Characterization of mavacamten pharmacokinetics in patients with hypertrophic cardiomyopathy to inform dose titration.

Mavacamten is a selective, allosteric, reversible cardiac myosin inhibitor that has been developed for the treatment of adults with symptomatic obstructive hypertrophic cardiomyopathy (HCM). A population pharmacokinetic (PopPK) model was developed to characterize mavacamten pharmacokinetics (PK) and the variation in mavacamten exposure associated with intrinsic and extrinsic factors. Data from 12 clinical studies (phases 1, 2, and 3) were used.

Recommendation of mavacamten posology by model-based analyses in adults with obstructive hypertrophic cardiomyopathy.

Mavacamten is the first cardiac myosin inhibitor approved by the US Food and Drug Administration for the treatment of adults with symptomatic obstructive hypertrophic cardiomyopathy (HCM). The phase III EXPLORER-HCM (NCT03470545) study used a dose-titration scheme based on mavacamten exposure and echocardiographic assessment of Valsalva left ventricular outflow tract gradient (VLVOTg) and left ventricular ejection fraction (LVEF). Using population pharmacokinetic/exposure-response modeling and simulations of virtual patients, this in silico study evaluated alternative dose-titration regimens for mavacamten, including regimens that were guided by echocardiographic measures only.

Effects of Omeprazole and Verapamil on the Pharmacokinetics, Safety, and Tolerability of Mavacamten: Two Drug-Drug Interaction Studies in Healthy Participants.

Two open-label, Phase 1 studies assessed the effects of omeprazole (a weak to moderate cytochrome P450 [CYP] 2C19 inhibitor) and verapamil (a moderate CYP3A4 inhibitor) on the pharmacokinetics, safety, and tolerability of mavacamten. In the omeprazole study, healthy participants received mavacamten 15 mg alone or with a 31-day course of omeprazole 20 mg once daily. In the verapamil study, healthy participants received mavacamten 25 mg alone or with a 28-day course of verapamil 240 mg once daily.

Application of the Hartford Hospital Nomogram for Plazomicin Dosing Interval Selection in Patients with Complicated Urinary Tract Infection.

Plazomicin is a new FDA-approved aminoglycoside antibiotic for complicated urinary tract infections (cUTI). In the product labeling, trough-based therapeutic drug management (TDM) is recommended for cUTI patients with renal impairment to prevent elevated trough concentrations associated with serum creatinine increases of ≥0.5 mg/dl above baseline.

A Simulated Application of the Hartford Hospital Aminoglycoside Dosing Nomogram for Plazomicin Dosing Interval Selection in Patients With Serious Infections Caused by Carbapenem-Resistant Enterobacterales.

Purpose: In the Phase III Study of Plazomicin Compared With Colistin in Patients With Infection Due to Carbapenem-Resistant Enterobacteriaceae (CARE), plazomicin was studied for the treatment of critically ill patients with infections caused by carbapenem-resistant Enterobacterales. Initial plazomicin dosing was guided by creatinine clearance (CrCl) and subsequent doses adjusted by therapeutic drug monitoring to achieve AUC exposures within a target range (210-315 mg∙h/L). We applied the Hartford nomogram to evaluate whether this clinical tool could reduce plazomicin troughs levels and increase the proportion of patients within the target AUC range.

Population Pharmacokinetic Analyses for Plazomicin Using Pooled Data from Phase 1, 2, and 3 Clinical Studies.

Plazomicin is an aminoglycoside with activity against multidrug-resistant Plazomicin is dosed on a milligram-per-kilogram-of-body-weight basis and administered by a 30-min intravenous infusion every 24 h, with dose adjustments being made for renal impairment and a body weight (BW) of ≥125% of ideal BW. A population pharmacokinetic analysis was performed to identify patient factors that account for variability in pharmacokinetics and to determine if dose adjustments are warranted based on covariates. The analysis included 143 healthy adults and 421 adults with complicated urinary tract infection (cUTI), acute pyelonephritis, bloodstream infection, or hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia (HABP/VABP) from seven studies (phases 1 to 3).

A Phase 1 Study To Assess the Pharmacokinetics of Intravenous Plazomicin in Adult Subjects with Varying Degrees of Renal Function.

Plazomicin is an FDA-approved aminoglycoside for the treatment of complicated urinary tract infections. In this open-label study, 24 adults with normal renal function or mild, moderate, or severe renal impairment ( = 6 per group) received a single 7.5-mg/kg of body weight dose of plazomicin as a 30-min intravenous infusion.

Telavancin and hydroxy propyl-beta-cyclodextrin clearance during continuous renal replacement therapy: an in vitro study.

Background/aims: Telavancin is a lipoglycopeptide antimicrobial agent which has been approved in Europe and has been recently FDA approved in the United States. Telavancin's parenteral solution contains hydroxy propyl-beta -cyclodextrin (HP-beta -CD) to enhance its solubility. The disposition of telavancin and HP-beta -CD during continuous renal replacement therapies (CRRT ) has not been previously reported.