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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

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ABSTRACT

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.

No MeSH data available.


Probability of target attainment over a range of MIC values for EI50, EI80, and EI90. (A) EUCAST methodology; (B) CLSI methodology. For panel B, note that the EI80 and EI90 values overlap in the plot. AUC, area under the curve; CLSI, Clinical and Laboratory Standards Institute; EUCAST, European Committee on Antimicrobial Susceptibility Testing.
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Figure 3: Probability of target attainment over a range of MIC values for EI50, EI80, and EI90. (A) EUCAST methodology; (B) CLSI methodology. For panel B, note that the EI80 and EI90 values overlap in the plot. AUC, area under the curve; CLSI, Clinical and Laboratory Standards Institute; EUCAST, European Committee on Antimicrobial Susceptibility Testing.

Mentions: Overall, 5,000 patients were simulated using Monte Carlo simulation with the mean parameter estimates, including variability on patients, from the best model with covariates. BMI was randomly added based on values found in the National Health and Nutrition Examination Survey 2014 (NHANES; http://www.cdc.gov/nchs/nhanes.htm), with the difference in BMI ranges between Caucasian and Asian patients taken into consideration. The BMI range was 14 to 41 kg/m2 for Caucasian patients and 17 to 28 kg/m2 for Asian patients. All PD targets that were established from different experimental models were used in the PTA analysis. The results of PTA analysis performed for the nonneutropenic mouse model and for both CLSI and EUCAST methodologies are shown in Fig. 3. The AUC/MIC range was derived for each patient, and the percentages of patients above exposure index (EI) values of 50%, 80%, and 90% were plotted against the range of MIC values. The target values for EI50, EI80, and EI90 were 24.7, 29.8, and 33.3, respectively, for MICs determined according to EUCAST methodology and 50.4, 55.7, and 59.0, respectively, for MICs determined by CLSI methodology (23). These values indicate the exposures required for 50%, 80%, and 90% survival for all isolates. For all the PD target values, the PTA analysis demonstrated that >90% of the simulated patients would achieve adequate exposures to treat infections with MIC values of ≤1 mg/liter according to EUCAST methodology and that >90% of the simulated patients would achieve adequate exposures for treatment of infections with MICs of <1 mg/liter according to CLSI methodology.


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
Probability of target attainment over a range of MIC values for EI50, EI80, and EI90. (A) EUCAST methodology; (B) CLSI methodology. For panel B, note that the EI80 and EI90 values overlap in the plot. AUC, area under the curve; CLSI, Clinical and Laboratory Standards Institute; EUCAST, European Committee on Antimicrobial Susceptibility Testing.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4997882&req=5

Figure 3: Probability of target attainment over a range of MIC values for EI50, EI80, and EI90. (A) EUCAST methodology; (B) CLSI methodology. For panel B, note that the EI80 and EI90 values overlap in the plot. AUC, area under the curve; CLSI, Clinical and Laboratory Standards Institute; EUCAST, European Committee on Antimicrobial Susceptibility Testing.
Mentions: Overall, 5,000 patients were simulated using Monte Carlo simulation with the mean parameter estimates, including variability on patients, from the best model with covariates. BMI was randomly added based on values found in the National Health and Nutrition Examination Survey 2014 (NHANES; http://www.cdc.gov/nchs/nhanes.htm), with the difference in BMI ranges between Caucasian and Asian patients taken into consideration. The BMI range was 14 to 41 kg/m2 for Caucasian patients and 17 to 28 kg/m2 for Asian patients. All PD targets that were established from different experimental models were used in the PTA analysis. The results of PTA analysis performed for the nonneutropenic mouse model and for both CLSI and EUCAST methodologies are shown in Fig. 3. The AUC/MIC range was derived for each patient, and the percentages of patients above exposure index (EI) values of 50%, 80%, and 90% were plotted against the range of MIC values. The target values for EI50, EI80, and EI90 were 24.7, 29.8, and 33.3, respectively, for MICs determined according to EUCAST methodology and 50.4, 55.7, and 59.0, respectively, for MICs determined by CLSI methodology (23). These values indicate the exposures required for 50%, 80%, and 90% survival for all isolates. For all the PD target values, the PTA analysis demonstrated that >90% of the simulated patients would achieve adequate exposures to treat infections with MIC values of ≤1 mg/liter according to EUCAST methodology and that >90% of the simulated patients would achieve adequate exposures for treatment of infections with MICs of <1 mg/liter according to CLSI methodology.

View Article: PubMed Central - PubMed

ABSTRACT

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&ndash;24) was &sim;100 mg&middot;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 &gt;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 &gt;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.

No MeSH data available.