Population Pharmacokinetics (PK) of Micafungin in Neonates and Children.

W. W. HOPE1, J. J. KEIRNS 2, D. N. BUELL 2, N. L. SEIBEL 3, G. P. HERESI 4, G. L. DRUSANO 5, T. J. WALSH 1;

Author address: 

1NCI, Bethesda, MD, 2Astellas Pharma US, Deerfield, IL, 3Children's Natl. Med. Ctr., Washington, DC, 4UT Med. Sch. at Houston, Houston, TX, 5Ordway Res. Inst., Albany, NY.

Abstract: 

Background: Micafungin is an echinocandin that has been used in neonates and children. We developed three pediatric population PK models for micafungin. Methods: Micafungin was administered over 0.5 and 1 hour in neonates (n=22) and children (n=72), respectively. Serum concentrations were determined by HPLC. Samples were obtained on day 1 and at steady state in the majority of patients. Data were modeled using the nonparameteric adaptive grid program with adaptive γ and weighted using the inverse of the estimated assay variance. The relationships between the individual Bayesian parameter estimates and relevant covariates were studied. Results: The mean ± SD weight and postconceptional age in neonates was 1.37 ± 0.39 kg and 31.14 ± 3.26 weeks, respectively. The weight and age in children was 35.65 ± 18.66 kg and 9.01 ± 4.47 years, respectively. The population PK parameters in neonates were: Vc 0.34 ± 0.11 L, Kcp 3.42 ± 5.72 h-1, Kpc 2.63 ± 6.12 h-1, clearance 0.077 ± 0.065 L/h; r2 98.5%; mean weighted error (MWE) -0.74, bias adjusted mean weighted squared error (BMWSE) 26.18. The population PK parameters in children were: Vc 5.85 ± 3.42 L, Kcp 0.97 ± 2.04 h-1, Kpc 1.54 ± 4.03 h-1, clearance 0.64 ± 0.36 L/h; r2 95.9%, MWE -0.93, BMWSE 22.2. In children, there was a linear relationship between clearance and weight. An expanded model incorporating weight produced a significantly more likely solution (p=0.013) and revealed: Vc 5.18 ± 2.75 L, Kcp 1.85 ± 4.23 h-1, Kpc 2.39 ± 6.37 h-1, clearance = (A + Bx weight), where A=0.48 ± 0.21 L/h and B=0.0034 ± 0.0045 L/h/kg; r2 95.9%, MWE -0.49, BMWSE 23.23. For all three models, the parameter means and dispersions could be recapitulated using Monte Carlo simulation. Conclusions: Pediatric population PK models for micafungin have been developed and will aid in a further understanding of the prophylactic and therapeutic role of this agent.
2006

abstract No: 

M-299

Full conference title: 

46th Interscience Conference on Antimicrobial Agents and Chemotherapy
    • ICAAC 46th