Pharmacokinetic/Pharmacodynamic Analysis the Probability of Target Attainment of Posaconazole against Mucorales Species in Patients with Mucormycosis

The objective of this study was to investigate the probability of target attainment of various posaconazole dosing regimens against Mucorales species in patients with mucormycosis. According to pharmacokinetic/pharmacodynamic parameters of posaconazole in adults, the dosage regimen of posaconazole for mucormycosis included 50, 100, 200 and 400 mg orally q12h. Monte Carlo Simulation analysed the published parameters of pharmacokinetics and the MIC values of mucormycosis in Mucorales species. The results showed that posaconazole did not affect Rhizopus arrhizus and Mucor sp. The optimal dosage of posaconazole for Rhizopus microsporus and Rhizomucor pusillus was 400 mg orally q12h and the best dosage regimen for Lichtheimia corymbifera was 200 mg orally q12h. The antifungal activity of posaconazole against mucormycosis was different, and the dosage regimen needs to adjust according to fungal species.


Introduction
Mucormycosis was a fatal fungal infection caused by Mucorales, which was a subdivision of mucoromycotina. Mucormycosis was the second common fungal infection in hematological malignancies and organ transplantation [1]. It has been reported more and more not only in patients with diabetes or ketoacidosis but also after trauma in patients with normal immune function, even in healthy people with food-borne outbreaks caused by Trichoderma [2] [3] [4] [5]. There were many kinds of pathogens creating mucormycosis, such as Rhizopus, Mucor, Lichtheimia, Apophysomyces and Saksenaea, and so on [3] [6].
Posaconazole was the first triazole drug to treat mucormycosis, which was used in refractory mucormycosis or polyene resistant patients [7]. The pharmacological mechanism of posaconazole on fungal infection was that the affinity of fungal P450 demethylase (CYP51) increases, which leads to the rise of penetration or decrease of outflow of the fungal cell membrane [8]. Currently, there are limited reports on the treatment of mucormycosis by the dose of posaconazole, with the maximum daily dose of 800 mg [9]. Therefore, in this study, the administration scheme of posaconazole for the treatment of mucormycosis needs to be optimized, and the optimal drug administration scheme optimised to provide a basis for clinical application.

Pharmacokinetic Parameter
The pharmacokinetic (PK) parameters of posaconazole were derived from the previously published literature [10]. The research reported that the age of people was from 18 to 44 years old, and four different dosages of posaconazole included 50, 100, 200 and 400 mg orally q12h. The PK data of posaconazole was established according to the blood drug concentration at different time in the previously published literature, and those data were summarised in Table 1.

Minimum Inhibition Concentration (MIC) Distribution of Mucorales
The MICs data for Mucorales were obtained from Andrew M. et al. [11]. Posaconazole was assessed against 238 isolates of Mucorales using Clinical and Laboratory Standards Institute (CLSI) broth microdilution methods (see Table 2).
The number of MIC distributions of posaconazole against Lichtheimia corymbifera, Rhizopus arrhizus, Rhizopus microsporus, Mucor sp. and Rhizomucor pusillus were gathered and were used for each simulation to calculate the probability of target attainment (PTA) and the cumulative fraction of response (CFR).

Probability of Target Attainment (PTA) Analysis
In this study, the results Monte Carlo simulation of four different administration dosage of posaconazole showed that the patients with mucormycosis meet the requirement of PTA ≥ 90% in the dosage of 400 mg orally q12h. However, the dosage of posaconazole 50 mg could not be up to standard.  Figure 1).

Cumulative Fraction of Response (CFR) Analysis
The CFR values of each dose regimen simulated by Monte Carlo were shown in

Discussion
Currently, the antifungal studies on mucormycosis were limited. Considering the range of fungal pathogens and the limited availability of antifungal agents, it was recommended to conduct in vitro antifungal susceptibility tests for individual isolates of invasive fungal infections in high-risk patients, to optimise treatment strategies and detect drug-resistant strains [11]. Posaconazole was recommended for treating the patients with mucormycosis by the European Society for Clinical Microbiology and the European Confederation of Medical Mycology [14].
Posaconazole was a concentration-dependent antifungal drug, which the main parameter of PK/PD analysis was the AUC/MIC. According to before the neutropenia model of mouse, AUC/MIC was set more than 100 for as to the target values of posaconazole for treatment mucormycosis [15]. In this study, the re- at the beginning of treatment [15].
Although the Monte Carlo simulation based on certain PK and strain data was convenient to optimise the type and dose of antibacterial drugs for treatment, the results of this study also had some limitations. First of all, because there were many kinds of pathogenic bacteria about mucormycosis [16].

Conclusion
In summary, Monte Carlo simulation was simple, with optimisation design, economy, safety and predictability of clinical characteristics in determining antimicrobial activity. In this study, none of the simulated posaconazole dosage regimens were effective against Rhizopus arrhizus and Mucor sp. For Rhizopus microsporus and Rhizomucor pusillus, high doses of posaconazole (400 mg orally q12h.) should be recommended and used for patients with mucormycosis. However, when patients with mucormycosis caused by Lichtheimia corymbifera, the dosage of posaconazole with 200 mg orally q12h could achieve better target attainment. So patients with mucormycosis by using posaconazole were not only Monte Carlo simulation but also in combination with the clinical condition.

Funding
This study was funded by the Study and Development Fund for Sciences and Technology in Chengde City (No. 201701A086 and No. 201701A087).

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

Conflicts of Interest
The authors declare no conflicts of interest regarding the publication of this paper.