Repeated-Dose Pharmacokinetics of an Oral Solution of Itraconazole in Infants and Children
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The safety, tolerability, and pharmacokinetics of an oral solution of itraconazole and its active metabolite hydroxyitraconazole were investigated in an open multicenter study of 26 infants and children aged 6 months to 12 years with documented mucosal fungal infections or at risk for the development of invasive fungal disease. The most frequent underlying illness was acute lymphoblastic leukemia, except in the patients aged 6 months to 2 years, of whom six were liver transplant recipients. The patients were treated with itraconazole at a dosage of 5 mg/kg of body weight once daily for 2 weeks. Blood samples were taken after the first dose, during treatment, and up to 8 days after the last itraconazole dose. On day 1, the mean peak concentrations in plasma after the first and last doses (Cmax) and areas under the concentration-time curve from 0 to 24 h (AUC0-24) for itraconazole and hydroxyitraconazole were lower in the children aged 6 months to 2 years than in children aged 2 to 12 years but were comparable on day 14. The mean AUC0-24-based accumulation factors of itraconazole and hydroxyitraconazole from day 1 to 14 ranged from 3.3 to 8.6 and 2.3 to 11.4, respectively. After 14 days of treatment, Cmax, AUC0-24, and the half-life, respectively, were (mean +/- standard deviation) 571+/-416 ng/ml, 6,930+/-5,830 ng.h/ml, and 47+/-55 h in the children aged 6 months to 2 years; 534+/-431 ng/ml, 7,330+/-5,420 ng.h/ml, and 30.6+/-25.3 h in the children aged 2 to 5 years; and 631+/-358 ng/ml, 8,770+/-5,050 ng.h/ml, and 28.3+/-9.6 h in the children aged 5 to 12 years. There was a tendency to have more frequent low minimum concentrations of the drugs in plasma for both itraconazole and hydroxyitraconazole for the children aged 6 months to 2 years. The oral bioavailability of the solubilizer hydroxypropyl-beta-cyclodextrin was less than 1% in the majority of the patients. In conclusion, an itraconazole oral solution given at 5 mg/kg/day provides potentially therapeutic concentrations in plasma, which are, however, substantially lower than those attained in adult cancer patients, and is well tolerated and safe in infants and children.
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Itraconazole cyclodextrin oral solution (5 mg/kg per day) administered to infants and children was found to provide potentially therapeutic concentrations in plasma.
“Itraconazole cyclodextrin oral solution (5 mg/kg per day) administered to infants and children was found to provide potentially therapeutic concentrations in plasma [95].”
From Guidelines for Treatment of Candidiasis (2004) · cites this paper as [95]
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“100 12,713 (2,153) 8.06 (1.52) 303 (68) 530 (90) 2,902 (1,470) 0.0182 (0.0073) 44.2 (19.6) 18,177 (2,236) 5.56 (0.64) 650 (127) 757 (93) 1,028 (310) 0.0244 (0.0088) 31.6 (12.1) 200 39,858 ( 8 ,240) 5.18 (1.04) 1,249 (335) 1,661 (343) 4,111 (864) 0.0106 (0.0005) 65.4 (3.0) 50,407 (7,355) 4.03 (0.55) 1,793 (207) 2,100 (…”
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“However, this finding was only evident in children over the age of 2 years with the ratio in children under the age of two comparable between formulations (14, 18).”
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“The lower concentrations previously reported in children (3) could be related to the dose-dependent bioavailability of itraconazole, as previously demonstrated following oral administration to healthy volunteers (11).”
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BackgroundClinical Experience with Itraconazole in Systemic Fungal Infections
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“As reported in the previous studies [ 11 , 32], nausea, vomiting, and diarrhea are typical adverse effects of oral ITC, in particular of the oral solution.”
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“Earlier studies have reported mild gastrointestinal disturbances (23, 24) and abnormal laboratory values (6) at some time during therapy.”
BackgroundAntifungal treatment in pediatric patients
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“In a study of 26 pediatric oncology patients (ages 6 months to 12 years), itraconazole oral solution produced a maximum concentration lower than in adults, whereas other pharmacokinetic properties such as half-life are similar to that of adults [ 53 ].”
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Administration and Dosing of Systemic Antifungal Agents in Pediatric Patients
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Rhoden, E. E., Nix, W. A., Weldon, W. C., & Selvarangan, R. (2017) · Antiviral Research · doi:10.1016/j.antiviral.2017.11.011 · Cited by 34 · see citing works
Groll, A. H., & Ritter, J. (2005) · Klinische Pädiatrie · doi:10.1055/s-2005-872501 · Cited by 32 · see citing works
Efficacy and safety of itraconazole use in infants
Chen, S., Sun, K.-Y., Feng, X., Ran, X., Lama, J., & Ran, Y. (2016) · World Journal of Pediatrics · doi:10.1007/s12519-016-0034-x · Cited by 32 · see citing works
Cohen‐Wolkowiez, M., Moran, C., Benjamin, D. K., & Smith, P. B. (2009) · Current Opinion in Infectious Diseases · doi:10.1097/qco.0b013e3283321ccc · Cited by 30 · see citing works
INVASIVE ASPERGILLOSIS IN CHILDREN: UPDATE ON CURRENT GUIDELINES
Apsemidou, A., Petridis, N., Vyzantiadis, T., & Tragiannidis, A. (2018) · Mediterranean Journal of Hematology and Infectious Diseases · doi:10.4084/mjhid.2018.048 · Cited by 29 · see citing works
Clinical Pharmacokinetics of Triazoles in Pediatric Patients
Bury, D., Tissing, W. J. E., Muilwijk, E. W., Wolfs, T. F. W., & Brüggemann, R. J. M. (2021) · Clinical Pharmacokinetics · doi:10.1007/s40262-021-00994-3 · Cited by 27 · see citing works
“5–2 years, 2–5 years, and/or > 5 years [39, 42, 43].”
BackgroundProphylaxis and treatment of fungal infections associated with haematological malignancies
Aşçıoğlu, S. (2000) · International Journal of Antimicrobial Agents · doi:10.1016/s0924-8579(00)00159-x · Cited by 27 · see citing works
“Itraconazole oral solution also produces lower peak plasma concentrations in children than in adults with equivalent doses but the half-life is not shortened [84].”
BackgroundInfluentialClinical Pharmacokinetic Monitoring of Itraconazole Is Warranted in Only a Subset of Patients
Buchkowsky, S. S., Partovi, N., & Ensom, M. H. H. (2005) · Therapeutic Drug Monitoring · doi:10.1097/01.ftd.0000150135.22645.ea · Cited by 24 · see citing works
“The pharmacokinetics of repeated dose administration of itraconazole oral solution was examined in an open multicenter study of 26 infants and children (6 months to 12 years old) who either had a documented mucosal fungal infection or were at risk for invasive fungal infection.(72) The authors concluded that the level…”
BackgroundClinical pharmacology of antifungal agents in pediatric patients
Chiou, C. C., Walsh, T. J., & Groll, A. H. (2007) · Expert Opinion on Pharmacotherapy · doi:10.1517/14656566.8.15.2465 · Cited by 22 · see citing works
“It is effective in the treatment of oropharyngeal and esophageal candidiasis including adult and pediatric patients who have developed resistance to fluconazole [33,114,115,120].”
BackgroundItraconazole Dosing and Drug Monitoring at a Tertiary Children’s Hospital
Leong, Y. H., Boast, A., Cranswick, N., Curtis, N. C., & Gwee, A. (2018) · The Pediatric Infectious Disease Journal · doi:10.1097/inf.0000000000002048 · Cited by 22 · see citing works
Complexation of the interferon inducer, bropirimine, with hydroxypropyl-β-cyclodextrin
Echezarreta-López, M., Torres-Labandeira, J. J., Castineiras-Seijo, L., Santana-Penin, L., & Vila-Jato, J. L. (2000) · European Journal of Pharmaceutical Sciences · doi:10.1016/s0928-0987(99)00081-0 · Cited by 21 · see citing works
Pharmacokinetic evaluation of oral itraconazole for antifungal prophylaxis in children
Allegra, S., Fatiguso, G., Francia, S. D., Favata, F., Pirro, E., Carcieri, C., Nicolò, A. D., Cusato, J., Perri, G. D., & D’Avolio, A. (2017) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/1440-1681.12822 · Cited by 20 · see citing works
“Moreover, OS dose of 5 mg/kg/day results in lower concentrations in infants compared with children older than 2 years of age (36).”
BackgroundAntifungal Agents for the Treatment of Systemic Fungal Infections in Children
Allen, U. (2010) · Canadian Journal of Infectious Diseases and Medical Microbiology · doi:10.1155/2010/784549 · Cited by 20 · see citing works
“Pharmacokinetic studies [17] of itraconazole oral solution have demonstrated that children younger than five years of age tend to have lower plasma concentrations than older children or adults.”
BackgroundAntifungal agents for the treatment of systemic fungal infections in children
Allen, U., Canadian Paediatric Society, & Infectious Diseases and Immunization Committee (2010) · Paediatrics & Child Health · doi:10.1093/pch/15.9.603 · Cited by 20 · see citing works
“Pharmacokinetic studies [17] of itraconazole oral solution have demonstrated that children younger than five years of age tend to have lower plasma concentrations than older children or adults.”
BackgroundSrinivas, N. R. (2015) · Drug Development and Industrial Pharmacy · doi:10.3109/03639045.2015.1096278 · Cited by 17 · see citing works
Pediatric Invasive Aspergillosis
Wattier, R. L., & Ramírez-Àvila, L. (2016) · Journal of Fungi · doi:10.3390/jof2020019 · Cited by 17 · see citing works
Physicochemical Properties and Pharmacokinetics
Loftsson, Þ. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-801411-0.00003-2 · Cited by 17 · see citing works
Finer, G., Greenberg, D., Leibovitz, E., Leiberman, A., Shelef, I., & Kapelushnik, J. (2002) · Scandinavian Journal of Infectious Diseases · doi:10.1080/00365540110077137 · Cited by 17 · see citing works
“The half-life of oral itraconazole at a dosage of 5 mg:kg:d was shown to be similar in children and adults, although children with neoplastic disease had lower plasma concentrations compared with adults (13).”
Dermatologic Toxicology in Children
Spray, A., & Siegfried, E. C. (2001) · Pediatric Annals · doi:10.3928/0090-4481-20010401-07 · Cited by 17 · see citing works
Drugs Active against Fungi, Pneumocystis, and Microsporidia
Rex, J. H., & Stevens, D. A. (2015) · Elsevier eBooks · doi:10.1016/b978-1-4557-4801-3.00039-4 · Cited by 16 · see citing works
Pappas, P. G., Kauffman, C. A., Andes, D. R., Benjamin, D. K., Calandra, T., Edwards, J. E., Filler, S. G., Fisher, J. F., Kullberg, B. J., Ostrosky-Zeichner, L. L., et al. (2009) · Clinical Infectious Diseases · doi:10.1086/598961 · Cited by 15 · see citing works
“Cuando se administra a bebés y niños, la solución oral de itraconazol (5 mg/kg por dı́a) ofrece concentraciones en plasma potencialmente terapéuticas [66].”
BackgroundJuvenile animal testing of hydroxypropyl-β-cyclodextrin in support of pediatric drug development
Schaepdrijver, L. D., Mariën, D., Rhimi, C., Voets, M., van Heerden, M., & Lammens, L. (2015) · Reproductive Toxicology · doi:10.1016/j.reprotox.2015.05.010 · Cited by 15 · see citing works
Invasive Aspergillosis in Pediatric Leukemia Patients: Prevention and Treatment
Papachristou, S., Iosifidis, Ε., & Roilides, E. (2019) · Journal of Fungi · doi:10.3390/jof5010014 · Cited by 15 · see citing works
“Itraconazole, despite being the first in its class exhibiting anti-Aspergillus activity, has fallen into disuse, due to several limitations including unpredictable bioavailability, interactions with chemotherapeutic drugs such as cyclophosphamide, and interactions with drugs that cause QTc prolongation [2,82,85,99].”
BackgroundRex, J. H., & Stevens, D. A. (2010) · Elsevier eBooks · doi:10.1016/b978-0-443-06839-3.00040-0 · Cited by 15 · see citing works
Role of itraconazole in haematology/oncology
Pandya, N. A. (2003) · Archives of Disease in Childhood · doi:10.1136/adc.88.3.258 · Cited by 13 · see citing works
Shoham, S., Groll, A. H., Petraitis, V., & Walsh, T. J. (2016) · Elsevier eBooks · doi:10.1016/b978-0-7020-6285-8.00156-8 · Cited by 12 · see citing works
Clinical pharmacology of antifungal agents to overcome drug resistance in pediatric patients
Stergiopoulou, T., & Walsh, T. J. (2015) · Expert Opinion on Pharmacotherapy · doi:10.1517/14656566.2015.1000302 · Cited by 11 · see citing works
“Q12 [73-77]”
Kim, H., Shin, D., Kang, H. J., Yu, K., Lee, J. W., Kim, S. J., Kim, M. S., Song, E. S., Jang, M. K., Park, J. D., et al. (2015) · Clinical Drug Investigation · doi:10.1007/s40261-015-0297-3 · Cited by 10 · see citing works
“However, pharmacokinetics in children are less known and the pharmacokinetics of repeateddose intravenous itraconazole has not been reported, so that prediction is difficult in pediatric cancer patients [6, 7, 13].”
BackgroundMethodResultInfluentialItraconazole: Comprehensive Profile
Al‐Badr, A. A., & El‐Subbagh, H. I. (2009) · Profiles of drug substances, excipients, and related methodology · doi:10.1016/s1871-5125(09)34005-4 · Cited by 10 · see citing works
Boyle, B., & McCann, S. R. (2000) · Transplant Infectious Disease · doi:10.1034/j.1399-3062.2000.020205.x · Cited by 9 · see citing works
How Do Cyclodextrins and Dextrans Affect the Gut Microbiome? Review of Prebiotic Activity
Gościniak, A., Lainé, E., & Cielecka‐Piontek, J. (2024) · Molecules · doi:10.3390/molecules29225316 · Cited by 8 · see citing works
Kaliamurthy, J., Geraldine, P., & Thomas, P. A. (2003) · Mycoses · doi:10.1046/j.1439-0507.2003.00865.x · Cited by 8 · see citing works
Fungal Infections, Infestations and Parasitic Infections in Neonates
Carder, K. R. (2008) · Elsevier eBooks · doi:10.1016/b978-1-4160-3432-2.50017-0 · Cited by 7 · see citing works
Therapeutic drug monitoring for antifungal triazoles: pharmacologic background and current status
Groll, A. H., & Gastine, S. (2019) · Handbook of analytical separations · doi:10.1016/b978-0-444-64066-6.00009-5 · Cited by 6 · see citing works
Wattier, R. L., & Steinbach, W. J. (2017) · Elsevier eBooks · doi:10.1016/b978-0-323-40181-4.00293-0 · Cited by 6 · see citing works
Pediatric pharmacology of antifungal agents
Groll, A. H., Roilides, E., & Walsh, T. J. (2008) · Current Fungal Infection Reports · doi:10.1007/s12281-008-0008-0 · Cited by 6 · see citing works
“Treatment with cyclodextrin itraconazole achieved potentially therapeutic concentrations of itraconazole in plasma; however, these levels were substantially lower than those reported in adult cancer patients [ 35 ].”
BackgroundResultClinical Pharmacology of Itraconazole in Children and Adolescents
Drogouti, E., Pana, Z. D., Tragiannidis, A., Hempel, G., & Groll, A. H. (2015) · Current Fungal Infection Reports · doi:10.1007/s12281-015-0218-1 · Cited by 5 · see citing works
Pharmacocinétique et pharmacodynamie des antifongiques en pédiatrie
Jullien, V. (2011) · Archives de Pédiatrie · doi:10.1016/s0929-693x(11)70939-3 · Cited by 5 · see citing works
Shoham, S., Groll, A. H., & Walsh, T. J. (2010) · Elsevier eBooks · doi:10.1016/b978-0-323-04579-7.00149-0 · Cited by 5 · see citing works
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Emerging Treatments in Neonatal Fungal Infections: Progress and Prospects
Eletel, L., Thomas, T., Berry, E. A., & Kearns, G. L. (2025) · Pediatric Drugs · doi:10.1007/s40272-025-00688-4 · Cited by 4 · see citing works
“The variability in drug metabolism was attributed to the normal large variability in CYP3A4 activity, the enzyme primarily responsible for itraconazole metabolism [80–84].”
Die allergisch-bronchopulmonale Aspergillose bei zystischer Fibrose
Huttegger, I., Crameri, R., Eichler, I., Müller, F., Lindemann, H., & Griese, M. (2006) · Monatsschrift Kinderheilkunde · doi:10.1007/s00112-006-1417-1 · Cited by 4 · see citing works
Pneumocystis and Other Less Common Fungal Infections
Maldonado, Y. (2010) · Elsevier eBooks · doi:10.1016/b978-1-4160-6400-8.00034-1 · Cited by 4 · see citing works
CURRENT APPROACH TO INVASIVE ASPERGILLOSIS
Rodriguez, C. A., & Patrick, C. C. (2001) · The Pediatric Infectious Disease Journal · doi:10.1097/00006454-200103000-00019 · Cited by 4 · see citing works
Pharmacology of azole antifungal agents
Ashley, E. S. D. (2019) · CRC Press eBooks · doi:10.1201/9780429402012-12 · Cited by 4 · see citing works
Fungal infections in pediatric patients
Groll, A. H., Roilides, E., & Walsh, T. J. (2009) · Elsevier eBooks · doi:10.1016/b978-1-4160-5680-5.00022-0 · Cited by 4 · see citing works
- Authors
- de Repentigny, L., Ratelle, J., Leclerc, J.-M., Cornu, G., Sokal, E. M., Jacqmin, P., & de Beule, K.
- Affiliations
- <!--label omitted: 1-->Department of Microbiology and Immunology,1 and
- Centre Hospitalier Universitaire Sainte-Justine (CA)
- UCLouvain (BE)
- <!--label omitted: 3-->Department of Pediatrics, University of Louvain Medical School, Brussels,3 and
- Janssen (Belgium) (BE)
- <!--label omitted: 4-->Janssen Research Foundation, Beerse,4 Belgium
- ORCID
- Leclerc, Jean-Marie
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 1998-02
- Volume
- 42
- Issue
- 2
- Pages
- 404-408
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC105422
- OpenAlex
- W2101916105
- Semantic Scholar
- 3d50b19d54d6f2b7142c74f7ccd7411765ca3c35
- Cited by
- 142
- References
- 20
- Citations by year
- 2025: 3 · 2024: 2 · 2022: 2 · 2021: 3 · 2020: 4 · 2019: 5 · 2018: 4 · 2017: 5 · 2016: 4 · 2015: 11 · 2014: 5 · 2013: 2 · 2012: 8
- FWCI
- 5.29
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- PubMed Central (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed (publishedVersion)
- Digital Access to Libraries (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Health Sciences › Medicine › Pharmacology › Antibiotics Pharmacokinetics and Efficacy
- Keywords
- itraconazole, hydroxyitraconazole, pharmacokinetics, infants, children, oral solution, repeated dosing, accumulation, age differences, acute lymphoblastic leukemia, invasive fungal infections, liver transplant recipients, oral bioavailability, drug safety and tolerability, antifungal agents, plasma concentration-time curve, half-life, accumulation factor
- MeSH terms
- Administration, Oral, Antifungal Agents, Child, Child, Preschool, Female, Humans, Infant, Infant, Newborn, Male, Mycoses, Opportunistic Infections, Itraconazole
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