1.
Impact of fedratinib on the pharmacokinetics of transporter probe substrates using a cocktail approach.
Ogasawara, K, Wood-Horrall, RN, Thomas, M, Thomas, M, Liu, L, Liu, M, Xue, Y, Surapaneni, S, Carayannopoulos, LN, Zhou, S, et al
Cancer chemotherapy and pharmacology. 2021;(6):941-952
Abstract
INTRODUCTION Fedratinib, an oral, selective Janus kinase 2 inhibitor, has been shown to inhibit P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 2, and multidrug and toxin extrusion (MATE) 1 and MATE2-K in vitro. The objective of this study was to evaluate the influence of fedratinib on the pharmacokinetics (PK) of digoxin (P-gp substrate), rosuvastatin (OATP1B1/1B3 and BCRP substrate), and metformin (OCT2 and MATE1/2-K substrate). METHODS In this nonrandomized, fixed-sequence, open-label study, 24 healthy adult participants received single oral doses of digoxin 0.25 mg, rosuvastatin 10 mg, and metformin 1000 mg administered as a drug cocktail (day 1, period 1). After a 6-day washout, participants received oral fedratinib 600 mg 1 h before the cocktail on day 7 (period 2). An oral glucose tolerance test (OGTT) was performed to determine possible influences of fedratinib on the antihyperglycemic effect of metformin. RESULTS Plasma exposure to the three probe drugs was generally comparable in the presence or absence of fedratinib. Reduced metformin renal clearance by 36% and slightly higher plasma glucose levels after OGTT were observed in the presence of fedratinib. Single oral doses of the cocktail ± fedratinib were generally well tolerated. CONCLUSIONS These results suggest that fedratinib has minimal impact on the exposure of P-gp, BCRP, OATP1B1/1B3, OCT2, and MATE1/2-K substrates. Since renal clearance of metformin was decreased in the presence of fedratinib, caution should be exercised in using coadministered drugs that are renally excreted via OCT2 and MATEs. TRIAL REGISTRATION Clinicaltrials.gov NCT04231435 on January 18, 2020.
2.
Population Pharmacokinetic Studies of Digoxin in Adult Patients: A Systematic Review.
Abdel Jalil, M, Abdullah, N, Alsous, M, Abu-Hammour, K
European journal of drug metabolism and pharmacokinetics. 2021;(3):325-342
Abstract
BACKGROUND Digoxin is a cardiac glycoside that was introduced to cardiovascular medicine more than 200 years ago. Its use is associated with large variability, which complicates achieving the desired therapeutic outcomes. OBJECTIVES To present a synthesis of the available literature on the population pharmacokinetics of digoxin in adults and to identify the sources of variability in its pharmacokinetics. METHODS This is a PROSPERO registered systematic review (CRD42018105300). A literature search was conducted using the ISI Web of Science, Science Direct, PubMed, and SCOPUS databases to identify digoxin population pharmacokinetic studies of adults that utilized the nonlinear mixed-effect modeling approach. RESULTS Sixteen articles were included in the present analysis. Only two studies were conducted in elderly subjects as a separate population. Both the pharmacokinetics and pharmacodynamics of digoxin were investigated in one study. Furthermore, the reviewed studies were mostly conducted in East Asian populations (68.8%). Digoxin's pharmacokinetics were usually described by a one-compartment model because of the nature of the collected data. Weight, age, kidney function, presence of heart failure, and co-administered medications such as calcium channel blockers were the most commonly identified predictors of digoxin clearance. The value of apparent clearance in a typical study individual ranged from 0.005 to 0.2 l/h/kg, while the value of the apparent volume of distribution ranged from 3.14 to 15.2 l/kg. The quality of model evaluation was deemed excellent only in 31.3% of the studies. CONCLUSION This review provides information about variables that need to be considered when prescribing digoxin. The results highlight the need for prospective studies that allow two-compartment pharmacokinetic/pharmacodynamic models to be established, with a special focus on the elderly subpopulation.
3.
Ivabradine for chronic heart rate control in persistent atrial fibrillation. Design of the BRAKE-AF project.
Fontenla, A, López-Gil, M, Tamargo-Menéndez, J, Matía-Francés, R, Salgado-Aranda, R, Rey-Blas, JR, Miracle-Blanco, Á, Mejía-Martínez, E, Pastor-Fuentes, A, Toquero-Ramos, J, et al
Revista espanola de cardiologia (English ed.). 2020;(5):368-375
Abstract
INTRODUCTION AND OBJECTIVES Ivabradine is an inhibitor of the If channel, the main determinant of the pacemaker function of the sinus node. The drug has been approved for the treatment of angina and heart failure. There is some evidence of its role as an inhibitor of atrial-ventricular node (AVN) conduction. The aim of the BRAKE-AF project is to assess ivabradine use for rate control in atrial fibrillation (AF). METHODS A multicenter, randomized, parallel, open-label, noninferiority phase III clinical trial will be conducted to compare ivabradine vs digoxin in 232 patients with uncontrolled permanent AF despite beta-blockers or calcium channel blockers. The primary efficacy endpoint is the reduction in daytime heart rate measured by 24-hour Holter monitoring at 3 months. This clinical trial will be supported by an electrophysiological study of the effect of ivabradine on the action potential of the human AVN. To do this, an experimental model will be used with Chinese hamster ovarium cells transfected with the DNA encoding the expression of the t channels involved in this action potential and recording of the ionic currents with patch clamp techniques. RESULTS New data will be obtained on the effect of ivabradine on the human AVN and its safety and efficacy in patients with permanent AF. CONCLUSIONS The results of the BRAKE-AF project might allow inclusion of ivabradine within the limited arsenal of drugs currently available for rate control in AF. CLINICAL TRIAL REGISTRATION http://www.clinicaltrials.gov. Identifier: NCT03718273.