Pharmacokinetics of fluconazole in very low birth weight infants during the first two weeks of life
Abstract
OBJECTIVE: To find a dose of fluconazole for very low birth weight infants during an outbreak of Candida parapsilosis. METHODS: Twelve premature infants (mean gestational age, 27.4 weeks; mean birth weight, 912 gm) receiving fluconazole prophylactically from the first day of life were enrolled in an open phase I-II pharmacokinetics, safety, and tolerance trial. Up to 5 doses of 6 mg/kg were administered intravenously every 72 hours during the first 2 weeks of life. Pharmacokinetic characteristics of fluconazole were determined after the first, third, and fifth doses. RESULTS: The mean peak and trough concentrations after the 3 doses were 5.5 and 2.6 micrograms/ml, 12.8 and 4.3 micrograms/ml, and 10.0 and 2.9 micrograms/ml (p = 0.0002 and p = 0.07), respectively. The mean fluconazole half-lives were 88.6 hours (n = 7), 67.5 hours (n = 9), and 55.2 hours (n = 4; p = 0.3). The mean total clearance corrected for weight (CL/kg) was 0.18 ml/min/kg (n = 7), 0.33 ml/min/kg (n = 7), and 0.52 ml/min/kg (n = 4; p = 0.02), and the mean volume of distribution 1.18 L/kg (n = 7), 1.84 L/kg (n = 7), and 2.25 L/kg (n = 4; p = 0.05). Weight-corrected clearance increased with postnatal age (r = 0.61; p = 0.007). CONCLUSIONS: With the used fluconazole dose (6 mg/kg every 3 days), the mean serum peak and trough concentrations increased during the first week but decreased during the second week. After the first week we suggest a dose of 6 mg/kg every 2 days, or even daily.
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The pharmacokinetics of fluconazole vary with age.
“The pharmacokinetics of fluconazole vary with age [89][90][91][92].”
From Guidelines for Treatment of Candidiasis (2004) · cites this paper as [91]
The pharmacological properties of fluconazole vary with neonatal age.
“the pharmacological properties of fluconazole vary with neonatal age, making the choice of dosage somewhat difficult [86,90,91].”
From Guidelines for Treatment of Candidiasis (2004) · cites this paper as [91]
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Santolaya, M. E., Matute, T. A., Telles, F. D. Q., Colombo, A. L., Zurita, J., Tiraboschi, I. N., Cortés, J. A., Thompson-Moya, L., Guzmán-Blanco, M., Sifuentes‐Osornio, J., et al. (2013) · Revista Iberoamericana de Micología · doi:10.1016/j.riam.2013.05.012 · Cited by 18 · see citing works
“Long half-life that decreases with increasing postnatal age.(86) A population pharmacokinetic study in 55 neonates and young infants suggests that maintenance fluconazole doses of 12 mg/kg/day are necessary to achieve exposures similar to older children and adults(98) Well tolerated.”
BackgroundZhao, W., Guellec, C. B., Benjamin, D. K., Hope, W. W., Bourgeois, T., Watt, K., van den Anker, J. N., Matrot, B., Saxén, H., Hoppu, K., et al. (2014) · Clinical Pharmacokinetics · doi:10.1007/s40262-014-0169-7 · Cited by 18 · see citing works
“The same sampling was repeated after the third and fifth doses [38].”
Self-citationExternal Evaluation of Two Fluconazole Infant Population Pharmacokinetic Models
Hwang, M. F., Beechinor, R. J., Wade, K. C., et al. (2017) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01352-17 · Cited by 18 · see citing works
“The level of plasma protein binding of fluconazole is low at 11 to 12%, and it has a relatively long half-life, estimated to be 30 h in adult patients and 5 to 89 h in pediatric patients (6, 7).”
BackgroundCandida Infections in Newborns: a Review
Khoory, B. J., Vino, L., Dall’Agnola, A., & Fanos, V. (1999) · Journal of Chemotherapy · doi:10.1179/joc.1999.11.5.367 · Cited by 18 · see citing works
Pharmacokinetic Considerations when Prescribing in Children
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Neonatal liver abscesses associated with candidemia: three cases and review of literature
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“A small study of fluconazole in preterm infants reported prolonged plasma half-lives in the first 2 weeks of life [19].”
BackgroundUpdate on Invasive Candidiasis
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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
“La farmacocinética del fluconazol varı́a mucho con la edad [62–64].”
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“These findings indicate that twice-weekly prophylaxis regimens can provide adequate serum levels for the prevention of invasive candidiasis when the unit-specific minimum inhibitory concentration (MIC) is taken into account [26, 27].”
BackgroundCharoo, N. A., Cristofoletti, R., & Dressman, J. (2015) · Journal of Pharmacy and Pharmacology · doi:10.1111/jphp.12411 · Cited by 13 · see citing works
“2 h approximately 2 weeks after birth.([31]) Generally, renal function is reduced in infants, and adult values are reached in 6–12 months.”
BackgroundPharmacokinetics of Fluconazole in the Cerebrospinal Fluid of Children with Hydrocephalus
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“Fluconazole is commonly used in the treatment of mycotic infections, as well as in the prophylaxis of preterm infants [ ,”
BackgroundRecomendaciones para el manejo de la candidemia en neonatos en América Latina
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“For this author, fluconazole, rather than 5-FC, has become the second line agent after amphotericin B, when there is persistent candidemia beyond 5 days after initiation of therapy [107–109].”
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“Of the few studies that have evaluated safety in the newborn, most have been single-centre studies of ≤ 100 infants [47,48,73].”
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Treatment of Neonatal Fungal Infections
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“The pharmacokinetics of fluconazole in neonates, particularly preterm and low birth weight infants, is characterized by reduced clearance and a prolonged half-life due to immature renal and hepatic function, necessitating care-fully adjusted dosing regimens to prevent toxic accumulation [65].”
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“[14], data were given as ranges of means for patients who received fluconazole at different PMA.”
BackgroundMethod
- Authors
- Saxén, H., Hoppu, K., & Pohjavuori, M.
- Affiliations
- University of Helsinki (FI)
- Corresponding author
- Hoppu, Kalle
- ORCID
- Hoppu, Kalle
- Venue
- Clinical Pharmacology and Therapeutics
- Publisher
- Wiley
- Published
- 1993
- Volume
- 54
- Issue
- 3
- Pages
- 269-277
- ISSN
- 0009-9236 (ISSN-L)
- 1532-6535
- OpenAlex
- W1969659982
- Cited by
- 127
- References
- 0
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2022: 1 · 2021: 5 · 2020: 4 · 2019: 4 · 2018: 1 · 2017: 3 · 2016: 6 · 2015: 3 · 2014: 6 · 2013: 6 · 2012: 4
- FWCI
- 2.72
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Pharmacology & Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
- Health Sciences › Medicine › Pharmacology › Antibiotics Pharmacokinetics and Efficacy
- Keywords
- fluconazole, pharmacokinetics, very low birth weight infants, preterm infants, Candida parapsilosis, antifungal prophylaxis, intravenous administration, drug clearance, volume of distribution, half-life, postnatal age
- MeSH terms
- Candidiasis, Female, Half-Life, Humans, Infant, Low Birth Weight, Infant, Newborn, Infant, Premature, Infant, Premature, Diseases, Male, Pilot Projects, Fluconazole
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