Bioanalytical Assessment of Plasma Concentrations of Angiotensin-Converting Enzyme II Inhibitors and Angiotensin Receptor Blockers: A Pilot Study Among Patients Hospitalized With Acute Heart Failure.

BACKGROUND: Although angiotensin-converting enzyme II inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) improve chronic heart failure (HF) outcomes, their potential harms and benefits in acute HF (AHF) is less clear. STUDY QUESTION: We explored the relationship between ACEI or ARB plasma concentrations among patients with AHF with in-hospital change in estimated glomerular filtration rate (eGFR). DATA SOURCES AND STUDY DESIGN: From August 2016-June 2017, patients with AHF prescribed an outpatient ACEI or ARB were enrolled before AHF treatment. All patients were given twice their home dose of diuretic intravenously and received clinical care at the discretion of the medical team. Of 61 patients in the parent study, saved plasma from 34 who were prescribed an outpatient ACEI or ARB was included in this substudy. MEASURES AND OUTCOMES: Liquid chromatography-tandem mass spectrometry was performed to assess ACEI or ARB plasma concentrations before AHF treatment. Change in eGFR was computed using the Chronic Kidney Disease Epidemiology Collaboration equation, which adjusts for age, sex, and race; diuretic dose and enrollment eGFR were used to adjust for HF severity. Multiple linear regression adjusting for enrollment eGFR and diuretic dose was performed to examine the relationship between drug concentration (undetectable/low vs. in/above-range) and in-hospital change in eGFR. RESULTS: Of 34 patients with AHF, median age was 63 years (interquartile range, 58-78 years), 19 (55.9%) were women, median eGFR at enrollment was 55.6 mL/min (interquartile range, 35.2-75.3 mL/min), and for 11 (32.4%), no ACEI or ARB was detectable in plasma. Medication concentrations in- or above-reference range were associated with in-hospital decrease in eGFR of 8.3 mL/min (95% confidence interval, 15.3-1.3 mL/min decrease), after adjusting for enrollment eGFR and diuretic treatment. CONCLUSIONS: Bioanalytical assessment of medication levels may be useful to guide in-hospital ACEI and ARB therapy for patients with AHF.

Pharmacokinetic drug-drug interaction assessment between LCZ696, an angiotensin receptor neprilysin inhibitor, and hydrochlorothiazide, amlodipine, or carvedilol.

LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor in development for treatments of hypertension and heart failure indications. In 3 separate studies, pharmacokinetic drug-drug interactions (DDIs) potential was assessed when LCZ696 was coadministered with hydrochlorothiazide (HCTZ), amlodipine, or carvedilol. The studies used a open-label, single-sequence, 3-period, crossover design in healthy subjects. Blood samples were collected to determine the pharmacokinetic parameters of LCZ696 analytes (AHU377, LBQ657, and valsartan), HCTZ, amlodipine, or carvedilol (R[+]- and S[-]-carvedilol) for statistical analysis. When coadministered LCZ696 with HCTZ, the 90% CIs of the geometric mean ratios of AUCtau,ss of HCTZ and that of LBQ657 were within a 0.80-1.25 interval, whereas HCTZ Cmax,ss decreased by 26%, LBQ657 Cmax,ss increased by 19%, and the AUCtau,ss and Cmax,ss of valsartan increased by 14% and 16%, respectively. Pharmacokinetics of amlodipine, R(+)- and S(-)-carvedilol, or LBQ657 were not altered after coadministration of LCZ696 with amlodipine or carvedilol. Coadministration of LCZ696 400 mg once daily (qd) with HCTZ 25 mg qd, amlodipine 10 mg qd, or carvedilol 25 mg twice a day (bid) had no clinically relevant pharmacokinetic drug-drug interactions. LCZ696, HCTZ, amlodipine, and carvedilol were safe and well tolerated when given alone or concomitantly in the investigated studies.