Exposure-Response Relationships for Isavuconazole in Patients with Invasive Aspergillosis and Other Filamentous Fungi.

Isavuconazole, the active moiety of the water-soluble prodrug isavuconazonium sulfate, is a triazole antifungal agent for the treatment of invasive fungal infections. The purpose of this analysis was to characterize the isavuconazole exposure-response relationship for measures of efficacy and safety in patients with invasive aspergillosis and infections by other filamentous fungi from the SECURE clinical trial. Two hundred thirty-one patients who received the clinical dosing regimen and had exposure parameters were included in the analysis. The primary drug exposure parameters included were predicted trough steady-state plasma concentrations, predicted trough concentrations after 7 and 14 days of drug administration, and area under the curve estimated at steady state (AUCss). The exposure parameters were analyzed against efficacy endpoints that included all-cause mortality through day 42 in the intent-to-treat (ITT) and modified ITT populations, data review committee (DRC)-adjudicated overall response at end of treatment (EOT), and DRC-adjudicated clinical response at EOT. The safety endpoints analyzed were elevated or abnormal alanine aminotransferase, increased aspartate aminotransferase, and a combination of the two. The endpoints were analyzed using logistic regression models. No statistically significant relationship (P > 0.05) was found between isavuconazole exposure and either efficacy or safety endpoints. The lack of association between exposure and efficacy indicates that the isavuconazole exposures achieved by clinical dosing were appropriate for treating the infecting organisms in the SECURE study and that increases in alanine or aspartate aminotransferase were not related to increase in exposures. Without a clear relationship, there is no current clinical evidence for recommending routine therapeutic drug monitoring for isavuconazole.

Phase I trial to investigate the effect of renal impairment on isavuconazole pharmacokinetics.

PURPOSE: The purpose of the study is to evaluate the effect of renal impairment (RI) and end-stage renal disease (ESRD) on the pharmacokinetics (PK) of isavuconazole and the inactive cleavage product, BAL8728. METHODS: A single intravenous dose of the prodrug isavuconazonium sulfate (372 mg, equivalent to 200 mg isavuconazole and 75 mg of BAL8728 cleavage product) was administered to healthy controls (parts 1 and 2) and participants with mild, moderate, or severe RI (part 2) or ESRD (part 1); ESRD participants received two doses of 200 mg isavuconazole, 1 h post-dialysis (day 1) and prior to dialysis (day 15). Plasma PK parameters for isavuconazole included maximum concentration (C max), area under the concentration-time curve (AUC) from time of dose to 72 h (AUC72), AUC extrapolated to infinity (AUC∞), AUC to last measurable concentration (AUClast), half-life (t ½ h), volume of distribution (V z), and total clearance (CL), for the healthy control group versus those with mild, moderate, or severe RI or ESRD. RESULTS: Isavuconazole C max values were 4% higher in mild RI and 7, 14, and 21% lower in participants with moderate RI, severe RI, or ESRD versus the healthy control group, respectively. When hemodialysis occurred post-dose (day 15), participants with ESRD had a 30% increase in AUC72 for isavuconazole in parallel with reduction of extracellular volume induced by dialysis. Exposure (AUC∞ and AUClast) was not significantly different for participants with mild, moderate, or severe RI versus healthy controls although there was considerable variability. The t1/2 (day 1) was 125.5 ± 63.6 h (healthy control group), 204.5 ± 82.6 h (ESRD group) in part 1, and 140.5 ± 77.7 h (healthy control group), 117.0 ± 66.2 h (mild RI), 158.5 ± 56.4 h (moderate RI), and 145.8 ± 65.8 L/h (severe RI) in part 2. CL was 2.4 ± 0.8 L/h (healthy control group) and 2.9 ± 1.3 L/h (ESRD group) in part 1 and 2.4 ± 1.2 L/h (healthy control group), 2.5 ± 1.0 L/h (mild RI), 2.2 ± 0.8 L/h (moderate RI), and 2.4 ± 0.8 L/h (severe RI) in part 2. The V z was 382.6 ± 150.6 L in the healthy control group and 735.6 ± 277.3 L in ESRD patients on day 1 in part 1 of the study. In part 2 of the study, V z was 410.8 ± 89.7 L in the healthy control group, 341.6 ± 72.3 L in mild RI, 509.1 ± 262.2 L in moderate RI, and 439.4 L in severe RI. CONCLUSIONS: Based on the findings of this study, dose adjustments of isavuconazole are unlikely to be required in individuals with RI or in those with ESRD who receive hemodialysis.

Isavuconazole Population Pharmacokinetic Analysis Using Nonparametric Estimation in Patients with Invasive Fungal Disease (Results from the VITAL Study).

Isavuconazonium sulfate (Cresemba; Astellas Pharma Inc.), a water-soluble prodrug of the triazole antifungal agent isavuconazole, is available for the treatment of invasive aspergillosis (IA) and invasive mucormycosis. A population pharmacokinetic (PPK) model was constructed using nonparametric estimation to compare the pharmacokinetic (PK) behaviors of isavuconazole in patients treated in the phase 3 VITAL open-label clinical trial, which evaluated the efficacy and safety of the drug for treatment of renally impaired IA patients and patients with invasive fungal disease (IFD) caused by emerging molds, yeasts, and dimorphic fungi. Covariates examined were body mass index (BMI), weight, race, impact of estimated glomerular filtration rate (eGFR) on clearance (CL), and impact of weight on volume. PK parameters were compared based on IFD type and other patient characteristics. Simulations were performed to describe the MICs covered by the clinical dosing regimen. Concentrations (n = 458) from 136 patients were used to construct a 2-compartment model (first-order absorption compartment and central compartment). Weight-related covariates affected clearance, but eGFR did not. PK parameters and intersubject variability of CL were similar across different IFD groups and populations. Target attainment analyses demonstrated that the clinical dosing regimen would be sufficient for total drug area under the concentration-time curve (AUC)/MIC targets ranging from 50.5 for Aspergillus spp. (up to the CLSI MIC of 0.5 mg/liter) to 270 and 5,053 for Candida albicans (up to MICs of 0.125 and 0.004 mg/liter, respectively) and 312 for non-albicans Candida spp. (up to a MIC of 0.125 mg/liter). The estimations for Candida spp. were exploratory considering that no patients with Candida infections were included in the current analyses. (The VITAL trial is registered at ClinicalTrials.gov under number NCT00634049.).

Concomitant tacrolimus and micafungin pharmacokinetics in healthy volunteers.

Tacrolimus is an approved immunosuppressive agent and a known substrate for CYP3A. Micafungin is an echinocandin antifungal agent and a mild inhibitor of CYP3A metabolism in vitro. The objectives of this study were to evaluate the pharmacokinetics of tacrolimus (5 mg oral) and micafungin (100 mg intravenous) alone and with concomitant administration (n=26). Tacrolimus area under the concentration-time curve was 298+/-135 microg*h/L when tacrolimus was administered alone, 305+/-129 microg*h/L (P=.8; confidence interval 89%, 118%) when tacrolimus was given with single-dose micafungin, and 282+/-138 microg*h/L (P=.4; confidence interval 82%, 107%) when tacrolimus was given with steady-state micafungin. Despite the mild inhibition of CYP3A in vitro by micafungin, there does not appear to be a drug interaction with tacrolimus and micafungin either with single-dose or steady-state micafungin administration.

Concomitant cyclosporine and micafungin pharmacokinetics in healthy volunteers.

Cyclosporine is a marketed immunosuppressive agent and a known substrate for CYP3A. Micafungin is an antifungal agent and a mild inhibitor of CYP3A-mediated metabolism in vitro. The objectives of this study were to evaluate the pharmacokinetics of cyclosporine and micafungin before and with concomitant administration. The pharmacokinetics of single-dose oral cyclosporine (5 mg/kg) were estimated on days 1, 9, and 15 (n = 27). Subjects received micafungin (100 mg/d over 1 hour) on days 7, 9, and 11 through 15. Micafungin pharmacokinetics were estimated on days 7, 9, and 15. Mean apparent oral cyclosporine clearances were estimated to be 645+/-236 mL/h/kg, 546+/-101 mL/h/kg (P = .01), and 540+/-104 mL/h/kg (P = .02) for days 1, 9, and 15, respectively. Micafungin appears to be a mild inhibitor of cyclosporine metabolism.

Pharmacokinetics of micafungin in healthy volunteers, volunteers with moderate liver disease, and volunteers with renal dysfunction.

Micafungin is an antifungal agent metabolized by arylsulfatase with secondary metabolism by catechol-O-methyltransferase. The objectives of this study were to estimate the pharmacokinetic parameters and plasma protein binding of micafungin in volunteers with moderate hepatic dysfunction (n = 8), volunteers with creatinine clearance < 30 mL/min (n = 9), and matched controls (n = 8 and n = 9, respectively). Single-dose micafungin pharmacokinetics were estimated using noncompartmental techniques. There was a statistically lower area under the observed micafungin concentration-time curve (AUC) from time 0 to infinity for subjects with moderate hepatic dysfunction as compared to control subjects (97.5 +/- 19 microg.h/mL vs 125.9 +/- 26.4 microg.h/mL, P = .03), although there was no difference in micafungin weight-adjusted clearance (10.9 +/- 1.7 mL/h/kg vs 9.8 +/- 1.8 mL/h/kg, P = .2). The difference in area under the concentration-time curve may be explained by the differences in body weight between subjects and controls. Renal dysfunction did not alter micafungin pharmacokinetics.

The effect of moderate hepatic impairment on the pharmacokinetics of ipragliflozin, a novel sodium glucose co-transporter 2 (SGLT2) inhibitor.

BACKGROUND: Ipragliflozin (ASP1941), a potent selective sodium glucose co-transporter 2 inhibitor, is in development for the treatment of type 2 diabetes mellitus. Ipragliflozin is primarily eliminated via conjugation by the liver as five pharmacologically inactive metabolites (M1, M2, M3, M4 and M6). This study evaluated the effect of moderate hepatic impairment on the pharmacokinetics of ipragliflozin and its metabolites. METHODS: In an open-label, single-dose, parallel-group study, 16 subjects (eight with moderate hepatic impairment [Child-Pugh score 7-9] and eight healthy, matched controls) received a single oral dose of 100-mg ipragliflozin. Plasma concentrations of ipragliflozin and its metabolites were determined. Adverse events (AEs) and other clinical laboratory parameters were monitored. RESULTS: All subjects completed the study. Least-squares geometric mean ratios (GMRs) (90 % confidence interval [CI]) for maximum plasma concentration (C max) and area under the plasma concentration-time curve from time zero to infinity (AUC∞) of ipragliflozin were 127 % (93-173 %) and 125 % (94-166 %), respectively, in moderate hepatic impairment versus controls. No changes in elimination half-life and protein binding of ipragliflozin were observed in moderate hepatic impairment subjects. Least-squares GMRs for C max and AUC∞ of M2, the major metabolite, were respectively 95 % (68-133 %) and 100 % (77-130 %) in moderate hepatic impairment versus controls. No deaths, other serious AEs or AEs leading to discontinuation occurred. CONCLUSIONS: Moderate hepatic impairment had no clinically relevant effects on the single-dose pharmacokinetics of ipragliflozin and its major metabolite, M2. A single oral dose of ipragliflozin, 100 mg, was well tolerated in both healthy subjects and those with moderate hepatic impairment.

Population pharmacokinetics of vernakalant hydrochloride injection (RSD1235) in patients with atrial fibrillation or atrial flutter.

Vernakalant hydrochloride is a novel, predominantly atrial-selective antiarrhythmic drug that effectively and rapidly terminates atrial fibrillation (AF). Plasma vernakalant concentration data from 5 phase 2 and 3 clinical trials of vernakalant in patients with AF or atrial flutter and a phase 1 study in healthy volunteers were used to construct a population pharmacokinetic model. Plasma vernakalant concentration-time data were best fit by a 2-compartment mammillary model, with rapid first-order elimination from the central compartment. Median systemic clearance was 0.35 L/h/kg (or 28 L/h for an 80-kg patient), with intersubject variability estimated to be 40%. Clearance was significantly influenced by CYP2D6 genotype, age, serum creatinine concentration, and subject status (patient vs volunteer). The intercompartmental clearance was also influenced by subject status, whereas the volumes of the central compartment and peripheral compartment were unaffected by any covariates. Based on the final pharmacokinetic model, the area under the plasma vernakalant concentration-time curve from 0 to 90 minutes was estimated to be 15% higher in CYP2D6 poor metabolizers than extensive metabolizers, with age and serum creatinine having much smaller influences on exposure. These data suggest that dose adjustments based on patient characteristics, including use of concomitant drugs, are unnecessary for intravenous vernakalant.