Safety of Micafungin in Infants: Insights into Optimal Dosing

Abstract

Introduction

Invasive Candida infections are a leading cause of mortality and morbidity in neonatal intensive care units (NICUs). Micafungin is a promising therapeutic option for treatment of invasive fungal infections in infants given its safety profile in older children and adults. Understanding micafungin safety in infants is particularly important because antifungals are most often used in premature infants with multiple underlying medical conditions in a critical care setting.

Areas covered

This article reviews the literature evaluating the safety profile of micafungin in infants and offers recommendations for optimal dosing for treatment of invasive candidiasis in the NICU setting. The review was performed using a Medline search in September 2010 for related articles from 1990 to present with the Mesh related terms ‘micafungin’ and ‘safety’ in combination with the free words ‘antifungal’, ‘candidiasis’, ‘drug toxicity’, ‘infant, premature’, and ‘infant, newborn’.

Expert opinion

Despite the limitations of the existing literature, we believe micafungin dosing of 10 mg/kg/day for all term and preterm infants is a viable treatment option in the NICU setting for management of invasive candidiasis. Although the number of infants for whom safety data are reported is small, higher doses of micafungin appear safe and well-tolerated in this population.

1. INTRODUCTION

Invasive Candida infections are a leading cause of mortality and morbidity in neonatal intensive care units (NICUs)[1–4]. The cumulative incidence of candidemia among extremely low birth weight infants (<1000 g birth weight) is 7%. Invasive Candida infections result in an associated mortality rate of 20–30% in this population and frequently lead to significant morbidities including neurodevelopmental impairment, chronic lung disease, and severe retinopathy of prematurity[1–2, 4].

Treatment of invasive Candida infections in infants typically consists of amphotericin B deoxycholate or fluconazole. However, use of echinocandin antifungals in this population is increasing[5–7]. Echinocandins compromise fungal cell wall synthesis by non-competitive inhibition of the enzyme 1,3-β glucan synthase, resulting in cell lysis [8]. This mechanism offers a high degree of specificity for fungi such as Candida. Echinocandins may play an increasingly important role in the treatment of invasive Candida infections with the rising incidence of both non-albicans species and fluconazole-resistant Candida species in the NICU[9] and studies demonstrating similar efficacy and improved safety profiles when compared to amphotericin B deoxycholate and fluconazole[10–11].

Micafungin (FK463; Astellas Pharma US, Inc, Deerfield, IL) is an echinocandin with established in vitro and in vivo concentration-dependent fungicidal activity against most Candida species[12–13], including fluconazole-resistant species and the species most commonly affecting infants (C. albicans, C. parapsilosis, C. glabrata, C. tropicalis, and C. krusei)[14]. Although the minimum inhibitory concentration (MIC) distribution for C. parapsilosis is over 100 times higher than that for other commonly isolated Candida species[15], the MIC breakpoint of 2 μg/mL for micafungin is inclusive of nearly all Candida isolates including C. parapsilosis[16]. Like other echinocandins, micafungin has a high molecular weight and is largely protein-bound in plasma, resulting in relatively low urine and cerebrospinal fluid (CSF) levels. It is metabolized by the liver, but because the cytochrome P450 system does not play a role, micafungin has few drug-drug interactions[17].

Micafungin is not approved for pediatric use in the United States. In the European Union and Japan, it is approved for children including neonates for treatment of invasive candidiasis and for prophylaxis against Candida infections in patients with anticipated neutropenia or patients undergoing allogeneic hematopoietic stem cell transplantation. While adult studies have demonstrated both efficacy and safety, there is a paucity of data demonstrating safety and optimal dosing in infants. Understanding micafungin safety in infants is particularly important because antifungals are most often used in premature infants with multiple underlying medical conditions in a critical care setting. The purpose of this article is to review the literature evaluating the safety profile of micafungin in infants and offer recommendations for optimal dosing for treatment of invasive candidiasis in the NICU setting.

2. SEARCH STRATEGY

This review was performed using a Medline search in September 2010 for related articles from 1990 to present with the Mesh related terms ‘micafungin’ and ‘safety’ in combination with the free words ‘antifungal’, ‘candidiasis’, ‘drug toxicity’, ‘infant, premature’, and ‘infant, newborn’. Both abstracts and manuscripts were considered. References from relevant articles were also reviewed. No language restriction was applied.

3. SAFETY PROFILE IN ADULTS, CHILDREN, AND INFANTS

3.1 Adults

Several trials in adult patients have demonstrated the safety of micafungin[18–21]. Two dose-escalation studies of adult cancer patients undergoing hematopoietic stem cell transplant showed micafungin to be well-tolerated in this high-risk group[19, 21]. A study of 74 patients assessed micafungin safety at 12.5, 25, 50, 75, 100, 150, and 200 mg/day in combination with fluconazole 400 mg/day for up to 4 weeks[19]. The second study of 36 patients assessed the maximum tolerated dose of micafungin at 3, 4, 6, and 8 mg/kg/day for up to 4 weeks[21]. In both studies, the maximum planned dose was reached with no apparent toxicity. Changes in hepatic and renal function showed no meaningful dose trend. Common adverse events related to micafungin use in adults included headache (7%), arthralgias (7%), hypophosphatemia (4%), insomnia (4%), and rash (4%)[19].

A dose-response trial found micafungin doses of 100 mg and 150 mg compared favorably with a fluconazole dose of 200 mg in safety and tolerability for treatment of esophageal candidiasis in 245 HIV-positive adult patients[20]. The study showed a comparable incidence of all-cause adverse events between the fluconazole group (89.2%) and the micafungin dose groups (93.3%). Micafungin was not associated with any clinically relevant laboratory changes, and there was no difference in the incidence of mild liver function test (LFT) changes between fluconazole (11.7%) and micafungin (12.9%) cohorts. Safety in adults has been demonstrated in hematopoietic stem cell transplant patients at 8 mg/kg/day and a mean area under the curve (AUC) up to 663 μg*hr/mL.[21–22]

3.2 Children

Pediatric studies have also examined the safety profile of micafungin [23–24]. A multicenter dose-escalation study of 77 febrile neutropenic pediatric patients ages 2 to 17 years assessed micafungin dosing ranging from 0.5 to 4 mg/kg/day and demonstrated excellent safety and tolerability [23]. Only two patients, ages 13 to 17 years, experienced modest LFT changes at 0.5 mg/kg that were considered possibly related to the micafungin. There were no other significant changes in LFTs, renal function, or hematology parameters. Nine patients (12%) experienced adverse events considered possibly related to micafungin; most common were diarrhea (2.6%), vomiting (2.6%), and headache (2.6%). There were no deaths or withdrawal from the study related to micafungin use, and no dose-limiting toxicity was observed.

An analysis of 296 pediatric patients that pooled adverse events data from several clinical trials found a favorable micafungin safety profile in a wide range of pediatric patients [25]. The average age was 6.5 years, and 26% were < 2 years of age and 6% were < 4 weeks of age. The patients had multiple underlying conditions, including neutropenia (40%), malignancy (38%), and hematopoietic stem cell or solid organ transplantation (34%). Adverse events considered at least possibly related to micafungin administration included: hypokalemia (3.0%), alanine transaminase (ALT) increase (3.0%), aspartate transaminase (AST) increase (2.0%), alkaline phosphatase increase (2.0%), hyperbilirubinemia (2.0%), and hypertension (2.0%). Seven patients (2.4%) with related adverse events required treatment cessation. The adverse events included neutropenia, jaw and joint pain, rash, increased AST and ALT, abnormal LFTs, and two serious adverse events: hyperbilirubinemia and increased serum creatinine. No follow-up data was available for the patient with hyperbilirubinemia. The patient with increased serum creatinine had levels elevated from a baseline of 57 μmol/L to 73 μmol/L. After treatment cessation, serum creatinine returned to 28 μmol/L.

3.3 Infants

Four recent trials have assessed the pharmacokinetics and safety of micafungin in infants (Table 1). A multi-center, single-dose, sequential-dose study assessed micafungin dosing of 0.75, 1.5, and 3 mg/kg in 18 premature infants > 1000 g and 0.75 mg/kg in 5 infants < 1000 g[26]. The study demonstrated favorable safety and tolerability across all dose levels in the premature infants. One subject > 1000 g experienced an adverse event possibly related to micafungin (moderate hypokalemia) in the 3.0 mg/kg cohort. Two subjects > 1000 g experienced serious adverse events unrelated to micafungin use: one subject developed necrotizing enterocolitis and another subject developed bronchopulmonary dysplasia. A subsequent single-center, multiple-dose study assessed micafungin dosing at 15 mg/kg (a dose extrapolated from the initial infant pharmacokinetic study above[26] and a hematogenous Candida meningoencephalitis (HCME) model developed in rabbits[27]) in 5 premature infants > 1000 g and 7 premature infants < 1000 g[28]. No adverse events were considered related to micafungin use, though all patients had at least one adverse event. This was consistent with the underlying conditions of the critically ill patient population. Mean serum potassium was higher at the end of therapy (4.6 versus 4.0 mmol/L at baseline), but there was no other hematologic or serum chemistry laboratory changes.

Table 1.

Pharmacokinetic and Safety Trials of Micafungin in Infants

	N	Mean weight at time of therapy (g)	Dose (mg/kg)	Subjects with drug-related adverse events (%)	Drug -related adverse events
Kawada et al.[29]	25	Unknown	1.0	0 (0%)	None
Heresi et al.[26]	23	1374	0.75, 1.5, 3	1 (4%)	hypokalemia
Smith et al.[28]	12	996	15	0 (0%)	None
Benjamin et al.[30]	13	1449	7, 10	3 (23%)	increased alkaline phosphatase, phlebitis, hypokalemia, elevated temperature

Another study assessed the safety of micafungin prophylaxis at a dose of 1 mg/kg in 25 infants <1500 g birth weight[29]. Infants were given micafungin once daily for 6 weeks. Micafungin was well tolerated in all cases, and there were no adverse events leading to treatment cessation. Additionally, there were no abnormal LFTs or renal function tests considered related to micafungin use.

Finally, a multi-center, multiple-dose study assessed micafungin dosing at 7 mg/kg in 7 premature infants > 1000 g and 10 mg/kg in 6 premature infants < 1000 g [30]. The majority, 12/13 (92.3%), of the infants in this critically ill population experienced an adverse event. Three subjects experienced adverse events considered possibly or probably related to micafungin (increased alkaline phosphatase, infusion site phlebitis, hypokalemia, and elevated temperature). The increase in alkaline phosphatase was considered a serious adverse event. No deaths occurred in the study, and no patients withdrew because of an adverse event. There was minimal or no evidence of laboratory changes in LFTs, renal function, or hematologic parameters.

4. INVASIVE CANDIDIASIS CONSIDERATIONS IN INFANTS

In contrast to invasive candidiasis in adults and older children, invasive candidiasis commonly manifests as HCME in premature infants [31]. Neonatal HCME, a complication of Candida spreading to the central nervous system (CNS), warrants attention given its associated high mortality rates, neurodevelopmental sequelae, and difficulty in dignosis using blood and CSF cultures [1, 4, 32–33].

An in vivo-to-clinical bridging study of HCME in a rabbit model provided a proof-of-principle that micafungin can treat neonatal HCME at high doses [27]. Specifically, the study administered micafungin doses up to 16 mg/kg to rabbits with HCME and demonstrated a dose-proportional exposure-response relationship where 8 mg/kg achieved near-maximal effect in this model. These results were replicated using Monte Carlo simulations in neonatal pharmacokinetic data described elsewhere [26], suggesting that doses of micafungin in the range of 9 to 15 mg/kg are required to achieve fungicidal concentrations in the CNS for treatment of neonatal HCME.

5. PHARMACOKINETIC CONSIDERATIONS IN INFANTS

The pharmacokinetics of micafungin, particularly its weight-based clearance rate, varies by age group. Comparison of single dose studies in adult, pediatric, and infant patient populations shows micafungin clearance in premature infants > 1000 g to be ~1.7 times that of children ages 2 to 8 years and ~ 2.6 times that of adults and children ages 9 to 17 years [19, 23, 26]. Another pharmacokinetics study showed higher micafungin clearance in infants immediately after birth compared to infants 3 to 8 weeks old [26, 29]. Higher clearance rates in young infants may be attributable to differences in plasma protein binding by micafungin. The wide discrepancy in weight-based clearance between infants and adults suggests higher weight-based doses in infants are required to achieve comparable systemic exposure levels.

6. CONCLUSIONS

Studies of micafungin in adults and older children show micafungin to be well-tolerated. Recent studies in premature infants have explored safety of micafungin at weight-adjusted doses higher than previously studied in older patients. The concern for HCME and the increased clearance of micafungin in infants indicate that higher doses are potentially needed to achieve effective systemic exposure levels. Doses up to 15 mg/kg in premature infants were well-tolerated in these small trials. Doses of 10 mg/kg provide adequate systemic exposure levels to treat suspected HCME in an animal model [27].

7. EXPERT OPINION

Although results from several trials of micafungin in infants have shown the drug to be well-tolerated, these trials are small and safety was assessed in infants that received a maximum of 5 days of antifungal therapy. Only 25 of the infants for whom safety was reported received > 3 mg/kg/day [30, 34]. Safety following extended periods of administration and long term safety in this population is unknown.

We believe recommended dosing in adults should not be extrapolated to infants. Currently, recommended dose of micafungin for treatment for invasive candidiasis in adults is 100–150 mg daily [35]. The propensity for HCME in infants requires effective drug concentrations in the CNS, and the increased weight-based clearance of micafungin in infants requires relatively higher doses in infants compared with older patients. A recent study combining pharmacokinetic data from the 3 trials in infants found that micafungin exhibits linear pharmacokinetics for doses ranging from 0.75 to 15 mg/kg [36]. In addition, the study suggests that infant doses of 10 mg/kg/day result in over 80% of patients having systemic exposure levels with near-maximum fungicidal effect in the CNS.

There are no antifungal drugs approved for invasive candidiasis in the United States for use in infants < 3 months of age. Management is limited by a lack of trials studying the efficacy, pharmacokinetics, safety, and dosing of antifungals in this population. Optimal agent and length of therapy for neonatal candidiasis is unknown. Previous antifungal efficacy studies are limited to case series or underpowered trials [5, 37–40]. Despite the limitations of the existing literature, we believe micafungin dosing of 10 mg/kg/day for all term and preterm infants is a viable treatment option in the NICU setting for management of invasive candidiasis. Although there are no studies demonstrating the efficacy of micafungin prophylaxis in preterm infants, adult dosing for micafungin to prevent candidiasis in immunocompromised patients (50 mg/day) is 33–50% of the daily dose used to treat invasive and esophageal candidiasis, respectively. Based on this review, more clinical studies are warranted to better define micafungin safety profiles at weight-adjusted doses higher than doses recommended in adults. Efficacy trials are needed to assess treatment response at these higher doses and ensure adequate CNS exposure.

Article Highlights.

• Micafungin is an echinocandin antifungal with an excellent safety profile in adults but lacks large safety studies in infants.

• Higher micafungin doses per kg in infants show favorable safety profiles and are well-tolerated in small studies.

• Infants may require higher systemic exposure levels of micafungin because of increased concern for hematogenous Candida meningoencephalitis.

• Infants require higher doses per kg of micafungin because of increased clearance.

• Recent safety and pharmacokinetic trials in infants may help guide optimal dosing.

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