Efavirenz but Not Atazanavir/Ritonavir Significantly Reduces Atovaquone Concentrations in HIV-Infected Subjects

Mónica M. Calderón, Scott R. Penzak, Alice K. Pau, Parag Kumar, Maryellen McManus, Raul M. Alfaro, Joseph A. Kovacs

Research output: Contribution to journalArticle

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Abstract

Background. The current study was conducted to determine if efavirenz (EFV) or atazanavir/ritonavir (ATV/r)-based combination antiretroviral therapy (cART) impacted steady-state atovaquone plasma concentrations in human immunodeficiency virus (HIV)-infected patients receiving treatment doses of atovaquone. Methods. Thirty HIV-infected volunteers were recruited, 10 taking no cART and 10 each taking cART that included EFV or ATV/r. Subjects were randomly assigned to atovaquone 750 mg twice daily (BID) for 14 days followed by atovaquone 1500 mg BID for 14 days, or vice-versa, with a washout period in between. On day 14 of each phase, blood was sampled for pharmacokinetic studies, and the area under the concentration-time curve (AUCτ) and average concentration (Cavg) were calculated and compared using an unpaired t test. Results. Twenty-nine subjects completed both dosing cohorts. Subjects receiving EFV-based cART had 47% and 44% lower atovaquone AUCτ than subjects not receiving cART at atovaquone doses of 750 mg BID and 1500 mg BID, respectively (P ≤. 01). Only 5 of 10 subjects receiving EFV-based cART plus atovaquone 750 mg BID had an atovaquone Cavg >15 μg/mL, which has previously been associated with successful treatment of Pneumocystis jiroveci pneumonia. AUCτ and Cavg did not significantly differ for concurrent ATV/r for 750 mg BID or 1500 mg BID when compared to the group not receiving cART. Nine of 10 subjects not receiving cART, 8 of 10 subjects receiving ATV/r, and 2 of 10 subjects receiving EFV in combination with atovaquone 750 mg BID achieved an atovaquone Cavg >18.5 μg/mL, a concentration that has previously been associated with successful treatment of Toxoplasma encephalitis (TE). Conclusions. These data suggest that the currently recommended dose of atovaquone 750 mg BID for treatment of mild to moderate PCP may not be adequate in patients receiving concurrent EFV. Furthermore, doses lower than the currently recommended dose of 1500 mg BID may achieve plasma concentrations adequate to treat TE in HIV-infected patients not receiving EFV.

Original languageEnglish
Pages (from-to)1036-1042
Number of pages7
JournalClinical Infectious Diseases
Volume62
Issue number8
DOIs
StatePublished - 15 Apr 2016

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efavirenz
Atovaquone
Ritonavir
HIV
Therapeutics
Toxoplasma
Encephalitis
Atazanavir Sulfate

Keywords

  • Pneumocystis jiroveci pneumonia
  • atovaquone
  • drug interaction
  • efavirenz
  • toxoplasma encephalitis

Cite this

Calderón, M. M., Penzak, S. R., Pau, A. K., Kumar, P., McManus, M., Alfaro, R. M., & Kovacs, J. A. (2016). Efavirenz but Not Atazanavir/Ritonavir Significantly Reduces Atovaquone Concentrations in HIV-Infected Subjects. Clinical Infectious Diseases, 62(8), 1036-1042. https://doi.org/10.1093/cid/ciw028
Calderón, Mónica M. ; Penzak, Scott R. ; Pau, Alice K. ; Kumar, Parag ; McManus, Maryellen ; Alfaro, Raul M. ; Kovacs, Joseph A. / Efavirenz but Not Atazanavir/Ritonavir Significantly Reduces Atovaquone Concentrations in HIV-Infected Subjects. In: Clinical Infectious Diseases. 2016 ; Vol. 62, No. 8. pp. 1036-1042.
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abstract = "Background. The current study was conducted to determine if efavirenz (EFV) or atazanavir/ritonavir (ATV/r)-based combination antiretroviral therapy (cART) impacted steady-state atovaquone plasma concentrations in human immunodeficiency virus (HIV)-infected patients receiving treatment doses of atovaquone. Methods. Thirty HIV-infected volunteers were recruited, 10 taking no cART and 10 each taking cART that included EFV or ATV/r. Subjects were randomly assigned to atovaquone 750 mg twice daily (BID) for 14 days followed by atovaquone 1500 mg BID for 14 days, or vice-versa, with a washout period in between. On day 14 of each phase, blood was sampled for pharmacokinetic studies, and the area under the concentration-time curve (AUCτ) and average concentration (Cavg) were calculated and compared using an unpaired t test. Results. Twenty-nine subjects completed both dosing cohorts. Subjects receiving EFV-based cART had 47{\%} and 44{\%} lower atovaquone AUCτ than subjects not receiving cART at atovaquone doses of 750 mg BID and 1500 mg BID, respectively (P ≤. 01). Only 5 of 10 subjects receiving EFV-based cART plus atovaquone 750 mg BID had an atovaquone Cavg >15 μg/mL, which has previously been associated with successful treatment of Pneumocystis jiroveci pneumonia. AUCτ and Cavg did not significantly differ for concurrent ATV/r for 750 mg BID or 1500 mg BID when compared to the group not receiving cART. Nine of 10 subjects not receiving cART, 8 of 10 subjects receiving ATV/r, and 2 of 10 subjects receiving EFV in combination with atovaquone 750 mg BID achieved an atovaquone Cavg >18.5 μg/mL, a concentration that has previously been associated with successful treatment of Toxoplasma encephalitis (TE). Conclusions. These data suggest that the currently recommended dose of atovaquone 750 mg BID for treatment of mild to moderate PCP may not be adequate in patients receiving concurrent EFV. Furthermore, doses lower than the currently recommended dose of 1500 mg BID may achieve plasma concentrations adequate to treat TE in HIV-infected patients not receiving EFV.",
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author = "Calder{\'o}n, {M{\'o}nica M.} and Penzak, {Scott R.} and Pau, {Alice K.} and Parag Kumar and Maryellen McManus and Alfaro, {Raul M.} and Kovacs, {Joseph A.}",
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Calderón, MM, Penzak, SR, Pau, AK, Kumar, P, McManus, M, Alfaro, RM & Kovacs, JA 2016, 'Efavirenz but Not Atazanavir/Ritonavir Significantly Reduces Atovaquone Concentrations in HIV-Infected Subjects', Clinical Infectious Diseases, vol. 62, no. 8, pp. 1036-1042. https://doi.org/10.1093/cid/ciw028

Efavirenz but Not Atazanavir/Ritonavir Significantly Reduces Atovaquone Concentrations in HIV-Infected Subjects. / Calderón, Mónica M.; Penzak, Scott R.; Pau, Alice K.; Kumar, Parag; McManus, Maryellen; Alfaro, Raul M.; Kovacs, Joseph A.

In: Clinical Infectious Diseases, Vol. 62, No. 8, 15.04.2016, p. 1036-1042.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Efavirenz but Not Atazanavir/Ritonavir Significantly Reduces Atovaquone Concentrations in HIV-Infected Subjects

AU - Calderón, Mónica M.

AU - Penzak, Scott R.

AU - Pau, Alice K.

AU - Kumar, Parag

AU - McManus, Maryellen

AU - Alfaro, Raul M.

AU - Kovacs, Joseph A.

PY - 2016/4/15

Y1 - 2016/4/15

N2 - Background. The current study was conducted to determine if efavirenz (EFV) or atazanavir/ritonavir (ATV/r)-based combination antiretroviral therapy (cART) impacted steady-state atovaquone plasma concentrations in human immunodeficiency virus (HIV)-infected patients receiving treatment doses of atovaquone. Methods. Thirty HIV-infected volunteers were recruited, 10 taking no cART and 10 each taking cART that included EFV or ATV/r. Subjects were randomly assigned to atovaquone 750 mg twice daily (BID) for 14 days followed by atovaquone 1500 mg BID for 14 days, or vice-versa, with a washout period in between. On day 14 of each phase, blood was sampled for pharmacokinetic studies, and the area under the concentration-time curve (AUCτ) and average concentration (Cavg) were calculated and compared using an unpaired t test. Results. Twenty-nine subjects completed both dosing cohorts. Subjects receiving EFV-based cART had 47% and 44% lower atovaquone AUCτ than subjects not receiving cART at atovaquone doses of 750 mg BID and 1500 mg BID, respectively (P ≤. 01). Only 5 of 10 subjects receiving EFV-based cART plus atovaquone 750 mg BID had an atovaquone Cavg >15 μg/mL, which has previously been associated with successful treatment of Pneumocystis jiroveci pneumonia. AUCτ and Cavg did not significantly differ for concurrent ATV/r for 750 mg BID or 1500 mg BID when compared to the group not receiving cART. Nine of 10 subjects not receiving cART, 8 of 10 subjects receiving ATV/r, and 2 of 10 subjects receiving EFV in combination with atovaquone 750 mg BID achieved an atovaquone Cavg >18.5 μg/mL, a concentration that has previously been associated with successful treatment of Toxoplasma encephalitis (TE). Conclusions. These data suggest that the currently recommended dose of atovaquone 750 mg BID for treatment of mild to moderate PCP may not be adequate in patients receiving concurrent EFV. Furthermore, doses lower than the currently recommended dose of 1500 mg BID may achieve plasma concentrations adequate to treat TE in HIV-infected patients not receiving EFV.

AB - Background. The current study was conducted to determine if efavirenz (EFV) or atazanavir/ritonavir (ATV/r)-based combination antiretroviral therapy (cART) impacted steady-state atovaquone plasma concentrations in human immunodeficiency virus (HIV)-infected patients receiving treatment doses of atovaquone. Methods. Thirty HIV-infected volunteers were recruited, 10 taking no cART and 10 each taking cART that included EFV or ATV/r. Subjects were randomly assigned to atovaquone 750 mg twice daily (BID) for 14 days followed by atovaquone 1500 mg BID for 14 days, or vice-versa, with a washout period in between. On day 14 of each phase, blood was sampled for pharmacokinetic studies, and the area under the concentration-time curve (AUCτ) and average concentration (Cavg) were calculated and compared using an unpaired t test. Results. Twenty-nine subjects completed both dosing cohorts. Subjects receiving EFV-based cART had 47% and 44% lower atovaquone AUCτ than subjects not receiving cART at atovaquone doses of 750 mg BID and 1500 mg BID, respectively (P ≤. 01). Only 5 of 10 subjects receiving EFV-based cART plus atovaquone 750 mg BID had an atovaquone Cavg >15 μg/mL, which has previously been associated with successful treatment of Pneumocystis jiroveci pneumonia. AUCτ and Cavg did not significantly differ for concurrent ATV/r for 750 mg BID or 1500 mg BID when compared to the group not receiving cART. Nine of 10 subjects not receiving cART, 8 of 10 subjects receiving ATV/r, and 2 of 10 subjects receiving EFV in combination with atovaquone 750 mg BID achieved an atovaquone Cavg >18.5 μg/mL, a concentration that has previously been associated with successful treatment of Toxoplasma encephalitis (TE). Conclusions. These data suggest that the currently recommended dose of atovaquone 750 mg BID for treatment of mild to moderate PCP may not be adequate in patients receiving concurrent EFV. Furthermore, doses lower than the currently recommended dose of 1500 mg BID may achieve plasma concentrations adequate to treat TE in HIV-infected patients not receiving EFV.

KW - Pneumocystis jiroveci pneumonia

KW - atovaquone

KW - drug interaction

KW - efavirenz

KW - toxoplasma encephalitis

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U2 - 10.1093/cid/ciw028

DO - 10.1093/cid/ciw028

M3 - Article

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AN - SCOPUS:84964911445

VL - 62

SP - 1036

EP - 1042

JO - Clinical Infectious Diseases

JF - Clinical Infectious Diseases

SN - 1058-4838

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