCLC) might be related to the IIV in plasma exposure. The aim of this study was to evaluate the exposure−response relationship for toxicity and efficacy of osimertinib in unselected patients with advanced EGFR-mutant NSCLC. This retrospective analysis included 87 patients treated with osimertinib. Exposure−toxicity analysis was performed in the entire cohort and survival analysis only in second-line patients (n = 45). No significant relationship between occurrence of dose-limiting toxicity and plasma exposure was observed in the entire cohort (p = 0.23, n = 86). The median overall survival (OS) was approximately two-fold shorter in the 4th quartile (Q4) of osimertinib trough plasma concentration (>235 ng/mL) than in the Q1−Q3 group (12.2 months [CI95% = 8.0−not reached (NR)] vs. 22.7 months [CI95% = 17.1−34.1]), but the difference was not statistically significant (p = 0.15). To refine this result, the exposure−survival relationship was explored in a cohort of 41 NSCLC patients treated with erlotinib. The Q4 erlotinib exposure group (>1728 ng/mL) exhibited a six-fold shorter median OS than the Q1−Q3 group (4.8 months [CI95% = 3.3-NR] vs. 22.8 months (CI95% = 10.6−37.4), p = 0.00011). These results suggest that high exposure to EGFR inhibitors might be related to worse survival in NSCLC patients.

Quantitative Prediction of Adverse Event Probability Due to Pharmacokinetic Interactions.

INTRODUCTION: Iatrogeny due to drug-drug interactions is insufficiently documented, due to the high number of possible combinations. OBJECTIVE: This study aimed to design a simple but general method to predict the variation of adverse events (AE) frequency due to a pharmacokinetic or pharmacodynamic interaction. METHODS: Three prediction models were designed using a logistic probability density function. Each prediction model was based on three components: the AE odds ratio of each drug in the combination, and the area under the curve ratio (Rauc) of the pharmacokinetic interaction, if any. Pharmacodynamic interaction was assumed to be additive on logit scale. Rauc was predicted using a well-validated mechanistic static model, freely available online. No combination study is required. The method was evaluated against a wide range of AEs (28 High Level Terms) and 211 drug combinations (involving 43 victim drugs and 55 perpetrators), by comparing the observed and predicted frequencies. The observed odds ratios were estimated with a disproportionality analysis from the FDA Adverse Event Reporting System, using an approach that minimizes biases. RESULTS: With the best model, the rate of prediction considered as correct (within 50-200% of the observed value) was 72%, and the bias was negligible (-5%). The AE odds ratio due to pharmacokinetic and pharmacodynamic interactions was equally well predicted. CONCLUSIONS: A simple workflow to implement the method in practice is proposed. This method may help to foresee and to anticipate the harmful consequences associated with drug-drug interactions, at virtually no experimental cost, when the odds ratio of an AE is known for each drug alone and the AUC ratio is known or predicted by a suitable model.

Simultaneous quantification of dabrafenib, hydroxy-dabrafenib and trametinib in human plasma by liquid chromatography-tandem mass spectrometry.

A new liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of dabrafenib (DAB), its main metabolite hydroxy-dabrafenib (OHD) and trametinib (TRA) in human plasma has been developed and validated. After addition of internal standard (dabrafenib-d9), extraction was achieved after protein precipitation with acetonitrile containing 1 % (v/v) formic acid. Chromatographic separation was performed on an Accucore® C18 (2.1 × 50 mm; 2.6 µm) column using a gradient elution of water acidified with 0.1 % (v/v) formic acid (A) and acetonitrile containing 0.1 % (v/v) formic acid (B) at a flow rate of 500 µL/min. The calibration ranged from 10 to 2000 ng/mL for DAB and OHD and from 5 to 50 ng/mL for TRA. This method was validated with satisfactory results including good precision (intra- and inter-assay coefficient of variation from 2.0 %-14.9 %) and good accuracy (inter- and intra-day bias between -1.2 % and 10.9 %), as well as long term stability in unprocessed plasma at -20 °C. This newly proposed method is useful for clinical research purposes as well as therapeutic drug monitoring for patients with a Rapidly Accelerated Fibrosarcoma kinase B (BRAF)-mutated cancer.