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Vol. 20. Issue 4.
Pages 405 (July - August 2016)
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Vol. 20. Issue 4.
Pages 405 (July - August 2016)
Letter to the Editor
Open Access
Protease inhibitors and azolic antifungals in HIV patients with histoplasmosis: a clinical pharmacokinetics perspective
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Lucas Miyake Okumura
Hospital de Clínicas de Porto Alegre, Divisão de Farmácia Clínica, Porto Alegre, RS, Brazil
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Dear Editor,

A previous in vitro investigation found that a sinergistic effect might occur, when using itraconazole (ITRA) and ritonavir (RTV) against Histoplasma capsulatum,1 where an interesting mechanism of action was proposed. However, relevant pharmacokinetic (PK) issues were under explored. Herein, this letter attempts to deepen a clinical PK discussion not performed by Brilhante and colleagues.1

Firstly, the in vitro model1 did not account for drug penetration in macrophages, given that Histoplasma spp. are found as intracellular microorganisms after innate immunity recognition and phagocytation.2 Secondly, one should recognize the potential CYP3A4 competitive inhibition when using RTV and an azolic agent. By combining them, we expect an elevated plasma concentration of the azolic agent,3 as RTV has higher affinity to the aforementioned phase 1 enzyme, but not the opposite.1 The association of both drugs is a possible scenario4 when treating multiple drug resistant HIV infected patients. Whether non-CYP3A4 substrates are unavailable, clinicians should attempt to monitoring hepatic enzymes and random ITRA steady state serum concentrations (>1μg/mL) after 7–15 days.3

Finally, the previous report1 discussed that using both drugs might be clinically possible by “reducing itraconazole dose”. For several reasons,5 there is no evidence on lowering ITRA doses: (a) it has an erratic gastrointestinal absorption and food composition and gastric pH might influence drug's bioavailability (cyclodextrin-containing formulations are preferred); (b) ITRA has non-linear PK, thus, dose reductions may lead to unpredictable serum levels (zero order kinetics is dependent on enzyme saturation).

Conflicts of interest

The author declares no conflicts of interest.

References
[1]
R.S. Brilhante, É.P. Caetano, G.B. Riello, et al.
Antiretroviral drugs saquinavir and ritonavir reduce inhibitory concentration values of itraconazole against Histoplasma capsulatum strains in vitro.
Braz J Infect Dis, 20 (2016), pp. 155-159
[2]
A. Porta, B. Maresca.
Host response and Histoplasma capsulatum/macrophage molecular interactions.
Med Mycol, 38 (2000), pp. 399-406
[3]
L.J. Wheat, A.G. Freifeld, M.B. Kleiman, et al.
Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America.
Clin Infect Dis, 45 (2007), pp. 807-825
[4]
M. Nacher, A. Adenis, C. Aznar, et al.
How many have died from undiagnosed human immunodeficiency virus-associated histoplasmosis, a treatable disease? Time to act.
Am J Trop Med Hyg, 90 (2014), pp. 193-194
[5]
A.G. Prentice, A. Glasmacher.
Making sense of itraconazole pharmacokinetics.
J Antimicrob Chemother, 56 (2005), pp. i17-i22
Copyright © 2016. Elsevier Editora Ltda.. All rights reserved
The Brazilian Journal of Infectious Diseases

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