JAC Advance Access originally published online on July 12, 2007
Journal of Antimicrobial Chemotherapy 2007 60(4):908-909; doi:10.1093/jac/dkm272
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Correspondence |
Marked increase in steady-state serum levels achieved with itraconazole oral solution compared with capsule formulation
1 Department of Microbiology, Middlemore Hospital, Counties Manukau District Health Board, Auckland, New Zealand 2 Clinical Pharmacy Services, Middlemore Hospital, Counties Manukau District Health Board, Auckland, New Zealand 3 Department of Internal Medicine (Infectious Diseases), Middlemore Hospital, Counties Manukau District Health Board, Auckland, New Zealand 4 Clinical Pharmacy Services, Auckland District Health Board, Auckland, New Zealand
* Correspondence address. Microbiology Department, Auckland Hospital, Grafton, Auckland, New Zealand. Tel: +64-9-367-0000 ext. 23260; E-mail: joshuaf{at}adhb.govt.nz
Keywords: absorption , bioavailability , therapeutic drug monitoring
We report a case of markedly increased steady-state serum levels of itraconazole following a change from the capsule to oral solution preparation. Serum levels of itraconazole and its major metabolite, hydroxy-itraconazole, were measured by HPLC assay. Combined levels were measured to assess total antifungal activity in serum.1
A previously well 37-year-old male Tongan construction worker returned to New Zealand from Southern California USA, with disseminated coccidioidomycosis involving the lumbosacral spine. Following a course of conventional amphotericin B, he was started with itraconazole capsules 200 mg twice daily. Two weeks later, the serum levels of itraconazole and hydroxy-itraconazole were 470 and 870 µg/L, respectively. These levels were associated with clinical improvement and were within the range considered acceptable for therapy. However, 15 months later when the patient presented with clinical and radiological progression of disease, the combined itraconazole/hydroxy-itraconazole level was 220 µg/L. Repeated levels remained low despite increasing the dose to 400 mg twice daily (Table 1). The patient was treated in hospital and was observed to be swallowing the capsules, with no evidence to suggest poor compliance. The capsules were administered as recommended, after food and with an acidic beverage (Diet Coca-Cola®, pH = 3.39) to enhance absorption. After a formal search of the literature, the patient was not found to be taking any drugs reported to interfere with itraconazole absorption, metabolism or measurement by the HPLC assay (conventional amphotericin B, tramadol, amitriptyline, enoxaparin, hydrocortisone, docusate and senna). The low serum levels were associated with a persistently elevated C-reactive protein (CRP) and radiological progression of disease.
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Following a 6 week course of liposomal amphotericin B, he was changed to itraconazole oral solution at a dose of 200 mg twice daily. No other medications were changed at this time. Three weeks later, the itraconazole/hydroxy-itraconazole serum levels were found to be 830 and 1270 µg/L, respectively. Over the next 9 months the combined levels remained >1000 µg/L. During this time there was no evidence of disease progression and the CRP was consistently low (<10 mg/L).
The significant intra- and inter-patient variability of itraconazole steady-state serum concentrations is well described.2,3 In addition, many studies demonstrate a 40% to 60% greater bioavailability with the oral solution when compared with the capsule preparation.4–6 Occasional reports note steady-state serum concentrations to be up to 4–5-fold higher with itraconazole oral solution.7 However, after review of the literature, we could find no reports describing the dramatic difference in combined steady-state concentrations of up to 90-fold observed in this patient.
Itraconazole is an extremely lipophilic compound that is frequently poorly absorbed. However, increasing the water solubility of the drug can improve absorption from the gastrointestinal tract. In the oral solution formulation, this is achieved by non-covalent binding of the itraconazole salt to the compound hydroxypropyl-ß-cyclodextrin.6 The resulting itraconazole complex has greater water solubility than the unbound drug and is thus more readily absorbed through the intestinal mucosa. It appears that in certain individuals, such as the patient described, changing to itraconazole oral solution may result in steady-state serum levels an order of magnitude greater than those observed with capsules. The reason for this dramatic difference in serum levels is uncertain, but may relate to relatively poor absorption of lipophilic drugs and/or a relatively high sensitivity to the effect of hydroxypropyl-ß-cyclodextrin in these patients.
This case clearly illustrates that different formulations of itraconazole may have markedly different bioavailability within an individual immunocompetent patient. In selected patients, before alternative drugs are considered, a trial of oral solution is worth considering. In addition, after commencement of itraconazole treatment, a single acceptable itraconazole level may be insufficient to ensure adequate serum levels. Further levels may be required at intervals to confirm satisfactory absorption over time.
No specific financial support was obtained for the preparation of this article.
None to declare.
References
1
Odds FC, Vanden Bossche H. Antifungal activity of itraconazole compared with hydroxy-itraconazole in vitro. J Antimicrob Chemother (2000) 45:371–3.
2 Information for Healthcare Professionals. Sporanox Capsules Datasheet. New Zealand: Medsafe. 8 March 2006. www.medsafe.govt.nz/profs/datasheet/s/sporanoxcap.htm (9 July 2007, date last accessed).
3 Poirier J-M, Berlioz F, Isnard F, et al. Marked intra- and inter-patient variability of itraconazole steady state plasma concentrations. Thérapie (1996) 51:163–7.[Web of Science][Medline]
4 Information for Healthcare Professionals. Sporanox Oral Solution. New Zealand: Medsafe. 8 March 2006. http:www.medsafe.govt.nz/profs/datasheet/s/sporanoxsol.htm (9 July 2007, date last accessed).
5 Poirier J-M, Cheymol G. Optimisation of itraconazole therapy using target drug concentrations. Clin Pharmacokinet (1998) 35:461–73.[CrossRef][Web of Science][Medline]
6 Buchkowsky SS, Partovi N, Ensom MHH. Clinical pharmacokinetic monitoring of itraconazole is warranted in only a subset of patients. Ther Drug Monit (2005) 27:322–33.[CrossRef][Web of Science][Medline]
7 Redmann S, Charles BG. Markedly increased itraconazole (ICZ) plasma levels in cystic fibrosis (CF) patients after switching from capsules to oral solution—two case studies. Clin Exp Pharmacol Physiol (2004) 31(Suppl_1):A107.[CrossRef]
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