Protease inhibitors and azolic antifungals in HIV patients with histoplasmosis: a clinical pharmacokinetics perspective

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 (>1 μg/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
  Brilhante R.S, Caetano É.P, Riello G.B, et al. Antiretroviral drugs saquinavir and ritonavir reduce inhibitory concentration values of itraconazole against Histoplasma capsulatum strains in vitro. Braz J Infect Dis. 2016; 20:155-9
• ²
  Porta A, Maresca B. Host response and Histoplasma capsulatum/macrophage molecular interactions. Med Mycol. 2000; 38:399-406
• ³
  Wheat L.J, Freifeld A.G, Kleiman M.B, et al. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis. 2007; 45:807-25
• ⁴
  Nacher M, Adenis A, Aznar C, et al. How many have died from undiagnosed human immunodeficiency virus-associated histoplasmosis, a treatable disease? Time to act. Am J Trop Med Hyg. 2014; 90:193-4
• ⁵
  Prentice A.G, Glasmacher A. Making sense of itraconazole pharmacokinetics. J Antimicrob Chemother. 2005; 56:i17-22

Publication Dates

• Publication in this collection
  Jul-Aug 2016

History

• Received
  17 Feb 2016
• Accepted
  03 Mar 2016