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No Dose Adjustment for Isavuconazole Based on Age or Sex.

ABSTRACT: This phase 1, open-label, single-dose, parallel-group study evaluated the pharmacokinetics (PK) of isavuconazole after a single oral dose of the prodrug isavuconazonium sulfate in healthy nonelderly (age, 18 to 45?years) and elderly (age, ?65?years) males and females. Overall, 48 subjects were enrolled in the study (n?=?12 each in groups of nonelderly males and females and elderly males and females). All subjects received a single oral dose of 372?mg of isavuconazonium sulfate (equivalent to 200?mg isavuconazole). PK samples were collected for analysis of isavuconazole plasma concentrations from the predose time point up to 336?h postdose. Data were analyzed using population pharmacokinetic (PPK) analysis. The resulting PPK model included two compartments with Weibull absorption function as well as interindividual variability with respect to clearance, intercompartment clearance, volumes of central and peripheral compartments, and two Weibull absorption parameters, RA and KAMAX. The PPK analysis showed that elderly females had the highest exposure versus males (ratio of total area under the time-concentration curve [AUC], 138; 90% confidence interval [CI], 118 to 161) and versus nonelderly females (ratio of AUC, 147; 90% CI, 123 to 176). Higher exposures in elderly females were not associated with significant toxicity or treatment-emergent adverse events, as measured in this study. No dose adjustments appear to be necessary based on either age group or sex even with an increase in exposure for elderly females. (This study has been registered at ClinicalTrials.gov under registration no. NCT01657890.).

SUBMITTER: Desai AV

PROVIDER: S-EPMC6535513 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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No Dose Adjustment for Isavuconazole Based on Age or Sex.

Desai Amit V AV Han David D Kowalski Donna L DL Lademacher Christopher C Pearlman Helene H Yamazaki Takao T

Antimicrobial agents and chemotherapy 20190524 6

This phase 1, open-label, single-dose, parallel-group study evaluated the pharmacokinetics (PK) of isavuconazole after a single oral dose of the prodrug isavuconazonium sulfate in healthy nonelderly (age, 18 to 45 years) and elderly (age, ≥65 years) males and females. Overall, 48 subjects were enrolled in the study (<i>n </i>=<i> </i>12 each in groups of nonelderly males and females and elderly males and females). All subjects received a single oral dose of 372 mg of isavuconazonium sulfate (equ ...[more]

PMID: 30962330

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Project description:BackgroundMost emergency departments rely on acuity assessment, triage, to recognize critically ill patients that need urgent treatment, and to allocate resources according to need. The accuracy of commonly used triage instruments such as the Emergency Severity Index (ESI) is lower for older adults compared to young patients. We aim to examine, whether adjusting the triage category by age leads to improvement in sensitivity without excessive increase in patient numbers in the higher triage categories. The primary outcome measure was 3-day mortality and secondary outcomes were 30-day mortality, hospital admission, and HDU/ICU admissions.MethodsWe gathered data of all adult patients who had an unscheduled visit to any of our three emergency departments within one month. The data was analysed for 3-day mortality, 30-day mortality, hospital admission, and high dependency unit or intensive care unit (HDU/ICU) admission. The analysis was run for both the standard ESI triage method and a local 3-level Helsinki University Hospital (HUH) method. A further analysis was run for both triage methods with age adjustment. Net reclassification improvement values were calculated to demonstrate the effect of age adjustment.ResultsThirteen thousand seven hundred fifty-nine patients met the study criteria, median age was 57. 3-day mortality AUCs for unadjusted HUH and ESI triage were 0.77 (0.65-0.88) and 0.72 (0.57-0.87); 30-day mortality AUCs were 0.64 (0.59-0.69) and 0.69 (0.64-0.73); hospital admission AUCs were 0.60 (0.68-0.71) and 0.66 (0.65-0.68) and HDU/ICU admission AUCs were 0.67 (0.64-0.70) and 0.82 (0.79-0.86), respectively. Age adjustment improved accuracy for 30-day mortality and hospital admission. With the threshold age of 80, AUCs for 30-day mortality were 0.73 (0.68-0.77) and 0.77 (0.73-0.81) and for hospital admission, 0.66 (0.65-0.67) and 0.72 (0.71-0.73) for the HUH and ESI triage. The effect was similar with all cut off ages.ConclusionMoving older adults into a more urgent triage category based on age, improved the triage instruments' performance slightly in predicting 30-day mortality and hospital admission without excessive increase in patient numbers in the higher triage categories. Age adjustment did not improve HDU/ICU admission or 3-day mortality prediction.

Dataset Information

No Dose Adjustment for Isavuconazole Based on Age or Sex.

Publications

No Dose Adjustment for Isavuconazole Based on Age or Sex.

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