Based on PK/PD and Monte Carlo Simulation Analysis of the Dosing Regimens of Micafungin in Children with Febrile Neutropenic ()
1. Introduction
Neutropenia is the most common cause of death and morbidity in childhood cancer patients. Invasive fungal infections have significant morbidity and mortality in pediatric patients. It is found shortly after chemotherapy-induced neutropenia or hematopoietic Stem Cell Transplantation (HSCT). Among patients, about one-third of neutropenia episodes have a febrile reaction. When the absolute neutrophil count is less than 500 cells/L, the risk of serious bacterial or fungal infection increases [1]. At present, Micafungin is one of the main drugs for the treatment of bacterial infections in children with neutropenia.
Micafungin is an echinocandin antifungal drug that selectively inhibits the synthesis of 1,3-β-D-glucan in the cell wall of fungi [2]. At present, the invasive fungal infection in patients with neutropenia is Candida spp. and Micafungin has good antibacterial activity against the above-mentioned bacteria and is effective against azole-resistant Candida [3]. In addition, Micafungin slowly degrades through the catechol-o-methyltransferase pathway, has no inhibitory effect on cytochrome P450 enzymes [4], and has become a common medicine for the treatment of patients with febrile neutropenia.
Mote Carlo Simulation (MCS) is an effective tool for dose screening in clinical treatment. It can evaluate the efficacy of antibacterial drugs, maximize the possibility of obtaining clinical efficacy, and minimize the possibility of antimicrobial resistance sex. This method has been used to analyze the suitability of the dosing regimen of Micafungin in critically ill patients with invasive fungal infection [5] and critically burned patients with abdominal cavity infection [6]. In this study, Monte Carlo simulation was used to optimize the dosing regimen of Micafungin in children with invasive Candida infection and febrile neutrophil deficiency, which provides a basis for clinical application.
2. Materials and Methods
2.1. Pharmacokinetic Parameters
Micafungin is a concentration-dependent antifungal drug, and its antibacterial effect is evaluated by the ratio AUC/MIC of Area under the concentration time curve (AUC) and Minimum inhibitory concentration (MIC) [7]. The calculation formula is:fAUC/MIC = (f × dose)/(CL × MIC), where Dose is the administered dose. In the formula, f = 1 − PBs represents the free drug fraction. The plasma protein binding rate for Micafungin is 99% representative [8], so its f-value is 1%; and CL is drug clearance rate.
The pharmacokinetic parameters of Micafungin in children with febrile neutrophil deficiency are derived from the research literature of Seibel et al. [3], as shown in Table 1.
2.2. Microbial Information
MIC distributions of Micafungin against Candida spp.derived from EUCAST website (https://mic.eucast.org/search/, MIC distributions for Micafungin, 2021-10-20) (shown in Table 2).
2.3. Monte Carlo Simulations
MCSs combine pharmacokinetic parameters and MIC distribution characteristics
![]()
Table 1. Pharmacokinetic parameters of Micafungin in children with febrile neutropenia.
![]()
Table 2. MIC distributions of Micafungin against Candida spp.
to evaluate the probability of AUC/MIC pharmacodynamic target values in plasma [9] [10]. Use to obtain PK/PD parameters, conduct MCSs analysis on 10,000 simulated patients to obtain the PTA value of Probability of target attainment (PTA). The percentage of subjects which PTA reaches the target PK/PD value, PTA ≥ 90% is the best. The target Candida target value f AUC/MIC ≥ 10 is the best antifungal effect [11]. According to the MIC value distribution of Micafungin against Candida spp. published by EUCAST, calculate the expected probability of the corresponding strain to the target value, that is, the Cumulative fraction of response (CFR) value, and CFR ≥ 90% is considered to be the most effective treatment for empirical treatment which is the best choice [10], its calculation formula is as follows:
2.4. Calculation Software
Crystal Ball (Version 11.1.2.4.600, Oracle) was used for Monte Carlo simulation of drug administration schemes.
3. Results
3.1. PTA
PTA values of Micafungin under MIC distribution of the different Candida spp. infection in Febrile Neutropenic Pediatric Patients were shown in Figure 1. In
![]()
Figure 1. PTA of Micafungin estimated at different MIC values in patients with Candidainfections.
Candida albicans, PTA was up to the standard for MIC ≤ 0.008 μg/mL, ≤0.016 μg/mL, ≤0.064 μg/ml, ≤0.032 μg/mL, ≤0.125 μg/mL and ≤0.125 μg/mL of dosage regimen included 0.5 mg/kg, 1 mg/kg, 1.5 mg/kg, 2 mg/kg, 3 mg/kg and 4 mg/kg respectively. In Candida glabrata, PTA was reached the standard for MIC ≤ 0.004 μg/ml, ≤0.016 μg/ml, ≤0.016 μg/ml, ≤0.032 μg/ml, ≤0.064 μg/ml and ≤0.125 μg/ml of dosage regimen included 0.5 mg/kg, 1 mg/kg, 1.5 mg/kg, 2 mg/kg, 3 mg/kg and 4 mg/kg respectively. In Candida guilliermondii, PTA of all MIC values did not meet the standards. When the administration scheme of C. krusei was 0.5 mg/kg, PTA of all MIC values did not meet the standards, and the rest reached the standards: 1 mg/kg, 1.5 mg/kg, 2 mg/kg with MIC ≤ 0.016 μg/ml; 3 mg/kg, 4 mg/kg with MIC ≤ 0.032 μg/ml, ≤0.064 μg/ml respectively. In C. parapsilosis, the PTA < 90% of all MIC values was dosage regimen of 0.5 mg/kg. And the rest reached the standards: 1 mg/kg, 1.5 mg/kg with MIC ≤ 0.016 μg/ml; 2 mg/kg, 3 mg/kg, 4 mg/kg with MIC ≤ 0.032 μg/ml, ≤ 0.064 μg/ml respectively. In C. tropicalis, the PTA < 90% of all MIC values was dosage regimen of 0.5 mg/kg and 1 mg/kg. And the rest reached the standards: 1.5 mg/kg, 2 mg/kg with MIC ≤ 0.016 μg/ml; 3 mg/kg, 4 mg/kg with MIC ≤ 0.032 μg/ml, ≤0.064 μg/ml respectively.
3.2. Cumulative Fraction of Response (CFR)
According to MCS analysis results, the CFR values of children who were neutropenia with fever treated with Micafungin under different administration regimens were obtained (shown in Table 3). The results showed that Micafungin had poor antibacterial effect on C. guilliermondii,C. krusei, C. parapsilosis, and CFR of C. guilliermondii, C. krusei, C. parapsilosis 4 mg/kg of Micafungin less than 90%. CFR of C. albicans and C. glabrata excluding with the dosage of Micafungin 1 mg/kg more than 90%. CFR of C. tropicalis at 3 to 4 mg/kg administration of Micafungin more than 90%.
4. Discussion
Invasive fungal infections are the leading cause of death in children with neutropenia, with a high mortality rate for severe infections despite the introduction of antifungal agents in treatment [1]. Micafennet is currently the preferred drug for the treatment of Candida infection. ANDES et al. [12] showed that micafennet had good antibacterial effect when f AUC/MIC approached 10. Lepak et al. [11] showed that micafennet had good antifungal effect on Candida when f AUC/MIC was ≥10. Therefore, our study set as that the target Candida spp. target value f AUC/MIC ≥ 10 is the best antifungal effect. According to PK/PD parameters of micafennet in children with neutropenia, MCS was used to analyze whether different administration regimens of micafennet could reach the target value, so as to make the antifungal treatment of patients more reasonable.
Micafengin was initially administered at different doses for different Candida species, with a recommended dose of 0.5 - 4 mg/kg for children with neutropenia.
![]()
Table 3. CFR expectation values (%) against six species of Candida spp. for Micafungin.
Our study showed that when micafengin administration regimen was 0.5 mg/kg, 1 mg/kg, 1.5 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, The infection caused by C. guilliermondii, C. krusei, C. Parapsilosis is not effective, The optimal dosing regimen for C. albicans and C. glabrata and C. tropicalis is 1 mg/kg, 1 mg/kg, and 3 mg/kg, respectively, and the results were similar to the recommended dosing regimen for micafennet for invasive Candida infection in children that has been reported [13].
Considering the imperfection of immune function in children and the immature development of liver and kidney organs, the drug should not be used empirically according to the adult dose. MCSs is a random sampling analysis method, which simulates tens of thousands of times according to the pharmacological process of drugs in different patients and fully considers the difference in drug sensitivity of different strains of the same pathogen, so as to calculate PTA and CFR values and evaluate the rationality of drug administration plan. However, this study still has some limitations. Due to the lack of grouping studies of children in different age groups, relevant PK data cannot be obtained, so patients cannot be evaluated according to specific age. In summary, micafennet has been recognized for the prevention and treatment of invasive Candida infections in infants and children. In the treatment of invasive fungal infection in children with neutropenia, micafennet should be fully considered to adjust the administration regimen. The results of this study showed that, for infection caused by C. albicans, C. glabrata and C. tropicalis, the optimal administration regimen was 1 mg/kg, 1 mg/kg, and 3 mg/kg, respectively. For C. guilliermondii, C. krusei, C. parapsilosis infection when the antifungal effect is not good, it is recommended to adjust other drugs or combined drugs.
5. Conclusion
In conclusion, the results of PK/PD modelling and Monte Carlo simulations suggest that Micafungin has significant effects on C. albicans and C. glabrata, C. tropicalis in children with febrile neutropenic. The optimal administration regimen was 1 mg/kg, 1mg/kg and 3 mg/kg. In the case of infection caused by C. guilliermondii, C. krusei and C. parapsilosis, Micafungin has a poor antifungal effect, and then it is suggested to adjust other drugs or combine with other antifungal drugs.
Acknowledgements
This study was funded by the Study and Development Fund for Sciences and Technology in Chengde City (No. 202006A072) and the Hospital Pharmacy scientific research project of the Hebei Pharmaceutical Society (No. 2020-Hbsyxhqn0030).
NOTES
*Corresponding author.
#Jiuli Hu and Ying Wang contributed equally to this work.