Pharmacology and toxicity of high-dose ketoconazole
Open accessAbstract
One hundred sixty patients were entered in two multicenter protocols to receive 400 to 2,000 mg of ketoconazole once daily for nonmeningeal or meningeal coccidiodomycosis. For 24 h after administration of all doses, mean concentrations in serum exceeded MICs for Coccidioides immitis (trough concentrations, greater than 1 microgram/ml). Mean peak concentrations occurred 4 to 6 h after administration, ranging from 7 to 17 micrograms/ml for doses of 400 to 2,000 mg. Incremental increases in peak concentrations in serum were greatest at doses of less than or equal to 1,200 mg. To investigate whether long-term therapy altered concentrations in serum, serial data were studied by several methods. The results suggested a trend to increased levels in serum with prolonged therapy, but were not statistically significant. All 168 cerebrospinal fluid (CSF) samples from meningitis patients contained less than or equal to 2.9 micrograms/ml, and only 6 contained greater than 1 microgram/ml. There was no apparent relation between dose, time after dose, site of CSF sampling, or concurrent inflammation and CSF ketoconazole concentration. Neither concentration in serum, toxicity, nor outcome correlated with dose, calculated in milligrams per kilogram at the fixed doses (400-mg increments) under study. Likewise, at the various doses, concentration in serum did not correlate with outcome or toxicity, suggesting that individual drug disposition was not an important factor in outcome or toxicity. Toxicity was reversible, and principal side effects were nausea and vomiting (50%), gynecomastia (21%), decreased libido (13%), alopecia (8%), elevated liver function tests (5%), pruritus (5%), and rash (4%). Gastrointestinal and endocrinologic toxicity were dose related and increased at doses greater than 800 mg. The cumulative percent toxicity requiring discontinuation of drug was 6, 17, 23, and 56% at 400-, 800-, 1,200-, and 1,600-mg doses. Doses of >400 mg are thus markedly more toxic, and efficacy data for nonmeningeal disease have not demonstrated that they are more efficacious.
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Administration of 400-1200 mg/day ketoconazole corresponds to ~12-25 μM serum ketoconazole detected in patients 4-6 h after drug intake.
“corresponding to ~12-25 µM serum-ketoconazole detected in patients 4-6 h after drug intake (61).”
From Establishment of a novel human fetal adrenal culture model that supports de novo and manipulated steroidogenesis (2021) · cites this paper as [61]
Ketoconazole concentrations below 10 μM did not reduce cell viability of human adrenal carcinoma cells.
“This is in line with a previous study which found ketoconazole concentrations below 10 µM did not reduce cell viability of human adrenal carcinoma cells (61).”
From Establishment of a novel human fetal adrenal culture model that supports de novo and manipulated steroidogenesis (2021) · cites this paper as [61]
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- Authors
- Sugar, A. M., Alsip, S. G., Galgiani, J. N., Graybill, J. R., Dismukes, W. E., Cloud, G. A., Craven, P. C., & Stevens, D. A.
- Affiliations
- Santa Clara Valley Medical Center (US)
- Venue
- Antimicrobial Agents and Chemotherapy
- Publisher
- American Society for Microbiology
- Published
- 1987-12
- Volume
- 31
- Issue
- 12
- Pages
- 1874-1878
- ISSN
- 0066-4804 (ISSN-L)
- 1098-6596
- PMC
- PMC175818
- OpenAlex
- W1969745666
- Cited by
- 129
- References
- 11
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 5 · 2021: 3 · 2020: 3 · 2019: 1 · 2018: 2 · 2017: 3 · 2016: 4 · 2015: 2 · 2014: 5 · 2013: 2 · 2012: 3
- FWCI
- 7.37
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Antimicrobial Agents and Chemotherapy (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Minnesota
- University of Cincinnati
- National Institutes of Health (n01ai052562-016, CA 13148)
- Comprehensive Cancer Center, University of Alabama at Birmingham
- National Cancer Institute (CA-13 148)
- National Institute of Allergy and Infectious Diseases (N01 AI 82570, N01-AI-52562)
- Topics
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Health Sciences › Medicine › Pharmacology › Antibiotics Pharmacokinetics and Efficacy
- Keywords
- ketoconazole, coccidioidomycosis, Coccidioides immitis, serum drug concentration, cerebrospinal fluid drug concentration, dose-response relationship, drug toxicity, nausea and vomiting, gynecomastia, liver function tests, antifungal pharmacokinetics
- MeSH terms
- Clinical Trials as Topic, Coccidioidomycosis, Double-Blind Method, Humans, Ketoconazole, Random Allocation
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