Randomized Pharmacokinetic Study of Fluconazole and Micafungin in Preterm Neonates with Suspected or Proven Fungal Infection

Presenter: Evelyne Jacqz-Aigrain (e-mail: [e-mail])

Introduction: Neonatal Candida infection requires urgent treatment because of high risk disease with possible central nervous system infection. Fluconazole prophylaxis is recommended in NICUs with a high incidence in fungal infections. Both fluconazole and micafungin are used for treatment in preterm and term neonates with proven or only suspected fungal infection, as candida infection is difficult to prove. Although fluconazole dose recommended in the marketing authorization is 6 mg/kg/day in neonates, maintenance doses currently used in NICUs in Europe is often higher, between 6 and 12 mg/kg. For Micafungin, the available data support the idea that only dosages greater than recommended (2 to 4 mg/kg/day) may ensure adequate coverage of the CNS. The drug-exposure target recommended for fluconazole is at least 400 mg*h/L and for micafungin is at least 166.5 mg*h/L. In this context, the current study is designed to further elucidate the pharmacokinetics of the two drugs in preterm neonates.

Methods: Drug dosages were administered as 2h infusion: fluconazole: 25 mg/kg loading dose and 12mg/kg or 20 mg/kg daily according to gestational and postnatal age, micafungin: 15 mg/kg loading dose and 10 mg/kg daily. For both drugs, sampling strategy included stratification by corrected gestational age and by sampling time with two samples in neonates <32 weeks and three in neonates ≥ 32 weeks. Pharmacokinetic samples (200 µL each) were drawn at days 1 (D1) and 5 (D5). Concentrations were measured by a highly sensitive HPLC-MSMS method. The study obtained ethic and regulatory approvals in France (five centers) and Spain.

Results: A total of 36 patients (22 boys and 14 girls) were randomized after parental consent: gestational age at birth and post-natal age were 29.5 ± 5.1 weeks and 2.9± 3.7 weeks respectively, birth and current weight were 1,417 ± 952 g and 1,736 ± 1,144 g respectively (mean ± SD). They received fluconazole (n = 18) or micafungin (n = 18) at doses defined by the protocol. A total of 164 concentrations (4.6 ±1.2 and 4.5 ±1.2 samples per patient for fluconazole and micafungin, respectively) were available for analysis. Concentrations after the first and fifth administrations are presented below (Table 1).

Table 1 Concentrations after the first and fifth administrations of Micafungin and Fluconazole

	Fluconazole			Micafungin
	Time (h)	N	Concentration (mg/L)	Time	N	Concentration (mg/L)
D1	2.4 ± 0.2	18	25.9 ± 2.5	2.4 ± 0.2	18	42.8 ± 10.8
D5	2.3 ± 0.2	15	42.3 ± 12.3	2.3 ± 0.2	13	34.8 ± 17.9

Conclusion: Population PK was conducted after administration of doses that were higher than currently used to optimize efficacy and the concept of a loading dose present in antifungal treatment strategies for adults was applied for both drugs. Analysis is ongoing using NONMEN to determine population PK parameters and optimize dosage. The results will also allow to evaluate the tolerability and to describe short-term safety of fluconazole and micafungin in neonates with suspected or culture-proven Candidiasis.

This work is part of the TINN (Treat Infections in NeoNates) network supported by the European Commission under the Health Cooperation Work Programme of the 7th Framework Programme (Grant agreement no. 223614).