Optimizing the Dosage Regimen of Micafungin against Candida spp in HIV Positive Patients with EC Based on Mote Carlo Simulation

The objective of our study was to explore the possibility of the antifungal efficacy of various micafungin dosage regimens against Candida spp in HIV positive patients with EC. According to pharmacokinetic/pharmacodynamics parameters of micafungin in HIV positive patients and MICs distribution of micafungin against Candida spp. in published studies, the dosage regimens of micafungin were 50, 100 and 150 mg QD iv. Monte Carlo Simulation analysed the probability of target attainment and cumulative fraction of response. The results showed that micafungin has good antifungal effect in treating HIV positive patients with EC when pathomycetes are Candida albicans, Candida glabrata or Candida tropicalis, in dosage at 100 mg QD and 150 mg QD.


Introduction
In recent years, invasive fungal infections (IFIs) had been a significant factor in the morbidity and mortality of inpatients with invasive infections, especially in patients with immunodeficiency [1] [2]. The primary pathogenic fungi for IFIs are Candida albicans, Candida glabrata, Candida krusei, Candida parapsilosis and Candida tropicalis [1]. phagal candidiasis (EC) is a common and severe complication, the incidence is 15% -20%, and micafungin has shown great efficacy and tolerability in treating EC in HIV positive patients [3]. Micafungin is an echinocandin antifungal agent, which plays an antifungal role in selective inhibiting the synthase of β-(1,3)-D-glucan in the fungal cell wall [4] [5]. Micafungin mainly binds to albumin in vivo, the protein binding rate in plasma is 99% [6]. In vivo, micafungin is metabolized by the liver and excreted through the biliary tract, and mainly excreted through faeces [7]. Studies showed that micafungin has antifungal activities against Candida spp. both in vitro and in vivo, even for fluconazole resistance fungus [8] [9] [10] [11].
Monte Carlo simulation (MCS) is a useful tool for clinical treatment of dose selection, which can be sufficient to evaluate the effect of antifungal drugs and minimise the possibility of antifungal drug resistance. MCS has been used to assess the dosing regimens of micafungin in morbidly obese patients [12], critically ill patients with invasive fungal infection [13], critically burned patients with abdominal disease [14] and children [15]. In this study, MCS was used to optimise the micafungin dosage regimen of EC in HIV positive patients, to provide a basis for clinical application.

Pharmacokinetic Parameters
Pharmacokinetic parameters for micafungin in HIV positive patients with EC from the literature [3], PK data of intravenous micafungin in HIV-positive patients are shown in Table 1. Micafungin is a concentration-dependent antifungal drug with long-term aftereffects, and the antifungal effect is measured by fAUC 24h /MIC, PD target of Candida spp. is fAUC 24h /MIC = 10 [16], Free drug fraction f is 1%.

The Minimum Inhibitory Concentration (MIC) Data
The MICs distribution of Candida spp. is from the European Committee on Antimicrobial Susceptibility Testing (EUCAST) (http://www.eucast.org). The data has shown in Table 2.

Monte Carlo Simulation
The probability of target attainment (PTA) is the target value of Pharmacokinetic/pharmacodynamic (PK/PD); the calculation formula is

PTA Values
PTA values of micafungin against Candida spp. in HIV positive patients under different MICs distribution shown in Figure 1. The results showed that in dosage at 50 mg, the 5 Candida spp can reach the target when MIC is less than 0.032 μg/mL. In dosage at 100 mg and 150 mg, the 5 Candida spp can attain the goal when MIC is less than 0.064 μg/mL.

CFR
As the results are shown in Table 3

Discussion
Micafungin is one of three currently available echinocandins in the treatment of Candidiasis, and the FDA recommends a dose of 100 mg QD for adult Candidiasis [17]. In HIV positive patients confirmed EC, no effect of race or gender   on the pharmacokinetics of micafungin [3]. Pharmacokinetics of micafungin in treating patients with EC was linear, predictable, which is similar to the published studies in healthy adults [3].
In our study, the antifungal effect of micafungin against different Candida spp in HIV positive patients with EC was quite different. For Candida krusei and Candida parapsilosis, micafungin has no antifungal impact, which is similar to the published studies in intensive care unit patients [18]. Our study also showed that micafungin against Candida albicans, Candida glabrata and Candida tropicalis has good antifungal effect in dosage greater than or equal to 100 mg, which is similar to FDA recommendation [17].
In this study, MCS used to carry out hypothesis analysis based on certain PK and strain data, which was beneficial to optimise the type and dosage of micafungin against Candida spp in HIV positive patients with EC. However, the research results of this paper also have some limitations, such as the MIC distribution of micafungin from some regions but not world-wide, so it can not reflect the development trend and change of the fungus in the future.

Conclusion
In summary, MCS is a simple, safe method to optimise dosage regimen according to the characteristics of fungi and PK/PD parameters. When pathomycetes are Candida albicans, Candida glabrata or Candida tropicalis, micafungin has good antifungal effect in HIV positive patients with EC, when pathomycetes are Candida krusei or Candida parapsilosis, other antifungal treatments are needed.

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