CLINICAL
AND
LABORATORY OBSERVATIONS
Pharmacokinetic and Safety Profiles of Repeated-dose Prophylactic Micafungin in Children and Adolescents Undergoing Hematopoietic Stem Cell Transplantation Edythe Albano, MD,* Nkechi Azie, MD,w Mike Roy, PhD,w Robert Townsend, PhD,w and Antonio Arrieta, MDz
Summary: Micafungin is a potent echinocandin antifungal that can be used for both prophylaxis and treatment of Candida infections. This open-label study assessed the pharmacokinetics and safety profile of prophylactic micafungin in children and adolescents (aged 4 mo to 16 y) undergoing hematopoietic stem cell transplantation. Patients received once-daily doses of either 1 or 1.5 mg/kg micafungin, based on their body weight, for 10 to 14 days. In total, 40 patients received micafungin. Area under the plasma micafungin concentration–time curve was highest in patients aged 6 to 11 years in the 1.5 mg/kg treatment group. Peak plasma micafungin concentration displayed no age-related differences, but was higher in the 1.5 mg/kg versus the 1 mg/kg group. Clearance at steady state by weight and volume of distribution by weight were considerably higher in patients aged 4 months to 5 years. Results from this study show that age and body weight affect micafungin pharmacokinetics in pediatric patients undergoing hematopoietic stem cell transplantation. Key Words: candidemia, hematopoietic stem cell transplant, micafungin, pediatric, pharmacokinetics
(J Pediatr Hematol Oncol 2015;37:e45–e50)
P
revention strategies for invasive fungal disease in immunocompromised patients, such as hematopoietic stem cell transplant (HSCT) recipients, are based on
Received for publication August 2, 2013; accepted June 21, 2014. From the *Department of Pediatrics, School of Medicine and Children’s Hospital Colorado, University of Colorado, Aurora, CO; wAstellas Pharma Global Development, Northbrook, IL; and zDivision of Infectious Disease, Children’s Hospital of Orange County, Orange, CA. E.A. was an investigator on this study, was involved in analysis and interpretation of data, and provided direction for and intellectual content of manuscript drafts through meetings and correspondence. N.A. was involved in acquisition of data, participated in evaluation and assessment of data, and provided direction for and intellectual content of manuscript drafts through meetings and correspondence. M.R. was involved in the concept and design of the study, acquisition, evaluation and assessment of data, and provided direction for and intellectual content of manuscript drafts through meetings and correspondence. R.T. was involved in analysis and interpretation of data, and provided direction for and intellectual content of manuscript drafts through meetings and correspondence. A.A. was an investigator on this study, was involved in the concept and design of the study, evaluation and assessment of data, and provided direction for and intellectual content of manuscript drafts through meetings and correspondence. N.A. and R.T. are employees of Astellas. M.R. was previously an employee of Astellas. A.A. has received grants from Astellas, Pfizer, and Merck, and consultancy fees from Astellas and Pfizer. E.A. declares no conflict of interest. Reprints: Edythe Albano, MD, Department of Pediatrics, School of Medicine and Children’s Hospital Colorado, University of Colorado, 13123 East 16th Avenue, Aurora, CO 80045 (e-mail: [email protected]). Copyright r 2014 Wolters Kluwer Health, Inc. All rights reserved.
J Pediatr Hematol Oncol
environmental precautions and antimicrobial prophylaxis with antifungal medications, such as micafungin, fluconazole, or posaconazole.1 Although data suggest that treatment recommendations for invasive fungal infections should be similar for pediatric and adult patients,2 pharmacokinetic (PK) profiles of these medications observed in pediatric populations often differ from those reported from studies in adults.3 Micafungin is an echinocandin antifungal agent with potent activity against Aspergillus4 and Candida spp.,5 including non-albicans and fluconazole-resistant Candida spp.6,7 It is metabolized in the liver either into M1 (catechol form) followed by M2 (methoxy form) by the action of arylsulfatase and catechol-O-methyltransferase, respectively; or into M5 by side chain hydroxylation.8 Importantly, micafungin is not significantly metabolized by the CYP450 3A system, which may explain why this agent displays few unwanted drug–drug interactions.9 Micafungin exhibits linear PK and can be used without dose adjustment in patients with moderate-to-severe renal impairment and mild-to-moderate hepatic impairment. However, although the US Food and Drug Administration indicates that dose adjustment is not necessary for patients with severe hepatic impairment,8 the European Medicines Agency does not recommend the use of micafungin in this group of patients.10 Prophylactic micafungin therapy has been shown to be effective in both adult and pediatric patients undergoing HSCT,4 although current PK data in the latter population are limited. Previous studies and PK models suggest that PK may differ between age groups during early development.11–13 However, in these studies, micafungin therapy was initiated only following the onset of fever and neutropenia, or with a proven or presumptive diagnosis of candidemia. As yet, the PK of micafungin in pediatric patients during prophylactic treatment remain limited. Therefore, we evaluated the PK and safety of intravenous micafungin after repeated daily dosing as antifungal prophylaxis in children and adolescents undergoing HSCT.
MATERIALS AND METHODS Study Design This was a multicenter, open-label, repeat-dose phase I PK study (ClinicalTrials.gov identifier: NCT00606268). Each center received written approval from the Institutional Review Board (IRB) before commencing study activities. The study was conducted in accordance with the principles based on the International Conference on Harmonisation Guidelines, Good Clinical Practice, and the
Volume 37, Number 1, January 2015
www.jpho-online.com |
e45
Albano et al
J Pediatr Hematol Oncol
applicable laws and regulations. An IRB-approved written informed consent was obtained from each patient or their parent(s) or legal guardian(s), as appropriate, before the initiation of any study-specific procedures. Patients were enrolled according to age and stratified by weight into 2 treatment arms to receive either once-daily micafungin 1 mg/kg for patients weighing Z25 kg or 1.5 mg/kg for those weighing < 25 kg. The study drug was administered as an infusion over 1 hour for 10 to 14 days, with the maximum daily dose not exceeding 50 mg. The maximum daily dose was based on good prophylactic efficacy observed with this dose in a previous trial of micafungin in HSCT recipients.4 Micafungin therapy was initiated within 48 hours of the start of the patient’s transplant-related conditioning regimen. A physical examination was performed at baseline and at the end of therapy (EOT; within 72 h after last dose of study drug). Vital signs were measured at baseline, twice daily (before the start of the infusion and within 1 h postinfusion) during the treatment period, at EOT, and at study end (EOS; 14 d after the last dose of study drug). Medications for treatment of the patient’s underlying condition, received within 7 days before the first dose of micafungin, as well as all other concomitant medications (from baseline to EOS) were recorded.
were recorded. Safety evaluations included AE assessments, clinical laboratory evaluations, vital sign assessments, electrocardiograms, and physical examinations. Blood samples were collected for hematology (hemoglobin, hematocrit, red blood cell count, platelets, and white blood cell count, including differential) and serum chemistry (aspartate transaminase, alanine transaminase, alkaline phosphatase, g-glutamyl transferase, total bilirubin, blood urea nitrogen, calcium, serum creatinine, potassium, sodium, magnesium, chloride, and bicarbonate) measurements at baseline, twice during the treatment period, at EOT, and at EOS.
Patients Children (aged 4 mo to 11 y) and adolescents (aged 12 to 16 y) undergoing autologous, syngeneic, or allogeneic HSCT were eligible for inclusion in the study. Patients were excluded if they had significant liver disease (aspartate transaminase or alanine transaminase 10 the upper limit of normal, and total bilirubin or alkaline phosphatase >5 the upper limit of normal), an active fungal infection, hypersensitivity to echinocandins, or had received echinocandin treatment within 1 week of the first dose of study drug. Female patients who were pregnant or nursing were also excluded from the study.
PK Analyses The primary PK parameters calculated were the steady-state (day 7) micafungin; M1, M2, and M5 area under the plasma micafungin analyte concentration–time curve from time 0 (start of infusion) to 24 hours postinfusion start (AUCtau); and peak analyte concentration (Cmax). Secondary parameters included time to Cmax (Tmax), as well as micafungin clearance at steady state (CLss), volume of distribution (Vss), and half-life. To measure plasma analytes, whole-blood samples of B1 mL were collected into heparinized tubes at the following time points relative to the start of day 7 of the micafungin infusion: within 1 hour before the start of infusion; immediately (within 3 min) postinfusion; and at 2, 4, and 10 hours after start of the infusion. Single-blood samples for trough analyte concentration measurements were collected within 10 minutes before the infusion start time (predose/time 0) on days 4, 6, and 8. Plasma analyte concentrations were determined using validated highperformance liquid chromatography with fluorescence detection methods. The lower limit of quantification for micafungin and metabolite measurements was 0.05 mg/mL.
Safety Analyses Adverse events (AEs) with onset during treatment or within 14 days after the final study drug administration
e46 | www.jpho-online.com
Volume 37, Number 1, January 2015
Statistical Analyses Patients enrolled in the study who received at least 1 dose of micafungin comprised the safety analysis set. The PK analysis set consisted of those patients from the safety analysis set whose plasma micafungin concentration data were adequate for the derivation of at least 1 PK parameter. Descriptive statistics for continuous variables included the number of patients, mean, geometric mean, SD, SE, median, minimum, maximum, and coefficient of variation. Frequencies and percentages were used to describe categorical data; unless otherwise specified, summaries were presented for each treatment, for each age cohort (4 to
AND
LABORATORY OBSERVATIONS
Pharmacokinetic and Safety Profiles of Repeated-dose Prophylactic Micafungin in Children and Adolescents Undergoing Hematopoietic Stem Cell Transplantation Edythe Albano, MD,* Nkechi Azie, MD,w Mike Roy, PhD,w Robert Townsend, PhD,w and Antonio Arrieta, MDz
Summary: Micafungin is a potent echinocandin antifungal that can be used for both prophylaxis and treatment of Candida infections. This open-label study assessed the pharmacokinetics and safety profile of prophylactic micafungin in children and adolescents (aged 4 mo to 16 y) undergoing hematopoietic stem cell transplantation. Patients received once-daily doses of either 1 or 1.5 mg/kg micafungin, based on their body weight, for 10 to 14 days. In total, 40 patients received micafungin. Area under the plasma micafungin concentration–time curve was highest in patients aged 6 to 11 years in the 1.5 mg/kg treatment group. Peak plasma micafungin concentration displayed no age-related differences, but was higher in the 1.5 mg/kg versus the 1 mg/kg group. Clearance at steady state by weight and volume of distribution by weight were considerably higher in patients aged 4 months to 5 years. Results from this study show that age and body weight affect micafungin pharmacokinetics in pediatric patients undergoing hematopoietic stem cell transplantation. Key Words: candidemia, hematopoietic stem cell transplant, micafungin, pediatric, pharmacokinetics
(J Pediatr Hematol Oncol 2015;37:e45–e50)
P
revention strategies for invasive fungal disease in immunocompromised patients, such as hematopoietic stem cell transplant (HSCT) recipients, are based on
Received for publication August 2, 2013; accepted June 21, 2014. From the *Department of Pediatrics, School of Medicine and Children’s Hospital Colorado, University of Colorado, Aurora, CO; wAstellas Pharma Global Development, Northbrook, IL; and zDivision of Infectious Disease, Children’s Hospital of Orange County, Orange, CA. E.A. was an investigator on this study, was involved in analysis and interpretation of data, and provided direction for and intellectual content of manuscript drafts through meetings and correspondence. N.A. was involved in acquisition of data, participated in evaluation and assessment of data, and provided direction for and intellectual content of manuscript drafts through meetings and correspondence. M.R. was involved in the concept and design of the study, acquisition, evaluation and assessment of data, and provided direction for and intellectual content of manuscript drafts through meetings and correspondence. R.T. was involved in analysis and interpretation of data, and provided direction for and intellectual content of manuscript drafts through meetings and correspondence. A.A. was an investigator on this study, was involved in the concept and design of the study, evaluation and assessment of data, and provided direction for and intellectual content of manuscript drafts through meetings and correspondence. N.A. and R.T. are employees of Astellas. M.R. was previously an employee of Astellas. A.A. has received grants from Astellas, Pfizer, and Merck, and consultancy fees from Astellas and Pfizer. E.A. declares no conflict of interest. Reprints: Edythe Albano, MD, Department of Pediatrics, School of Medicine and Children’s Hospital Colorado, University of Colorado, 13123 East 16th Avenue, Aurora, CO 80045 (e-mail: [email protected]). Copyright r 2014 Wolters Kluwer Health, Inc. All rights reserved.
J Pediatr Hematol Oncol
environmental precautions and antimicrobial prophylaxis with antifungal medications, such as micafungin, fluconazole, or posaconazole.1 Although data suggest that treatment recommendations for invasive fungal infections should be similar for pediatric and adult patients,2 pharmacokinetic (PK) profiles of these medications observed in pediatric populations often differ from those reported from studies in adults.3 Micafungin is an echinocandin antifungal agent with potent activity against Aspergillus4 and Candida spp.,5 including non-albicans and fluconazole-resistant Candida spp.6,7 It is metabolized in the liver either into M1 (catechol form) followed by M2 (methoxy form) by the action of arylsulfatase and catechol-O-methyltransferase, respectively; or into M5 by side chain hydroxylation.8 Importantly, micafungin is not significantly metabolized by the CYP450 3A system, which may explain why this agent displays few unwanted drug–drug interactions.9 Micafungin exhibits linear PK and can be used without dose adjustment in patients with moderate-to-severe renal impairment and mild-to-moderate hepatic impairment. However, although the US Food and Drug Administration indicates that dose adjustment is not necessary for patients with severe hepatic impairment,8 the European Medicines Agency does not recommend the use of micafungin in this group of patients.10 Prophylactic micafungin therapy has been shown to be effective in both adult and pediatric patients undergoing HSCT,4 although current PK data in the latter population are limited. Previous studies and PK models suggest that PK may differ between age groups during early development.11–13 However, in these studies, micafungin therapy was initiated only following the onset of fever and neutropenia, or with a proven or presumptive diagnosis of candidemia. As yet, the PK of micafungin in pediatric patients during prophylactic treatment remain limited. Therefore, we evaluated the PK and safety of intravenous micafungin after repeated daily dosing as antifungal prophylaxis in children and adolescents undergoing HSCT.
MATERIALS AND METHODS Study Design This was a multicenter, open-label, repeat-dose phase I PK study (ClinicalTrials.gov identifier: NCT00606268). Each center received written approval from the Institutional Review Board (IRB) before commencing study activities. The study was conducted in accordance with the principles based on the International Conference on Harmonisation Guidelines, Good Clinical Practice, and the
Volume 37, Number 1, January 2015
www.jpho-online.com |
e45
Albano et al
J Pediatr Hematol Oncol
applicable laws and regulations. An IRB-approved written informed consent was obtained from each patient or their parent(s) or legal guardian(s), as appropriate, before the initiation of any study-specific procedures. Patients were enrolled according to age and stratified by weight into 2 treatment arms to receive either once-daily micafungin 1 mg/kg for patients weighing Z25 kg or 1.5 mg/kg for those weighing < 25 kg. The study drug was administered as an infusion over 1 hour for 10 to 14 days, with the maximum daily dose not exceeding 50 mg. The maximum daily dose was based on good prophylactic efficacy observed with this dose in a previous trial of micafungin in HSCT recipients.4 Micafungin therapy was initiated within 48 hours of the start of the patient’s transplant-related conditioning regimen. A physical examination was performed at baseline and at the end of therapy (EOT; within 72 h after last dose of study drug). Vital signs were measured at baseline, twice daily (before the start of the infusion and within 1 h postinfusion) during the treatment period, at EOT, and at study end (EOS; 14 d after the last dose of study drug). Medications for treatment of the patient’s underlying condition, received within 7 days before the first dose of micafungin, as well as all other concomitant medications (from baseline to EOS) were recorded.
were recorded. Safety evaluations included AE assessments, clinical laboratory evaluations, vital sign assessments, electrocardiograms, and physical examinations. Blood samples were collected for hematology (hemoglobin, hematocrit, red blood cell count, platelets, and white blood cell count, including differential) and serum chemistry (aspartate transaminase, alanine transaminase, alkaline phosphatase, g-glutamyl transferase, total bilirubin, blood urea nitrogen, calcium, serum creatinine, potassium, sodium, magnesium, chloride, and bicarbonate) measurements at baseline, twice during the treatment period, at EOT, and at EOS.
Patients Children (aged 4 mo to 11 y) and adolescents (aged 12 to 16 y) undergoing autologous, syngeneic, or allogeneic HSCT were eligible for inclusion in the study. Patients were excluded if they had significant liver disease (aspartate transaminase or alanine transaminase 10 the upper limit of normal, and total bilirubin or alkaline phosphatase >5 the upper limit of normal), an active fungal infection, hypersensitivity to echinocandins, or had received echinocandin treatment within 1 week of the first dose of study drug. Female patients who were pregnant or nursing were also excluded from the study.
PK Analyses The primary PK parameters calculated were the steady-state (day 7) micafungin; M1, M2, and M5 area under the plasma micafungin analyte concentration–time curve from time 0 (start of infusion) to 24 hours postinfusion start (AUCtau); and peak analyte concentration (Cmax). Secondary parameters included time to Cmax (Tmax), as well as micafungin clearance at steady state (CLss), volume of distribution (Vss), and half-life. To measure plasma analytes, whole-blood samples of B1 mL were collected into heparinized tubes at the following time points relative to the start of day 7 of the micafungin infusion: within 1 hour before the start of infusion; immediately (within 3 min) postinfusion; and at 2, 4, and 10 hours after start of the infusion. Single-blood samples for trough analyte concentration measurements were collected within 10 minutes before the infusion start time (predose/time 0) on days 4, 6, and 8. Plasma analyte concentrations were determined using validated highperformance liquid chromatography with fluorescence detection methods. The lower limit of quantification for micafungin and metabolite measurements was 0.05 mg/mL.
Safety Analyses Adverse events (AEs) with onset during treatment or within 14 days after the final study drug administration
e46 | www.jpho-online.com
Volume 37, Number 1, January 2015
Statistical Analyses Patients enrolled in the study who received at least 1 dose of micafungin comprised the safety analysis set. The PK analysis set consisted of those patients from the safety analysis set whose plasma micafungin concentration data were adequate for the derivation of at least 1 PK parameter. Descriptive statistics for continuous variables included the number of patients, mean, geometric mean, SD, SE, median, minimum, maximum, and coefficient of variation. Frequencies and percentages were used to describe categorical data; unless otherwise specified, summaries were presented for each treatment, for each age cohort (4 to
