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. Herein, the utility of the Hartford nomogram to prevent plazomicin trough concentrations exceeding the TDM trough of 3 µg/ml and optimize the area under the curve (AUC) was assessed. The AUC reference range was defined as the 5th to 95th percentile AUC observed in the phase 3 cUTI trial (EPIC) (121 to 368 µg · h/ml). Observed 10-h plazomicin concentrations from patients in EPIC (n = 281) were plotted on the nomogram to determine an eligible dosing interval (every 24 h [q24h], q36h, q48h). Based on creatinine clearance (CLcr), a 15- or 10-mg/kg of body weight dose was simulated with the nomogram-derived interval. The nomogram recommended an extended interval (q36h and q48h) in 31% of patients. Compared with the 15 mg/kg q24h regimen received by patients with CLcr of ≥60 ml/min in EPIC, the nomogram-derived interval reduced the proportion of patients with troughs of ≥3 µg/ml (q36h, 27% versus 0%, P = 0.021; q48h, 57% versus 0%, P = 0.002) while significantly increasing the number of patients within the AUC range. Compared with the 8 to 12 mg/kg q24h regimen (received by patients with CLcr of >30 to 59 ml/min in EPIC), the nomogram-derived interval significantly reduced the proportion of troughs of ≥3µg/ml in the q48h cohort (72% versus 0%, P < 0.001) while maintaining a similar proportion of patients in the AUC range. Simulated application of the Hartford nomogram optimized plazomicin exposures in patients with cUTI while reducing troughs to <3 µg/ml.

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 Enterobacteriaceae 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 three-compartment structural pharmacokinetic model with a zero-order rate constant for the intravenous infusion and linear first-order elimination kinetics best described the plasma concentration-time profiles. The base structural model included creatinine clearance (CLCR) as a time-varying covariate for clearance. The covariates included age, BW, height, body surface area, body mass index, sex, race, and disease-related factors. The ranges of the α-, ß-, and γ-phase half-lives for the analysis population were 0.328 to 1.58, 2.77 to 5.38, and 25.8 to 36.5 h, respectively. Total and renal clearances in a typical cUTI or HABP/VABP patient were 4.57 and 4.08 liters/h, respectively. Starting dose adjustments for CLCR are sufficient for minimizing the variation in plasma exposure across patient populations; adjustments based on other covariates are not warranted. The results support initial dosing on a milligram-per-kilogram basis with adjustments for CLCR and BW. Subsequent adjustments based on therapeutic drug management are recommended in certain subsets of patients, including the critically ill and renally impaired.

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 (n = 6 per group) received a single 7.5-mg/kg of body weight dose of plazomicin as a 30-min intravenous infusion. Total clearance declined with renal impairment, resulting in 1.98-fold and 4.42-fold higher plazomicin exposures, as measured by the area under the concentration-time curve from 0 h to infinity, in subjects with moderate and severe impairment, respectively, than in subjects with normal renal function. (This study has been registered at ClinicalTrials.gov under identifier NCT01462136.).

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. Mavacamten exposure-response models for VLVOTg (efficacy) and LVEF (safety) were developed using patient data from five clinical studies and characterized using nonlinear mixed-effects models. Simulations of five echocardiography-guided regimens were performed in virtual cohorts constructed based on either expected or equal population distributions of cytochrome P450 2C19 (CYP2C19) metabolizer phenotypes. Each regimen aimed to maximize the proportions of patients who achieved a VLVOTg below 30 mm Hg while maintaining LVEF above 50% over 40 weeks and 104 weeks, respectively. The exposure-response models successfully characterized mavacamten efficacy and safety parameters. Overall, the simulated regimen with the optimal benefit-risk profile across CYP2C19 phenotypes had steps for down-titration at weeks 4 and 8 (for VLVOTg <20 mm Hg), and up-titration at week 12 (for VLVOTg ≥30 mm Hg and LVEF ≥55%), and every 12 weeks thereafter. This simulation-optimized regimen is recommended in the mavacamten US prescribing information.

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. Evaluable participants were those who had at least one mavacamten concentration measurement with associated sampling time and dosing information. The base model included key covariates: body weight, cytochrome P450 isozyme 2C19 (CYP2C19) phenotype with respect to PK, and formulation. The final model was generated using stepwise covariate testing and refinement processes. Simulations were performed to evaluate PK: apparent clearance (CL/F); apparent central and peripheral volumes of distribution; and steady-state average, trough, and maximum concentrations. Overall, 9244 measurable PK observations from 497 participants were included. A two-compartment model structure was selected. After stepwise covariate model building and refinement, additional covariates included were: specified mavacamten dose, omeprazole or esomeprazole administration, health/disease status, estimated glomerular filtration rate, fed status, and sex. The final PopPK model accurately characterized mavacamten concentrations. At any given dose, CYP2C19 phenotype was the most influential covariate on exposure parameters (e.g., median CL/F was reduced by 72% in CYP2C19:poor metabolizers compared with the reference participant [CYP2C19:normal metabolizer]). CL/F was also approximately 16% higher in women than in men but lower in participants receiving concomitant omeprazole or esomeprazole (by 33% and 42%, respectively) than in participants not receiving such concomitant therapy.

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. In the omeprazole study, 27 of 29 randomized participants completed the study. Nine participants receiving mavacamten alone were normal metabolizers (NMs) of CYP2C19 substrates, and 6 were rapid metabolizers; 8 NMs and 6 rapid metabolizers received mavacamten + omeprazole. In both studies, mavacamten showed no safety signals and was generally well tolerated. Overall mavacamten exposure (area under the plasma concentration-time curve) increased by approximately 50% with omeprazole coadministration; maximum observed concentration (Cmax ), time to Cmax , and elimination half-life were not affected appreciably. In the verapamil study, 25 of 26 randomized participants received the study drug(s) and were included in the pharmacokinetic analyses; 24 completed the study. In the pharmacokinetic population, 12 participants received mavacamten alone (11 NMs, 1 poor metabolizer) and 13 received mavacamten + verapamil (7 NMs, 4 intermediate metabolizers, 2 poor metabolizers). Following verapamil coadministration in NMs and intermediate metabolizers, mavacamten area under the plasma concentration-time curve was minimally increased (by less than 20%), and Cmax was modestly increased (by 52%). These results suggest that mavacamten can be coadministered with weak CYP2C19 and moderate CYP3A4 inhibitors.

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. METHODS: The transmembrane clearances (CLtm ) of telavancin and HP-beta -CD during continuous hemofiltration and hemodialysis were assessed using an in vitro bovine blood model with AN69 and polysulfone hemodiafilters at varying ultrafiltrate and dialysate flow rates (1, 2, 3, & 6 l/hr). RESULTS: The mean telavancin sieving coefficient ranged from 0.25 to 0.31 during continuous hemofiltration. At all ultrafiltration rates, no differences were observed in telavancin CLtm between the two hemodiafilter types. For continuous hemodialysis, mean telavancin saturation coefficients ranged from 0.10 to 0.43 and CLtm tended to be higher for the polysulfone hemodiafilter than the AN69 hemodiafilter, especially at higher flow rates. Mean HP-beta -CD sieving coefficients ranged from 0.63 to 1.03 and saturation coefficients from 0.63 to 1.38, resulting in a CLtm that was similar to ultrafiltrate and dialysate flow rates. CONCLUSION: Telavancin CLtm is dependent on hemodiafilter type, dialysate and ultrafiltration rates. CRRT with high ultrafiltrate or dialysate rates may result in sufficient telavancin clearance to alter telavancin dosing. HP-beta -CD clearance by continuous hemodialysis or continuous hemofiltration is substantial and may be sufficient to prevent HP-beta -CD accumulation in subjects receiving CRRT . Pharmacokinetic studies conducted in patients receiving CRRT and telavancin are needed to confirm these in vitro findings.

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 AUC0-24 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. METHODS: Thirty-seven patients enrolled in cohorts 1 or 2 of CARE were eligible for analyses. Observed 10-hour concentrations after the initial dose were plotted on the Hartford nomogram to determine an eligible dosing interval group (q24h, q36h or q48h). On the basis of baseline CrCl, a 15- or 10-mg/kg dose was simulated with the nomogram-recommended dosing interval. The proportion of patients in each dosing interval group with a trough ≥3 mg/L (trough threshold associated with serum creatinine increases ≥0.5 mg/dL in product label) was quantified. Simulated interval-normalized AUC0-24 was compared with the target AUC range. FINDINGS: Among the 28 patients with a CrCl ≥60 mL/min, the nomogram recommended every-24-hour dosing in 61% and an extended-interval (q36h or q48h) in 39% of patients. For patients with a CrCl ≥30-59 mL/min (n = 9), the nomogram recommended every-24-hour dosing and an extended-interval in 22% and 78% of patients, respectively. Among both renal function cohorts, exposure simulation with the nomogram significantly reduced the proportion of patients with trough concentrations ≥3 mg/L (CrCl ≥60 mL/min cohort: 91% vs 9%, P < 0.001; CrCl ≥30-59 mL/min cohort, 100% vs 0%, P < 0.001). Relative to the observed mean (SD) AUC0-24 of 309 mg∙h/mL (96 mg∙h/mL), simulation of extended intervals resulted in a mean interval-normalized AUC0-24 of 210 mg∙h/mL (40 mg∙h/mL) in all patients eligible for an extended interval, resulting in a similar proportion (49% vs 54%) of patients within the target AUC0-24 range after the first dose. IMPLICATIONS: Application of the Hartford nomogram successfully reduced the likelihood of elevated plazomicin trough concentrations while improving AUC exposures in these patients with carbapenem-resistant Enterobacterales infections.