Evaluation of Dosages Regimen of Fluconazole in Patients of Candidemia with Gender by PK/PD and Mote Carlo Simulation ()
1. Introduction
Candida is the normal flora of the human body, usually parasitic in the normal skin, oral cavity, gastrointestinal tract, and genitourinary tract mucosa. Under normal circumstances, the body has a perfect defense system against Candida. When the normal bacterial community is maladjusted, the normal physiological barrier is destroyed and the human immunity is low due to various reasons, they can invade the human body and cause diseases, leading to opportunistic infections [1] . Candidiasis, the most common form of invasive candidiasis, is an opportunistic bloodstream infection caused by Candida, which can be cultured in the blood of loyal individuals. It occurs in those with immune deficiency, long-term immunosuppressive therapy, critically ill, or long-term use of broad-spectrum antibiotics [2] [3] .
Fluconazole was introduced as a treatment for Candidiasis two decades ago and remained the most frequently prescribed drug for Candidemia [4] . Fluconazole can effectively inhibit the synthesis of ergosterol. It caused the loss of chromatin P-450 activation and phonogenic enzyme function, and the change of membrane permeability and death of fungal. Targeting fluconazole therapy to achieve predefined pharmacodynamic goals has been suggested as a means of optimising treatment of patients with Candidemia.
To maximize the likelihood of favorable clinical outcomes and minimize the probability of antimicrobial resistance, Monte Carlo simulation (MCS) is a computer simulation technology based on random numbers. Its basic principle is to randomly sample function distributions of different variables and substitute them into data models to obtain approximate solutions to research problems.
The method using the pharmacokinetic/pharmacodynamics (PK/PD) theory, the dynamic response can be drug in the body concentration-response relationship with aging. The optimal dose and administration scheme of antibacterial drugs were studied by the probability of target attainment (PTA) and cumulative fraction of response (CFR), so as to determine the optimal treatment scheme. To eliminate pathogenic bacteria, it can improve the success rate of treatment, and reduce adverse drug reactions and bacterial resistance [5] [6] .
In this study, with the aid of PK/PD theory, the MCS model was applied to optimize the clinical administration scheme of fluconazole to Candida spp. with the population of different genders as the research object, in order to provide medication reference for clinical individualization.
2. Materials and Methods
2.1. Pharmacokinetic Parameters
Information regarding the pharmacokinetic parameters of fluconazole was obtained from published studies.
Information from studies that evaluated clinically relevant dosage regimens and provided the mean results for the pharmacokinetic parameters of interest with
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Table 1. Pharmacokinetic parameters for fluconazole.
corresponding measures of variability of areas under the concentration-time curve at steady-state (AUCs) were included. PK parameters of each administration regimen are shown in Table 1.
Estimates of pharmacokinetic parameters of fluconazole of subjects from five different ethnicities after a single oral administration of 200 mg tablet of fluconazole (n = 10 for each group).
f = 1-PBs, plasma protein binding of fluconazole is 12% [10] .
2.2. The Minimum Inhibitory Concentration (MIC) Data of Candida spp.
The MIC distribution of fluconazole against Candida spp. for seven species is derived from the Data from published articles [8] [9] [10] [11] (shown in Table 2).
2.3. Monte Carlo Simulation
MCS evaluates antifungal dosage regimens by integrating pharmacokinetic (PK) parameters, Minimum Inhibitory Concentration (MIC) distribution, and pharmacodynamics (PD) parameters. Crystal Ball (version 11.1.2.4.600, Oracle) software was used for Monte Carlo Simulation to obtain a probability of target attainment (PTA) and a cumulative fraction of response (CFR) for each dosing regimen of fluconazole. The PK/PD parameters of fluconazole were expressed in AUC/MIC ratio. The formula is f AUC24h/MIC > 55.2 [11] , where CL follows a lognormal distribution, dose (mg) and f follow a uniform distribution, and MIC follows a custom distribution. CFR ≥ 90% is considered as the best plan.
3. Results
3.1. PTA Values
PTA Analysis of fluconazole in healthy adults for 7Candida spp. was shown in Table 1. The results showed that PTA values were more than 90% for C. albicans, C. tropicalis and C. lusitaniae when MIC was less than 1 g/ml in each dosing regimen. For C. tropicalis each dosing regimen of fluconazole attained the PTA when MIC was less than 2 g/ml. As C. glabrata,C. parapsilosis,C. krusei,C. guilliermondii for PTA with more than 90%, MIC of fluconazole 200 mg were less than 32 g/ml, 64 g/ml and 64 g/ml, respectively (shown in Figure 1).
3.2. CFR
The CFR of different dosing regimens of fluconazole in a single dose of healthy adults were shown in Table 3. The results showed that fluconazole had an excellent antifungal effect in the treatment of C. albicans andC. lusitaniae with a CFR
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Figure 1. Probability of target attainment (PTA) of fluconazole at dose of 100 mg IV and 200 mg IV for treating Candida strains with different MIC values in patients with gender.
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Table 2. Wild-type MIC distributions of fluconazole for seven species of Candida using CLSI broth microdilution methods [8] .
more than 90% with male and female. However, the dosage of fluconazole with CFR is more than 90% for C. parapsilosis and C. tropicalisis less in men than in women. And the dossage of fluconazole 100 mg IV in men and 200 mg IV in women for C. parapsilosis andC. tropicalis. The other Candida spp., such as C. glabrata, C. krusei,C. guilliermondii, of CFRs less than 90% of fluconazole 100 mg IV and 200 mg IV with different gender.
4. Discussion
Fluconazole, as a bis-triazole agent used in the treatment of fungal infections, with vaginal candidiasis being one of the commonest indications to fluconazole treatment [12] , is time-dependent antifungal and has a long antibacterial aftereffect, with a small amount of liver metabolism, prototype kidney excretion, low protein binding rate, wide tissue distribution, easy passage through the blood- brain barrier, good safety, etc.
Any species of Candida spp. more than154 species can cause candidiasis, but only 10% of candida species are known to cause infections in human [13] . The most common causes of candidiasis disease pathogenic bacteria are: C. albicans, C. parapsilosis, C. glabrata,C. tropicalis, and C. krusei.C. albicans is the most common cause of candidiasis. Clinically, C. albicans is the most common, accounting for 50% - 70% of candida infection; virulence is also the strongest. However, since the 1990s, the incidence of candidiasis caused by non-candida albicans has increased. Recent investigations have found that nearly half of all candida cases are caused by non-Candida albicans [14] . It is worth noting that in recent years there has been a marked increase in infections caused byC. glabrata, and C. krusei [15] [16] [17] . In recent years, New pathogenic Candida species, for instance, Candida auris has emerged as a multidrug-resistant ascomycete yeast pathogen with the capacity for easy transmission between patients and hospitals, as well as persistence on environmental surfaces [18] . Most isolates were from males, which has gender difference.
In this study, according to PK/PD analysis, Monte Carlo Simulation was used
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Table 3. CFR values (%) of 7 Candida spp. under different dosing regimens for different gender of fluconazole.
to obtain the PTA and CFR values of fluconazole for 7 species of Candida spp. with different genders and dosages under the distribution of MIC values. The results showed that C. albicans and C. lusitaniae had good antifungal effect at 100 mg IV and 200 mg IV in different genders, while C. parapsilosis and C. tropicalis. were affected by gender. Good antibacterial effect was observed in males at different doses, while CFR < 90% was observed in females at 100 mg IV and good antibacterial effect was observed when the dose increased to 200 mg IV. In this study, Monte Carlo Simulation analysis showed that fluconazole had different antibacterial activities among different candida genera in both males and females. Miriam del C ect [8] studies showed that gender difference of fluconazole was related to badyweight, most likely because of differenesin total body water (TBW) between males and females. It provides a basis for subsequent clinical research and application.
5. Conclusion
In conclusion, the results of PK/PD modelling and Monte Carlo simulations suggest that fluconazole had a good antibacterial effect on C. albicans,C. parapsilosis,C. tropicalis, andC. lusitaniae. The best dosing for C. albicans and C. glabrata is 100 mg IV for male, but the dose of fluconazole for female is 200 mg IV. Fluconazole had a bad antibacterial effect on C. glabrata, C. krusei,C. guilliermondii across genders.
Acknowledgements
This study was funded by the Study and Development Fund for Sciences and Technology in Chengde City (No. 202006A072).