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Safety, Effectiveness and Exposure-response of Micafungin in Infants

Application of an Established Pharmacokinetics Model to Electronic Health Records

Rivera-Chaparro, Nazario D., MD*,†; Ericson, Jessica, MD, MPH; Wu, Huali, PhD*; Smith, P. Brian, MD, MPH, MHS*,†; Clark, Reese H., MD§; Benjamin, Daniel K. Jr., MD, PhD*,†; Cohen-Wolkowiez, Michael, MD, PhD*,†; Greenberg, Rachel G., MD, MB, MHS*,†

The Pediatric Infectious Disease Journal: February 2019 - Volume 38 - Issue 2 - p e26–e28
doi: 10.1097/INF.0000000000002045
Antimicrobial Reports

Micafungin is used off-label in the United States to treat invasive candidiasis in neonates. We used an established pharmacokinetic model to determine micafungin exposures for 46 courses in 39 hospitalized infants. In this small cohort of infants, micafungin exposure was not associated with laboratory markers of liver toxicity, death or failure of microbiologic clearance.

From the *Duke Clinical Research Institute

Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina

Department of Pediatrics, Penn State College of Medicine, Hershey, Pennsylvania

§Pediatrix Medical Group, Inc., Sunrise, Florida.

Accepted for publication February 28, 2018.

N.D.R.-C. is supported by training grant T32 from the National Institute of Child Health and Human Development (T32GM086330-06). R.G.G. receives salary support from the National Institutes of Health (HHSN 275201000003I, HHSN272201300017I) and from the US Food and Drug Administration (HHSF223201610082C). M.C.-W. receives support for research from the National Institutes of Health (1R01-HD076676-01A1), National Institute of Allergy and Infectious Diseases (HHSN272201500006I, HHSN272201300017I), National Institute of Child Health and Human Development (HHSN275201000003I), Biomedical Advanced Research and Development Authority (HHSO100201300009C) and industry for drug development in adults and children (www.dcri.duke.edu/research/coi.jsp). D.K.B. receives support from the National Institutes of Health (award 2K24HD058735-06), National Institute of Child Health and Human Development (HHSN275201000003I), National Institute of Allergy and Infectious Diseases (HHSN272201500006I), Environmental Influences on Child Health Outcomes Program (1U2COD023375-01) and National Center for Advancing Translational Sciences (1U24TR001608-01); he also receives research support from Cempra Pharmaceuticals (subaward to HHSO100201300009C) and industry for neonatal and pediatric drug development (www.dcri.duke.edu/research/coi.jsp). P.B.S. receives salary support for research from the NIH (NIH-1R21HD080606-01A1), the National Institute for Child Health and Human Development (NICHD; HHSN275201000003I) and industry for drug development in adults and children (www.dcri.duke.edu/research/coi.jsp). H.W. receives salary support for research from the National Institutes of Health Clinical and Translational Science Award (5UL1TR001117-05). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR001117. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

The authors have no conflicts of interest to disclose.

Address for correspondence: Michael Cohen-Wolkowiez, MD, PhD, Duke Clinical Research Institute, 2400 Pratt Street, Durham, NC 27705. Email: michael.cohenwolkowiez@duke.edu.

Mortality of invasive candidiasis (IC) in extremely premature infants is as high as 30%.1 , 2 Standard of care for treatment of IC in the United States includes amphotericin B deoxycholate, lipid formulations of amphotericin B deoxycholate or fluconazole. However, because of concerns for toxicity (amphotericin B deoxycholate) or resistance among certain Candida species (fluconazole), echinocandins are increasingly used in infants.3

Micafungin is an echinocandin and is US Food and Drug Administration–approved in the United States for use in adults and children >4 months of age,4 though the European Medicines Agency has approved micafungin as a recommended treatment option in neonates.5 The safety of micafungin has been evaluated in small studies including infants <120 days of age with few adverse effects reported.6 A small pharmacokinetic (PK) study in infants showed that a dose of 10 mg/kg every 24 hours achieved desired therapeutic and safe exposures [area under the curve (AUC)0–24 target of 166.5 mg·h/L].7 However, the effectiveness and safety of micafungin in infants and the relationship between exposure and these outcomes have not been evaluated in larger cohorts of infants.

To evaluate these relationships, large clinical trials would need to be conducted, which are not feasible in this vulnerable population. Alternative approaches, including the use of electronic health records, can be leveraged to obtain answers to these questions. The objective of this study was to evaluate the safety, effectiveness and the exposure–response relationship of micafungin in infants <120 days of age using a combination of electronic health records and simulated drug exposure.

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MATERIALS AND METHODS

Included infants were exposed to micafungin before day of life 120 at 1 of 348 neonatal intensive care units managed by the Pediatrix Medical Group (Sunrise, FL) between 2006 and 2015. Data on multiple aspects of care were entered into a shared electronic health record to generate admission and daily progress notes and discharge summaries and then transferred to the Pediatrix Clinical Data Warehouse for quality-improvement and research purposes.8 From this database, the following elements were extracted: dosing frequency, including total daily dose of micafungin; gestational age (GA); daily weights; microbiologic culture data and laboratory values [alanine transaminase (ALT), aspartate aminotransferase (AST) and direct bilirubin]. Infants missing dosing information for micafungin were excluded from analyses relating exposure to safety and effectiveness. Clinical characteristics were reported, and analyses were performed at the course level.

Drug exposure simulations were performed using a previously published population PK model in young infants.7 Using simulated concentrations in each infant, AUC from 0 to 24 hours (AUC0–24) was generated on each day after initiating micafungin. Micafungin doses ≥9 mg/kg/d were considered to be therapeutic, and doses <9 mg/kg/d were considered to be underdosed.7

Values 3 times the upper limit of normal for AST (>360 U/L), ALT (>135 U/L) and direct bilirubin (>1.4 mg/dL) were considered laboratory adverse events. Laboratory adverse events were recorded if they occurred on a day that micafungin therapy was given. Unadjusted comparisons between groups were performed using Fisher exact test. Univariable generalized estimating equations were used to evaluate the association of micafungin AUC0–24 >166.5 and >249.8 mg·h/L (which represents 1.5 times the target AUC0–24), with elevated AST, ALT and direct bilirubin levels for each day. These AUC0–24 values were chosen based on a recent study that used 166.5 mg·h/L as the therapeutic target.7 Multiple observations per infant were accounted for using generalized estimating equations. P values of <0.05 were considered statistically significant. Analyses were performed using Stata 14.1 (College Station, TX).

Based on culture data, treatment courses were divided into 3 groups: (1) definite IC, defined as a positive culture for Candida obtained during micafungin therapy or 7 days before start of micafungin therapy from sterile body fluid (blood, suprapubic or catheterized urine, cerebrospinal fluid, abscess or peritoneal fluid); (2) probable IC, defined as a positive culture for Candida obtained during micafungin therapy or 7 days before start of micafungin therapy from another location (trachea, nonsterile urine, rectum, skin, umbilical cord) and (3) no IC, defined as either no positive cultures or unknown source. The proportion in each group in which the infant experienced death (defined as all-cause mortality before hospital discharge) or microbiologic clearance (defined as a negative blood culture on the last blood culture obtained before the end of therapy) was determined and compared using Fisher exact test.

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RESULTS

A total of 116 infants received 130 courses of micafungin. The median GA was 25 weeks (25th–75th percentiles: 24–27 weeks), median birth weight (BW) was 748 g (25th–75th percentiles: 591–940 g) and 77% of courses were prescribed to infants <1000 g BW. Median micafungin course duration was 12 days (25th–75th percentiles: 8–25 days); of note, 20 courses are missing the end date. Dosing data were available for 46 courses in 39 infants. Doses ranged from 2 to 15 mg/kg/d. The median doses for the underdosed and therapeutic subgroups were 6 mg/kg/d (25th–75th percentiles: 5.5–7 mg/kg/d) and 10 mg/kg/d (10–10.5 mg/kg/d), respectively. The majority of the courses (31/46, 67%) were therapeutic. The median AUC0–24 was 224 mg·h/L (25th–75th percentiles: 167–295 mg·h/L).

AST, ALT and direct bilirubin values were obtained in 56 of 130 (43%), 62 of 130 (48%) and 59 of 130 (45%) courses, respectively. Of these, 5 of 56 (9%) courses had an abnormal AST value, 5 of 62 (8%) courses had an abnormal ALT value and 44 of 59 (75%) courses had an abnormal direct bilirubin value. AUC0–24 >166.5 mg·h/L was not associated with elevated AST (P = 0.23), ALT (P = 0.33) or direct bilirubin (P = 0.11). Similarly, AUC0–24 >249.8 mg·h/L was not associated with elevated ALT (P = 0.73) or direct bilirubin (P = 0.23). No infants with AUC0·24 >249.8 mg·h/L had an elevated AST.

Of the 130 micafungin courses, 65 (50%) were associated with definite IC, 13 (10%) were associated with probable IC and 52 (40%) were associated with no IC. Of the positive cultures, 76% were obtained from blood, 10% from urine, 0.3% from the cerebrospinal fluid and 14% from other sites. Mortality data were available for 101 infants (114 courses), and 33 of 101 (33%) infants died. Death occurred after 16 of 59 (27%) courses associated with definite IC, 2 of 10 (20%) courses associated with probable IC and 19 of 45 (42%) courses associated with no IC. There was no difference in death or microbiologic clearance according to IC group or micafungin dosing or exposure at a course level (Table 1).

TABLE 1

TABLE 1

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DISCUSSION

This is the largest study to date exploring the safety and effectiveness of micafungin in infants. We leveraged a previously validated PK model and the availability of detailed micafungin data in our cohort to evaluate the exposure–response relationship. The micafungin US Food and Drug Administration label does not specifically address exposures associated with toxicity in children.4 In adults, doses resulting in AUC0–24 >663 mg·h/L may be associated with toxicity.4 Compared with adults, the simulated exposure in our population was lower and was not associated with increased liver toxicity.

Our findings are similar to those reported in a postmarketing surveillance study in 91 Japanese pediatric patients.9 In this study, the most common adverse effects observed were hyperbilirubinemia and abnormal hepatic function, but the 18 neonates included did not experience any adverse effects. Ten neonates included in the efficacy arm showed a clinical response rate of 90% measured by microbiologic clearance and overall clinical improvement. While effectiveness in our study was lower than that observed previously (33% of infants in our study died), the majority of infants in our study were extremely premature and critically ill. The previous study did not specify the GAs or BWs of affected infants. In other small investigations, no adverse effects were associated with micafungin exposure in 12 infants supported with extracorporeal membrane oxygenation10 or 18 infants who received high-dose micafungin for IC and meningoencephalitis.6 In the latter report, 14 of 18 (78%) infants had resolution of infection.6

Our study has several limitations: we used observational data with a relatively small sample size, complete dosing and laboratory data were not available for every course, cultures were not always obtained to document microbiologic clearance and we did not consider other concomitant antifungals to which infants may have been exposed, which was likely to impact effectiveness. We were also unable to determine whether some of the lower doses were given for prophylaxis rather than treatment. Additionally, we were unable to adjust for potential confounders because of low numbers of infants in each exposure group. Because of the small sample size, we were unable to evaluate other dosing regimens (such as ≤4 mg/kg/d).

Our data suggest that increased exposure to micafungin was not associated with adverse laboratory effects, including hepatic toxicity, in this group of infants. This study also provides proof of concept of a new methodology for the use of electronic medical record data to study drug effectiveness and safety in infants. Further prospective studies are needed to confirm safety and effectiveness of micafungin in hospitalized infants.

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REFERENCES

1. Viscoli C, Bassetti M, Castagnola E, et al. Micafungin for the treatment of proven and suspected invasive candidiasis in children and adults: findings from a multicenter prospective observational study. BMC Infect Dis. 2014;14:725.
2. Benjamin DK Jr, Stoll BJ, Fanaroff AA, et al; National Institute of Child Health and Human Development Neonatal Research Network. Neonatal candidiasis among extremely low birth weight infants: risk factors, mortality rates, and neurodevelopmental outcomes at 18 to 22 months. Pediatrics. 2006;117:84–92.
3. Greenberg RG, Benjamin DK Jr. Neonatal candidiasis: diagnosis, prevention, and treatment. J Infect. 2014;69(suppl 1):S19–S22.
4. Mycamine [package insert]. 2005.Northbrook, IL: Astellas Pharma US, Inc.
5. European Medicines Agency. Mycamine. 1995–2017. Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000734/human_med_000911.jsp. Accessed June 12, 2017.
6. Auriti C, Falcone M, Ronchetti MP, et al. High-dose micafungin for preterm neonates and infants with invasive and central nervous system Candidiasis. Antimicrob Agents Chemother. 2016;60:7333–7339.
7. Hope WW, Smith PB, Arrieta A, et al. Population pharmacokinetics of micafungin in neonates and young infants. Antimicrob Agents Chemother. 2010;54:2633–2637.
8. Spitzer AR, Ellsbury DL, Handler D, et al. The Pediatrix BabySteps Data Warehouse and the Pediatrix QualitySteps improvement project system–tools for “meaningful use” in continuous quality improvement. Clin Perinatol. 2010;37:49–70.
9. Kobayashi C, Hanadate T, Niwa T, et al. Safety and effectiveness of Micafungin in Japanese pediatric patients: results of a postmarketing surveillance study. J Pediatr Hematol Oncol. 2015;37:e285–e291.
10. Autmizguine J, Hornik CP, Benjamin DK Jr, et al. Pharmacokinetics and safety of Micafungin in infants supported with extracorporeal membrane oxygenation. Pediatr Infect Dis J. 2016;35:1204–1210.
Keywords:

Micafungin; safety; exposure; infants

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