Linear Pharmacokinetics of Micafungin and Its Active Metabolites in Japanese Pediatric Patients with Fungal Infections

Abstract

Development of novel medical products labeled for pediatric use is limited because it is difficult to obtain the safety and pharmacological effect data for the population at the time of approval. The International Conference on Harmonization has issued guidance E11 'clinical investigation of medical products in the pediatric population' to encourage this development. 1) In general, the dosing recommendations for pediatric patients are based on a milligrams per kilogram body weight. However, some drugs are known to exhibit agedependent pharmacokinetics. 2,3) In cases where the pharmacokinetics are represented as plasma clearance 4) or elimination half-life 5) and the disposition is age-related, direct application of the dosing regimen for adults to children with only consideration of body weight is inadequate. Therefore to assess age-related pharmacokinetics, is important and helpful to optimize the dosage regimen for children.Micafungin sodium, a new injectable anti-fungal drug classified as an echinocandin, [6][7][8][9] was first launched in Japan as Fungard TM for the treatment of deep-seated fungal infections such as Candidiasis and Aspergillosis. It was then also approved as Mycamine TM by the US Food and Drug Administration in March 2005 for the prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation and treatment for esophageal candidiasis.10)The pharmacokinetics of micafungin have been investigated in healthy adults, [11][12][13] adult patients undergoing a bone marrow or peripheral stem cell transplant, 14) febrile neutropenic pediatric patients, 15) volunteers with moderate liver disease and renal dysfunction, 16) and a study of drug-drug interaction with Tacrolimus. 17) In Japan, four phase I studies and one Phase II study in adult patients with fungal infections were conducted. Micafungin appeared to be well tolerated, and showed linear pharmacokinetics over the dose range of 2.5 to 150 mg/d (0.5-4.0 mg/kg in children). That is, the maximum plasma concentration of micafungin increased in proportion to the dose, 20) and the elimination half-life (t 1/2 ) was constant for the doses investigated at 13.5Ϯ3.1 h (meanϮS.D., nϭ95). The metabolites of micafungin, M1 (catechol form) and M2 (methoxy form), have comparable pharmacologically active in the experimental infection model, 18) and were detected in the plasma in the steady state after administration to the patient. However the plasma concentrations of M1 and M2 at the dose of 150 mg were very low compared with that of unchanged drug. 11)Thus, while the pharmacokinetics of micafungin and its metabolites in adults has been sufficiently investigated, the pediatric pharmacokinetics remain unclear. In this article, the pharmacokinetic analyses of micafungin and its metabolites in Japanese pediatric patients with fungal infections are described, and their dose-linear pharmacokinetic and age-related pharmacokinetic properties are clarified. The optimal dosage for pediatric use is also proposed herein. MATERIALS AND MET...

The Impact of Total Bilirubin on Plasma Micafungin Levels in Living-Donor Liver Transplantation Recipients with Severe Liver Dysfunction

“…12,21) In the present study, a good correlation was observed between the peak and trough concentrations of MCFG (Fig. 1A) as reported by Nakagawa et al 22) It is worth noting that the similar correlations between the peak and trough concentrations of MCFG are attributable to the fact that patients with severe liver dysfunctions have to provide additional information for the determination of appropriate dose regimens for LDLT-recipients.…”

“…1B), and this result is comparable to reports concerning patients with hematologic malignancies and pediatrics. [21][22][23] However, when the data obtained from the patients receiving a dose of 300 mg/d MCFG are excluded, the correlation is no longer significant. Additionally, because the correlation between dose and trough concentrations was as a result of a scatterplot, we investigated if other factors correlated with the trough concentration.…”

Clinical Pharmacodynamic Index Identification for Micafungin in Esophageal Candidiasis: Dosing Strategy Optimization

“…A comparison of exposure measurements for the two dosing regimens at the steady state is presented in Table 2. As previously shown in other dose escalation studies (26,27), pharmacokinetics increased in a linear manner with dose. Steady-state AUC 0 -48 values for the two dosing regimens were comparable.…”

Antifungal Activity of Micafungin in Serum

“…Blood samples were collected from patients just before (trough) and after (peak) micafungin infusion, at least 4 days after initiating treatment (steady state) (2). Micafungin concentration in serum was measured by high-performance liquid chromatography (HPLC) (9,12). The disk diffusion method was performed according to National Committee for Clinical Laboratory Standards (NCCLS) M44-A guidelines (5).…”