Background and Importance Isavuconazol has a safety profile and favorable pharmacokinetic characteristics. However, studies in real-life practice have found unexpected drug levels in different groups of patients.
Aim and Objectives To develop a population pharmacokinetic model (PopPK) that describes the behaviour of isavuconazole in prophylaxis and treatment of invasive fungal infections (IFI) and to evaluate possible factors affecting dosage.
Material and Methods A prospective, multidisciplinary study including immunosuppressed patients treated with oral and intravenous isavuconazole as prophylaxis or treatment for IFI was carried out from June 2020 to January 2022. Variables considered were: demographic, clinical, biochemical and genetic (polymorphisms, presence of inductors, inhibitors and the degree of saturation -DG- of drug-metabolising enzymes of CYP3A4, CYP3A5 and CYP2B6). DG was tested using SuperCYPsPred.
Blood samples were collected predose Isavuconazole was analysed using ultra performance liquid chromatography coupled with ultraviolet detection.
Non-linear mixed effects modelling using first-order conditional estimation with interaction (FOCEI) was used to develop the PopPK model using NONMEM v7.4. Data visualisation and statistical analyses were carried out in R v.3.4.
Results A total of 31 patients (10 females) from the haematology (19) and intensive care (12) services were included in the study. The median (interquartile range) age was 58 (17) years and total body weight was 77 (17) kg. The percentage of patients who presented non-wild type genotypic was 20% for CYP3A4. 99 samples were determined and the mean concentration (standard desviation) was 1.80 (0.95) µg/mL.
Isavuconazole PK was best described by a single-compartment model with first order absorption and elimination. Isavuconazole absorption rate was fixed at 22.6 1/h as previously reported by Cojutti et al. 2021. The apparent volume of distribution was 147 L and the apparent clearance (CL/F) was described by the following equation:
CL/F(L/h)=3.54*(ALB/2.9)-0.7*(BS/1,9)1,9*(1+0.8)3A4ind where serum albumin (ALB) is expressed in g/dL; body surface (BS) in m2 and 3A4ind indicates the presence of inductor drugs for CYP3A4.
The interindividual variability for CL/F was 40% and the residual variability was 30% (additive) and 0,05 µg/mL (proportional).
Conclusion and Relevance The developed PopPK model adequately characterises the kinetic behaviour of isavuconazole and includes the ALB, BS and the presence of inductors of CYP3A4 parameters that affect its clearance.
Conflict of Interest No conflict of interest
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