Monte Carlo Analysis of Different Administration Regiments for Isavuconazole against Candida spp. and Aspergillus spp.

In our study, we aimed to optimize the dosage regimen of Isavuconazole against Candida spp. and Aspergillus spp. by Monte Carlo simulation (MSC). Pharmacokinetic parameters and microbiological data of Isavuconazole were collected. Then we used MSC to simulate 10,000 patients analyzed by Crystal Ball to calculate probability of target attainment (PTA) and cumulative fraction of response (CFR). With dosages of 100 mg, 200 mg, and 400 mg in oral group and dosages of 100 mg, and 200 mg in intravenous administration, all have different degrees of antifungal effect. But when the dosage regimen was 50 mg IV, the therapeutic effect of Isavuconazole against Aspergillus spp. and Candida spp. were not good.


Introduction
At present, invasive fungal infection is one of the major infectious diseases in the world, and its main pathogenic bacterias are Aspergillus and Mucor, which is the main cause of high morbidity and mortality, and is one of the most serious disease burdens in the world [1]. At present, due to the safety and effectiveness of therapeutic drugs and other reasons, the treatment is less selective [2]. Isavuconazole is a triazole antifungal drug that inhibits the conversion of lanosterol to ergosterol by inhibiting cytochrome P450 (CYP)-dependent 14-α-demethylase in fungal cell membranes, thereby affecting the growth and replication of fungal cells. And thus play a pharmacological role [3]. The antimicrobial spectrum of How to cite this paper: Hu, J.L., Hu, C.C. and Zhu, X.Q. (2021) Monte Carlo Analysis of Different Administration Regiments for Isavuconazole against Candida spp. and Aspergillus spp. Pharmacology & Pharmacy, Pharmacology & Pharmacy Isavuconazole is broad, and in vitro activity tests have confirmed that Isavuconazole has inhibitory effects on mold, yeast, and dimorphic fungi [4] [5] [6], which was currently approved by the FDA for the treatment of primary treatment of invasive aspergillosis (IA) and mucormycosis, available in oral and intravenous forms [7]. In this study, combined with antifungal pharmacokinetics (PK)/pharmacodynamics (PD) and microbial information, Monte Carlo simulation was used to analyze the treatment regiments for Isavuconazole against Candida spp. and Aspergillus spp., so as to obtain the best treatment regiments for each pathogen, and also provide basis for early antifungal therapy ( Figure 1).

Pharmacokinetic Parameters
PK parameters are derived from published research [8]. In adult study subjects, there are two administration routes of Isavuconazole, oral administration and intravenous administration, with dosages of 100 mg, 200 mg, and 400 mg in oral group and dosages of 50 mg, 100 mg, and 200 mg in intravenous administration.
PK parameters of each administration regimen are shown in Table 1.

Monte Carlo Simulation
MCSs combines PK parameters of antibiotics with MIC distribution information of pathogenic bacteria to evaluate the probability of achieving each PD target in reality. Isavuconazole is a concentration-dependent antimicrobial agent, and the target value is expressed as AUC/MIC [10]. fAUC/MIC = (f × dose)/(CL × MIC).

Discussion
MCS combined with true fungus resistance of PK and PD information and microbes in the MIC value distribution of specific drugs, to simulate each fungus Pharmacology & Pharmacy Isavuconazole is a concentration-dependent antimicrobial agent, whose PD index is measured by AUC/MIC ratio. A series of studies have confirmed that PD target values of Isavuconazole in the treatment of Aspergillus spp. and Candida spp. Among Candida spp., the differences among species were great, C. tropicalis was 6.2, C. glabrata was 1.6, C. albicans was 50.5, and the others were 3.1, while the target value of Aspergillus spp. was generally believed to be 0.51 [12] [13]. In this study, the PD target values mentioned above were used for MCS, which was compared with non-albicans Candida spp. reported in the literature [14]. Compared with the AUC/MIC values of 312, the analysis results are more targeted and targeted.
PK/PD analysis combined with MCS analysis of antifungal drug dosage regimen can scientifically analyze the rationality of antibacterial drug administration regimen, provide reference for early clinical empirical drug use, and also be used Pharmacology & Pharmacy for optimization of antibacterial treatment regimen. However, there are also some limitations. First, Isavuconazole parameters are derived from adults in the study area, and differences among different races and ethnic groups are not fully considered. Secondly, MIC data are derived from EUCAST website, which lacks certain pertinence for data of regions not included in the study of EUCAST website.

Conclusion
In conclusion, different dosage regimens for Isavuconazole in different administration routes were used in this study, indicating that there are still differences in administration regimens for different strains with the same dose and different routes. However, when the dosage regimen was 50 mg IV, the therapeutic effect of Isavuconazole against Aspergillus spp. and Candida spp. were not good, which showed the treatment is not recommended.

Funding
This study was funded by the Study and Development Fund for Sciences and Technology in Chengde City (No. 202006A072).

Data Availability Statement
All data generated or analyzed during this study are included in this published article.