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Amit Desai - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetics and bioequivalence of isavuconazole administered as Isavuconazonium sulfate intravenous solution via nasogastric tube or orally in healthy subjects
Antimicrobial Agents and Chemotherapy, 2021Co-Authors: Amit Desai, Ronald Goldwater, Melanie Helmick, Nakyo Hoe, Selina Moy, Stephen Stanhope, Nancy MartinAbstract:For critically ill patients with invasive fungal infections, administration of Isavuconazonium sulfate (ISAVUSULF) via nasogastric (NG) tube can be an alternative route of drug administration. This was a randomized, open-label, 2-period, 2-sequence single-dose crossover study comparing single doses of 372 mg ISAVUSULF intravenous (IV) solution via NG tube (test formulation) to 372 mg ISAVUSULF capsules for oral administration (reference formulation) in healthy male and female subjects. A single dose of ISAVUSULF was administered under fasting conditions on Day 1 of each period, with a washout of 30 days between each period. Pharmacokinetic (PK) samples were collected predose through Day 21. Standard safety and tolerability assessments were conducted in each period. The analysis of variance estimate of the study population demonstrates that the isavuconazole IV NG tube administration Geometric least squares (LS) mean values of the observed maximum concentration (Cmax), area under the plasma concentration-time curve (AUC) to the last measurable concentration (AUClast), AUC to time infinity (AUCinf), and AUC from start of dosing to 72 hours (AUC72) were 105.3%, 97.6%, 99.3% and 97.8%, respectively, of the corresponding oral administration values. The Geometric LS mean ratio and 90% confidence intervals for the PK parameters were completely contained within the prespecified limits of 80% to 125%. There were no deaths or serious adverse events that led to the withdrawal of treatment during the study. The study met its primary endpoint of bioequivalence between the two routes of administration. Both routes of administration were well tolerated.
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two phase 1 open label mass balance studies to determine the pharmacokinetics of 14c labeled Isavuconazonium sulfate in healthy male volunteers
Clinical pharmacology in drug development, 2018Co-Authors: Robert Townsend, Shahzad Akhtar, Donna Kowalski, Takao Yamazaki, Kota Kato, Christine Hale, Christopher Lademacher, Amit DesaiAbstract:Isavuconazonium sulfate is the water-soluble prodrug of the active triazole isavuconazole. Two phase 1 studies were conducted to identify the metabolic profile and mass balance of isavuconazole and BAL8728 (inactive cleavage product). Seven subjects in study 1 (isavuconazole mass balance) received a single oral dose of [cyano-14 C]Isavuconazonium sulfate corresponding to 200 mg isavuconazole. Six subjects in study 2 (BAL8728 mass balance) received a single intravenous dose of [pyridinylmethyl-14 C]Isavuconazonium sulfate corresponding to 75 mg BAL8728. Pharmacokinetic parameters of radioactivity in whole blood and plasma and of isavuconazole and BAL8728 in plasma were assessed. Radioactivity ratio of blood/plasma, percentage of dose, and cumulative percentage of radioactive dose recovered in urine and feces for isavuconazole and BAL8728 were assessed. Metabolic profiling was carried out by high-performance liquid chromatography and mass spectrometry. Mean plasma isavuconazole pharmacokinetic parameters included apparent clearance (2.3 ± 0.7 L/h), apparent volume of distribution (301.8 ± 105.7 L), and terminal elimination half-life (99.9 ± 44.6 hours). In study 1, isavuconazole-derived radioactivity was recovered approximately equally in urine and feces (46.1% and 45.5%, respectively). In study 2, BAL8728-derived radioactivity was predominantly recovered in urine (96.0%). Isavuconazole (study 1) and M4 (cleavage metabolite of BAL8728; study 2) were the predominant circulating components of radioactivity in plasma.
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exposure response relationships for isavuconazole in patients with invasive aspergillosis and other filamentous fungi
Antimicrobial Agents and Chemotherapy, 2017Co-Authors: Amit Desai, Salim Mujais, Robert Townsend, Laura L Kovanda, William W Hope, Donna Kowalski, David R Andes, Johan W Mouton, Peter L BonateAbstract:textabstractIsavuconazole, 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.
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pharmacokinetic effects of isavuconazole coadministration with the cytochrome p450 enzyme substrates bupropion repaglinide caffeine dextromethorphan and methadone in healthy subjects
Clinical pharmacology in drug development, 2017Co-Authors: Takao Yamazaki, Amit Desai, Shahzad Akhtar, Donna Kowalski, Helene Pearlman, Christopher Lademacher, Ronald Goldwater, David Han, Corrie Howieson, Diane RammelsbergAbstract:This report describes phase 1 clinical trials performed to assess interactions of oral isavuconazole at the clinically targeted dose (200 mg, administered as Isavuconazonium sulfate 372 mg, 3 times a day for 2 days; 200 mg once daily [QD] thereafter) with single oral doses of the cytochrome P450 (CYP) substrates: bupropion hydrochloride (CYP2B6; 100 mg; n = 24), repaglinide (CYP2C8/CYP3A4; 0.5 mg; n = 24), caffeine (CYP1A2; 200 mg; n = 24), dextromethorphan hydrobromide (CYP2D6/CYP3A4; 30 mg; n = 24), and methadone (CYP2B6/CYP2C19/CYP3A4; 10 mg; n = 23). Compared with each drug alone, coadministration with isavuconazole changed the area under the concentration-time curves (AUC∞) and maximum concentrations (Cmax) as follows: bupropion, AUC∞ reduced 42%, Cmax reduced 31%; repaglinide, AUC∞ reduced 8%, Cmax reduced 14%; caffeine, AUC∞ increased 4%, Cmax reduced 1%; dextromethorphan, AUC∞ increased 18%, Cmax increased 17%; R-methadone, AUC∞ reduced 10%, Cmax increased 3%; S-methadone, AUC∞ reduced 35%, Cmax increased 1%. In all studies, there were no deaths, 1 serious adverse event (dextromethorphan study; perioral numbness, numbness of right arm and leg), and adverse events leading to study discontinuation were rare. Thus, isavuconazole is a mild inducer of CYP2B6 but does not appear to affect CYP1A2-, CYP2C8-, or CYP2D6-mediated metabolism.
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population pharmacokinetics of isavuconazole from phase 1 and phase 3 secure trials in adults and target attainment in patients with invasive infections due to aspergillus and other filamentous fungi
Antimicrobial Agents and Chemotherapy, 2016Co-Authors: Amit Desai, Robert Townsend, Laura L Kovanda, Donna Kowalski, Peter L BonateAbstract:Isavuconazole, the active moiety of the water-soluble prodrug Isavuconazonium sulfate, is a triazole antifungal agent used for the treatment of invasive fungal infections. The objective of this analysis was to develop a population pharmacokinetic (PPK) model to identify covariates that affect isavuconazole pharmacokinetics and to determine the probability of target attainment (PTA) for invasive aspergillosis patients. Data from nine phase 1 studies and one phase 3 clinical trial (SECURE) were pooled to develop the PPK model (NONMEM, version 7.2). Stepwise covariate modeling was performed in Perl-speaks-NONMEM, version 3.7.6. The area under the curve (AUC) at steady state was calculated for 5,000 patients by using Monte Carlo simulations. The PTA using the estimated pharmacodynamic (PD) target value (total AUC/MIC ratio) estimated from in vivo PD studies of invasive aspergillosis over a range of MIC values was calculated using simulated patient AUC values. A two-compartment model with a Weibull absorption function and a first-order elimination process adequately described plasma isavuconazole concentrations. The mean estimate for isavuconazole clearance was 2.360 liters/h (percent coefficient of variation [%CV], 34%), and the mean AUC from 0 to 24 h (AUC0-24) was ∼100 mg·h/liter. Clearance was approximately 36% lower in Asians than in Caucasians. The PTA calculated over a range of MIC values by use of the nonneutropenic murine efficacy index corresponding to 90% survival indicated that adequate isavuconazole exposures were achieved in >90% of simulated patients to treat infections with MICs up to and including 1 mg/liter according to European Committee on Antimicrobial Susceptibility Testing methodology and in >90% of simulated patients for infections with MICs up to and including 0.5 mg/liter according to Clinical and Laboratory Standards Institute methodology. The highest MIC result for PTA was the same for Caucasian and Asian patients.
William W Hope - One of the best experts on this subject based on the ideXlab platform.
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efficacy and associated drug exposures of isavuconazole and fluconazole in an experimental model of coccidioidomycosis
Antimicrobial Agents and Chemotherapy, 2021Co-Authors: Laura L Kovanda, William W Hope, Gabriele Sass, Marife Martinez, Karl V Clemons, Hasan Nazik, Therese M Kitt, Nathan P Wiederhold, David A StevensAbstract:Coccidioides spp. are important pathogens in endemic regions and new treatment options are needed. Isavuconazonium sulfate (ISAVUSULF) and fluconazole (FLU) were evaluated in experimental disseminated coccidioidomycosis to characterize drug exposures associated with efficacy.Macrobroth dilution was performed on Coccidioides isolates to measure minimal effective concentrations (MEC) and minimal fungicidal concentrations (MFC). Mice were inoculated with Coccidioides posadasii (Silveira strain). Treatment started 4 days post-inoculation. (Model 1) Mice were treated 19 days plus 30-day off-therapy observation, measuring survival through day 49 and residual fungal burden. Treatments included ISAVUSULF (prodrug: 186, 279, or 372 mg/kg twice-daily), FLU (20 or 100 mg/kg once-daily), and untreated. Model 2 included 7-day treatment with ISAVUSULF (prodrug: 74.4, 111.6, or 148.8 mg/kg twice-daily), FLU (20 or 100 mg/kg once-daily), and untreated. Serial plasma and tissues samples were obtained for PK and fungal burden measurement, respectively.MEC50 were 0.39 mg/L (ISAV) and 12.5 mg/L (FLU). Treatment with ISAVUSULF186 or both FLU doses resulted in higher survival compared to untreated. Treatment with ISAVUSULF 186 or 279 mg/kg twice-daily or FLU 100 mg/kg reduced fungal burden in all organs (Model 1). In model 2, >1 log10 CFU/organ reduction was demonstrated, with ISAV AUCs achieved with 111.6 mg/kg twice-daily (56.8 mg•h/L), in the spleen and liver. FLU AUCs, 100 and 500 mg•h/L, for 20 and 100 mg/kg doses, respectively, resulted in >1 log10 CFU/organ mean reduction in all organs.ISAVUSULF and FLU improved survival and reduced fungal burden. Increasing plasma drug exposures resulted in decreases in fungal burden.
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pharmacodynamics of isavuconazole in a rabbit model of cryptococcal meningoencephalitis
Antimicrobial Agents and Chemotherapy, 2019Co-Authors: Laura L Kovanda, Charles Giamberardino, Laura Mcentee, Dena L Toffaletti, Kelly S Franke, Andrew Bartuska, Gordon Smilnak, George C De Castro, Katelyn Ripple, William W HopeAbstract:Cryptococcus spp., important fungal pathogens, are the leading cause of fungus-related mortality in human immunodeficiency virus-infected patients, and new therapeutic options are desperately needed. Isavuconazonium sulfate, a newer triazole antifungal agent, was studied to characterize the exposure-response relationship in a rabbit model of cryptococcal meningoencephalitis. Rabbits treated with Isavuconazonium sulfate were compared with those treated with fluconazole and untreated controls. The fungal burden in the cerebrospinal fluid was measured serially over time, while the yeast concentrations in the brain and the eye (aqueous humor) were determined at the end of therapy. The exposure impact of Isavuconazonium sulfate dosing in the rabbit was linked using mathematical modeling. Similar significant reductions in the fungal burden in the brain and cerebrospinal fluid in rabbits treated with Isavuconazonium sulfate and fluconazole compared with that in the untreated controls were observed. No dose-dependent response was demonstrated with Isavuconazonium sulfate treatment in this study. The treatment of cryptococcal meningoencephalitis with Isavuconazonium sulfate was similar to that with fluconazole. Dose-dependent reductions in yeast over time were not demonstrated, which limited our ability to estimate the pharmacodynamic target. Further nonclinical and clinical studies are needed in order to characterize the extent of the exposure-response relationship in cryptococcal meningoencephalitis. However, this study suggests that Isavuconazonium sulfate, like fluconazole, could be beneficial in the setting of consolidation and maintenance therapy, rather than induction monotherapy, in high-burden cryptococcal meningoencephalitis.
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exposure response relationships for isavuconazole in patients with invasive aspergillosis and other filamentous fungi
Antimicrobial Agents and Chemotherapy, 2017Co-Authors: Amit Desai, Salim Mujais, Robert Townsend, Laura L Kovanda, William W Hope, Donna Kowalski, David R Andes, Johan W Mouton, Peter L BonateAbstract:textabstractIsavuconazole, 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.
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tissue distribution and elimination of isavuconazole following single and repeat oral dose administration of Isavuconazonium sulfate to rats
Antimicrobial Agents and Chemotherapy, 2017Co-Authors: Annehortense Schmitthoffmann, Robert Townsend, William W Hope, Kota Kato, Michael J Potchoiba, David R Andes, Jochen Spickermann, Marlowe J SchneidkrautAbstract:Quantitative whole-body autoradiography was used to assess the distribution and tissue penetration of isavuconazole in rats following single and repeated oral-dose administration of radiolabeled Isavuconazonium sulfate, the prodrug of isavuconazole. Following a single-dose administration of radiolabeled Isavuconazonium sulfate (labeled on the active moiety), radioactivity was detectable within 1 h postdose in 56 of 65 tissue/fluid specimens. The highest maximum concentrations (Cmax) were observed in bile and liver (66.6 and 24.7 μg eq/g, respectively). The lowest Cmax values were in bone and eye lens (0.070 and 0.077 μg eq/g, respectively). By 144 h postdose, radioactivity was undetectable in all tissues/fluids except liver (undetectable at 336 h) and adrenal gland tissues (undetectable at 672 h). Following daily administration for up to 21 days, 1-h-postdose Cmax values were the highest on or before day 14 in all except seven tissues/fluids, of which only rectum mucosa and small intestine mucosa had Cmax values >25% higher than all other 1-h-postdose values. For 24-h-postdose Cmax values, only large intestine, large intestine mucosa, and urine had the highest Cmax values at day 21. The penetration of single oral doses of unlabeled isavuconazole (25 mg/kg of body weight Isavuconazonium sulfate) and voriconazole (50 mg/kg) into rat brain (assessed using liquid chromatography-tandem mass spectrometry) was also compared. Brain concentration/plasma concentration ratios reached approximately 1.8:1 and 2:1, respectively. These data suggest that isavuconazole penetrates most tissues rapidly, reaches a steady state in most or all tissues/fluids within 14 days, does not accumulate in tissues/fluids over time, and achieves potentially efficacious concentrations in the brain.
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isavuconazole population pharmacokinetic analysis using nonparametric estimation in patients with invasive fungal disease results from the vital study
Antimicrobial Agents and Chemotherapy, 2016Co-Authors: Laura L Kovanda, Amit Desai, Robert Townsend, Shahzad Akhtar, Peter L Bonate, William W HopeAbstract: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.).
Robert Townsend - One of the best experts on this subject based on the ideXlab platform.
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two phase 1 open label mass balance studies to determine the pharmacokinetics of 14c labeled Isavuconazonium sulfate in healthy male volunteers
Clinical pharmacology in drug development, 2018Co-Authors: Robert Townsend, Shahzad Akhtar, Donna Kowalski, Takao Yamazaki, Kota Kato, Christine Hale, Christopher Lademacher, Amit DesaiAbstract:Isavuconazonium sulfate is the water-soluble prodrug of the active triazole isavuconazole. Two phase 1 studies were conducted to identify the metabolic profile and mass balance of isavuconazole and BAL8728 (inactive cleavage product). Seven subjects in study 1 (isavuconazole mass balance) received a single oral dose of [cyano-14 C]Isavuconazonium sulfate corresponding to 200 mg isavuconazole. Six subjects in study 2 (BAL8728 mass balance) received a single intravenous dose of [pyridinylmethyl-14 C]Isavuconazonium sulfate corresponding to 75 mg BAL8728. Pharmacokinetic parameters of radioactivity in whole blood and plasma and of isavuconazole and BAL8728 in plasma were assessed. Radioactivity ratio of blood/plasma, percentage of dose, and cumulative percentage of radioactive dose recovered in urine and feces for isavuconazole and BAL8728 were assessed. Metabolic profiling was carried out by high-performance liquid chromatography and mass spectrometry. Mean plasma isavuconazole pharmacokinetic parameters included apparent clearance (2.3 ± 0.7 L/h), apparent volume of distribution (301.8 ± 105.7 L), and terminal elimination half-life (99.9 ± 44.6 hours). In study 1, isavuconazole-derived radioactivity was recovered approximately equally in urine and feces (46.1% and 45.5%, respectively). In study 2, BAL8728-derived radioactivity was predominantly recovered in urine (96.0%). Isavuconazole (study 1) and M4 (cleavage metabolite of BAL8728; study 2) were the predominant circulating components of radioactivity in plasma.
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exposure response relationships for isavuconazole in patients with invasive aspergillosis and other filamentous fungi
Antimicrobial Agents and Chemotherapy, 2017Co-Authors: Amit Desai, Salim Mujais, Robert Townsend, Laura L Kovanda, William W Hope, Donna Kowalski, David R Andes, Johan W Mouton, Peter L BonateAbstract:textabstractIsavuconazole, 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.
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tissue distribution and elimination of isavuconazole following single and repeat oral dose administration of Isavuconazonium sulfate to rats
Antimicrobial Agents and Chemotherapy, 2017Co-Authors: Annehortense Schmitthoffmann, Robert Townsend, William W Hope, Kota Kato, Michael J Potchoiba, David R Andes, Jochen Spickermann, Marlowe J SchneidkrautAbstract:Quantitative whole-body autoradiography was used to assess the distribution and tissue penetration of isavuconazole in rats following single and repeated oral-dose administration of radiolabeled Isavuconazonium sulfate, the prodrug of isavuconazole. Following a single-dose administration of radiolabeled Isavuconazonium sulfate (labeled on the active moiety), radioactivity was detectable within 1 h postdose in 56 of 65 tissue/fluid specimens. The highest maximum concentrations (Cmax) were observed in bile and liver (66.6 and 24.7 μg eq/g, respectively). The lowest Cmax values were in bone and eye lens (0.070 and 0.077 μg eq/g, respectively). By 144 h postdose, radioactivity was undetectable in all tissues/fluids except liver (undetectable at 336 h) and adrenal gland tissues (undetectable at 672 h). Following daily administration for up to 21 days, 1-h-postdose Cmax values were the highest on or before day 14 in all except seven tissues/fluids, of which only rectum mucosa and small intestine mucosa had Cmax values >25% higher than all other 1-h-postdose values. For 24-h-postdose Cmax values, only large intestine, large intestine mucosa, and urine had the highest Cmax values at day 21. The penetration of single oral doses of unlabeled isavuconazole (25 mg/kg of body weight Isavuconazonium sulfate) and voriconazole (50 mg/kg) into rat brain (assessed using liquid chromatography-tandem mass spectrometry) was also compared. Brain concentration/plasma concentration ratios reached approximately 1.8:1 and 2:1, respectively. These data suggest that isavuconazole penetrates most tissues rapidly, reaches a steady state in most or all tissues/fluids within 14 days, does not accumulate in tissues/fluids over time, and achieves potentially efficacious concentrations in the brain.
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population pharmacokinetics of isavuconazole from phase 1 and phase 3 secure trials in adults and target attainment in patients with invasive infections due to aspergillus and other filamentous fungi
Antimicrobial Agents and Chemotherapy, 2016Co-Authors: Amit Desai, Robert Townsend, Laura L Kovanda, Donna Kowalski, Peter L BonateAbstract:Isavuconazole, the active moiety of the water-soluble prodrug Isavuconazonium sulfate, is a triazole antifungal agent used for the treatment of invasive fungal infections. The objective of this analysis was to develop a population pharmacokinetic (PPK) model to identify covariates that affect isavuconazole pharmacokinetics and to determine the probability of target attainment (PTA) for invasive aspergillosis patients. Data from nine phase 1 studies and one phase 3 clinical trial (SECURE) were pooled to develop the PPK model (NONMEM, version 7.2). Stepwise covariate modeling was performed in Perl-speaks-NONMEM, version 3.7.6. The area under the curve (AUC) at steady state was calculated for 5,000 patients by using Monte Carlo simulations. The PTA using the estimated pharmacodynamic (PD) target value (total AUC/MIC ratio) estimated from in vivo PD studies of invasive aspergillosis over a range of MIC values was calculated using simulated patient AUC values. A two-compartment model with a Weibull absorption function and a first-order elimination process adequately described plasma isavuconazole concentrations. The mean estimate for isavuconazole clearance was 2.360 liters/h (percent coefficient of variation [%CV], 34%), and the mean AUC from 0 to 24 h (AUC0-24) was ∼100 mg·h/liter. Clearance was approximately 36% lower in Asians than in Caucasians. The PTA calculated over a range of MIC values by use of the nonneutropenic murine efficacy index corresponding to 90% survival indicated that adequate isavuconazole exposures were achieved in >90% of simulated patients to treat infections with MICs up to and including 1 mg/liter according to European Committee on Antimicrobial Susceptibility Testing methodology and in >90% of simulated patients for infections with MICs up to and including 0.5 mg/liter according to Clinical and Laboratory Standards Institute methodology. The highest MIC result for PTA was the same for Caucasian and Asian patients.
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isavuconazole population pharmacokinetic analysis using nonparametric estimation in patients with invasive fungal disease results from the vital study
Antimicrobial Agents and Chemotherapy, 2016Co-Authors: Laura L Kovanda, Amit Desai, Robert Townsend, Shahzad Akhtar, Peter L Bonate, William W HopeAbstract: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.).
Laura L Kovanda - One of the best experts on this subject based on the ideXlab platform.
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efficacy and associated drug exposures of isavuconazole and fluconazole in an experimental model of coccidioidomycosis
Antimicrobial Agents and Chemotherapy, 2021Co-Authors: Laura L Kovanda, William W Hope, Gabriele Sass, Marife Martinez, Karl V Clemons, Hasan Nazik, Therese M Kitt, Nathan P Wiederhold, David A StevensAbstract:Coccidioides spp. are important pathogens in endemic regions and new treatment options are needed. Isavuconazonium sulfate (ISAVUSULF) and fluconazole (FLU) were evaluated in experimental disseminated coccidioidomycosis to characterize drug exposures associated with efficacy.Macrobroth dilution was performed on Coccidioides isolates to measure minimal effective concentrations (MEC) and minimal fungicidal concentrations (MFC). Mice were inoculated with Coccidioides posadasii (Silveira strain). Treatment started 4 days post-inoculation. (Model 1) Mice were treated 19 days plus 30-day off-therapy observation, measuring survival through day 49 and residual fungal burden. Treatments included ISAVUSULF (prodrug: 186, 279, or 372 mg/kg twice-daily), FLU (20 or 100 mg/kg once-daily), and untreated. Model 2 included 7-day treatment with ISAVUSULF (prodrug: 74.4, 111.6, or 148.8 mg/kg twice-daily), FLU (20 or 100 mg/kg once-daily), and untreated. Serial plasma and tissues samples were obtained for PK and fungal burden measurement, respectively.MEC50 were 0.39 mg/L (ISAV) and 12.5 mg/L (FLU). Treatment with ISAVUSULF186 or both FLU doses resulted in higher survival compared to untreated. Treatment with ISAVUSULF 186 or 279 mg/kg twice-daily or FLU 100 mg/kg reduced fungal burden in all organs (Model 1). In model 2, >1 log10 CFU/organ reduction was demonstrated, with ISAV AUCs achieved with 111.6 mg/kg twice-daily (56.8 mg•h/L), in the spleen and liver. FLU AUCs, 100 and 500 mg•h/L, for 20 and 100 mg/kg doses, respectively, resulted in >1 log10 CFU/organ mean reduction in all organs.ISAVUSULF and FLU improved survival and reduced fungal burden. Increasing plasma drug exposures resulted in decreases in fungal burden.
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pharmacodynamics of isavuconazole in a rabbit model of cryptococcal meningoencephalitis
Antimicrobial Agents and Chemotherapy, 2019Co-Authors: Laura L Kovanda, Charles Giamberardino, Laura Mcentee, Dena L Toffaletti, Kelly S Franke, Andrew Bartuska, Gordon Smilnak, George C De Castro, Katelyn Ripple, William W HopeAbstract:Cryptococcus spp., important fungal pathogens, are the leading cause of fungus-related mortality in human immunodeficiency virus-infected patients, and new therapeutic options are desperately needed. Isavuconazonium sulfate, a newer triazole antifungal agent, was studied to characterize the exposure-response relationship in a rabbit model of cryptococcal meningoencephalitis. Rabbits treated with Isavuconazonium sulfate were compared with those treated with fluconazole and untreated controls. The fungal burden in the cerebrospinal fluid was measured serially over time, while the yeast concentrations in the brain and the eye (aqueous humor) were determined at the end of therapy. The exposure impact of Isavuconazonium sulfate dosing in the rabbit was linked using mathematical modeling. Similar significant reductions in the fungal burden in the brain and cerebrospinal fluid in rabbits treated with Isavuconazonium sulfate and fluconazole compared with that in the untreated controls were observed. No dose-dependent response was demonstrated with Isavuconazonium sulfate treatment in this study. The treatment of cryptococcal meningoencephalitis with Isavuconazonium sulfate was similar to that with fluconazole. Dose-dependent reductions in yeast over time were not demonstrated, which limited our ability to estimate the pharmacodynamic target. Further nonclinical and clinical studies are needed in order to characterize the extent of the exposure-response relationship in cryptococcal meningoencephalitis. However, this study suggests that Isavuconazonium sulfate, like fluconazole, could be beneficial in the setting of consolidation and maintenance therapy, rather than induction monotherapy, in high-burden cryptococcal meningoencephalitis.
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exposure response relationships for isavuconazole in patients with invasive aspergillosis and other filamentous fungi
Antimicrobial Agents and Chemotherapy, 2017Co-Authors: Amit Desai, Salim Mujais, Robert Townsend, Laura L Kovanda, William W Hope, Donna Kowalski, David R Andes, Johan W Mouton, Peter L BonateAbstract:textabstractIsavuconazole, 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.
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population pharmacokinetics of isavuconazole from phase 1 and phase 3 secure trials in adults and target attainment in patients with invasive infections due to aspergillus and other filamentous fungi
Antimicrobial Agents and Chemotherapy, 2016Co-Authors: Amit Desai, Robert Townsend, Laura L Kovanda, Donna Kowalski, Peter L BonateAbstract:Isavuconazole, the active moiety of the water-soluble prodrug Isavuconazonium sulfate, is a triazole antifungal agent used for the treatment of invasive fungal infections. The objective of this analysis was to develop a population pharmacokinetic (PPK) model to identify covariates that affect isavuconazole pharmacokinetics and to determine the probability of target attainment (PTA) for invasive aspergillosis patients. Data from nine phase 1 studies and one phase 3 clinical trial (SECURE) were pooled to develop the PPK model (NONMEM, version 7.2). Stepwise covariate modeling was performed in Perl-speaks-NONMEM, version 3.7.6. The area under the curve (AUC) at steady state was calculated for 5,000 patients by using Monte Carlo simulations. The PTA using the estimated pharmacodynamic (PD) target value (total AUC/MIC ratio) estimated from in vivo PD studies of invasive aspergillosis over a range of MIC values was calculated using simulated patient AUC values. A two-compartment model with a Weibull absorption function and a first-order elimination process adequately described plasma isavuconazole concentrations. The mean estimate for isavuconazole clearance was 2.360 liters/h (percent coefficient of variation [%CV], 34%), and the mean AUC from 0 to 24 h (AUC0-24) was ∼100 mg·h/liter. Clearance was approximately 36% lower in Asians than in Caucasians. The PTA calculated over a range of MIC values by use of the nonneutropenic murine efficacy index corresponding to 90% survival indicated that adequate isavuconazole exposures were achieved in >90% of simulated patients to treat infections with MICs up to and including 1 mg/liter according to European Committee on Antimicrobial Susceptibility Testing methodology and in >90% of simulated patients for infections with MICs up to and including 0.5 mg/liter according to Clinical and Laboratory Standards Institute methodology. The highest MIC result for PTA was the same for Caucasian and Asian patients.
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isavuconazole population pharmacokinetic analysis using nonparametric estimation in patients with invasive fungal disease results from the vital study
Antimicrobial Agents and Chemotherapy, 2016Co-Authors: Laura L Kovanda, Amit Desai, Robert Townsend, Shahzad Akhtar, Peter L Bonate, William W HopeAbstract: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.).
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exposure response relationships for isavuconazole in patients with invasive aspergillosis and other filamentous fungi
Antimicrobial Agents and Chemotherapy, 2017Co-Authors: Amit Desai, Salim Mujais, Robert Townsend, Laura L Kovanda, William W Hope, Donna Kowalski, David R Andes, Johan W Mouton, Peter L BonateAbstract:textabstractIsavuconazole, 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.
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population pharmacokinetics of isavuconazole from phase 1 and phase 3 secure trials in adults and target attainment in patients with invasive infections due to aspergillus and other filamentous fungi
Antimicrobial Agents and Chemotherapy, 2016Co-Authors: Amit Desai, Robert Townsend, Laura L Kovanda, Donna Kowalski, Peter L BonateAbstract:Isavuconazole, the active moiety of the water-soluble prodrug Isavuconazonium sulfate, is a triazole antifungal agent used for the treatment of invasive fungal infections. The objective of this analysis was to develop a population pharmacokinetic (PPK) model to identify covariates that affect isavuconazole pharmacokinetics and to determine the probability of target attainment (PTA) for invasive aspergillosis patients. Data from nine phase 1 studies and one phase 3 clinical trial (SECURE) were pooled to develop the PPK model (NONMEM, version 7.2). Stepwise covariate modeling was performed in Perl-speaks-NONMEM, version 3.7.6. The area under the curve (AUC) at steady state was calculated for 5,000 patients by using Monte Carlo simulations. The PTA using the estimated pharmacodynamic (PD) target value (total AUC/MIC ratio) estimated from in vivo PD studies of invasive aspergillosis over a range of MIC values was calculated using simulated patient AUC values. A two-compartment model with a Weibull absorption function and a first-order elimination process adequately described plasma isavuconazole concentrations. The mean estimate for isavuconazole clearance was 2.360 liters/h (percent coefficient of variation [%CV], 34%), and the mean AUC from 0 to 24 h (AUC0-24) was ∼100 mg·h/liter. Clearance was approximately 36% lower in Asians than in Caucasians. The PTA calculated over a range of MIC values by use of the nonneutropenic murine efficacy index corresponding to 90% survival indicated that adequate isavuconazole exposures were achieved in >90% of simulated patients to treat infections with MICs up to and including 1 mg/liter according to European Committee on Antimicrobial Susceptibility Testing methodology and in >90% of simulated patients for infections with MICs up to and including 0.5 mg/liter according to Clinical and Laboratory Standards Institute methodology. The highest MIC result for PTA was the same for Caucasian and Asian patients.
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isavuconazole population pharmacokinetic analysis using nonparametric estimation in patients with invasive fungal disease results from the vital study
Antimicrobial Agents and Chemotherapy, 2016Co-Authors: Laura L Kovanda, Amit Desai, Robert Townsend, Shahzad Akhtar, Peter L Bonate, William W HopeAbstract: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.).
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Pharmacodynamics of isavuconazole in experimental invasive pulmonary aspergillosis: implications for clinical breakpoints
The Journal of antimicrobial chemotherapy, 2016Co-Authors: Laura L Kovanda, Amit Desai, Peter L Bonate, Ruta Petraitiene, Thomas J. Walsh, Vidmantas Petraitis, William W HopeAbstract:OBJECTIVES Isavuconazole, a novel triazole antifungal agent, has broad-spectrum activity against Aspergillus spp. and other pathogenic fungi. The isavuconazole exposure-response relationship in experimental invasive pulmonary aspergillosis using galactomannan index (GMI) suppression as a marker of disease clearance was explored. METHODS The impact of exposure on GMI suppression in persistently neutropenic rabbits treated with Isavuconazonium sulphate (isavuconazole-equivalent dosages of 20, 40 or 60 mg/kg every 24 h, after a 90 mg/kg loading dose) for 12 days was linked using mathematical modelling. Bridging to humans using population pharmacokinetic (PK) data from a clinical trial in invasive aspergillosis was performed using Monte Carlo simulations. RESULTS Mean plasma isavuconazole AUC/MIC (EC50) of 79.65 (95% CI 32.2, 127.1) produced a half-maximal effect in GMI suppression. The inhibitory sigmoid Emax curve dropped sharply after an AUC/MIC of ≥30 and was near maximum (EC80) at ∼130. Bridging the experimental PK/pharmacodynamic (PD) target to human population PK data was then used to return to the rabbit model to determine a clinically relevant PD endpoint. The clinical dosing regimen used in the trial would result in a mean GMI of 4.3 ± 1.8, which is a 50% reduction from the starting GMI in the experiment. CONCLUSIONS The clinical trial results showing the non-inferiority of isavuconazole to voriconazole for all-cause mortality further support the PK-PD endpoint, thereby demonstrating the usefulness of the rabbit model and endpoint for isavuconazole and implications on interpretive breakpoints. Importantly, the analysis supports this model as an important tool for development of antifungal agents.
