Pharmacokinetic/Pharmacodynamic (PK·PD) Analysis of Itraconazol against Aspergillus spp. in Patients with Fungal Infection -Investigation by using the Monte Carlo simulation

K. Yonezu1, H. Kasai2, H. Igari1, M. Nakano1

Author address: 

1Janssen pharmaceutical K.K., TOKYO, Japan 2Pharmacokinetics Analysis Group, TOKYO, Japan


Objectives: Since the 1990’s, in the area of antimicrobial research, rapid advances have been made in pharmacokinetic (PK) studies, including maximum blood concentration (Cmax), area under the blood concentration-time curve (AUC), elimination half-life (T1/2); and in pharmacodynamic (PD) studies, including minimum inhibitory concentration (MIC) and timekilling curve, greatly contributing to development of proper therapies for infections and development and marketing of novel antimicrobial agents. A notable achievement in this area was identification of the PK65381;PD parameters correlated with in vivo bactericidal action of antimicrobial agents. This enabled prediction of the therapeutic effect of a certain antimicrobial agent to some degree, based on pharmacokinetic characteristics as represented by such parameters as Cmax, AUC, and T1/2, and pharmacodynamic characteristics as represented by such parameters as breakpoint value, MIC50, and MIC90. On the other hand, in the field of antifungal research, evaluation of the optimal dosage based on PK65381;PD is not established enough. In this analysis, we performed Monte Carlo simulation using these pharmacokinetic parameters of Itraconazole in Japanese patients with mold infection, and the susceptibility data of Itraconazole against clinical isolates of Aspergillus spp. in Japan. Methods: Previously determined population pharmacokinetic (PK) parameters and plasma concentrations of itraconazole were used to postulate total clearance (CL) in individual patients. The area under the plasma concentration-time curve (AUC) at a dose of 200 mg was then determined by 200/CL. Finally, the ratio of AUC to the minimum inhibitory concentration (MIC) against Aspergillus spp. (AUC/MIC) was determined to investigate its correlation with clinical efficacy. The Monte Carlo simulation was performed with the distribution data of MIC of Itraconazole against these clinical isolates to generate the MIC data for n=10,000. Based on the time-course of blood concentrations and MIC for n=10,000, determined the probability of target attainment (TA%) for each range of AUC/MIC of these fungal infectious patients. Analyses were performed using NONMEM software (version V, level 1.1) (GloboMax LLC, Hannover, USA). Results: (1) The data of distribution of 11 isolated aspergillus spp are shown in Table 1. (2)The pharmacokinetic12539;pharmacodynamic (PK12539;PD) parameters obtained from the analyses are shown in Table 2. (3) The correlation between the probability of target attainment (TA%) and AUC/MIC is shown in Figure 1. (4) Using standard doses of itraconazole against Aspergillus spp, it was demonstrated that AUC/MIC were smaller than 10, and 90% cases were included in 0.5-10 (Figure 1). Conclusion: In this investigation, using standard dose of itraconazole against Aspergillus spp, AUC/MIC were under 10, and thus, 90% of patients receiving administration of 200mg/day itraconazole would be included from 0.15 to 10. To make sure of optimal AUC/MIC parameter for mold infection in clinical practices, we need further more investigation.

abstract No: 


Full conference title: 

4th Trends in Medical Mycology
    • TIMM 4th (2012)