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Clinical Trial
. 2016 Apr 15;62(8):1036-1042.
doi: 10.1093/cid/ciw028. Epub 2016 Jan 20.

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

Mónica M Calderón  1   2 , Scott R Penzak  1 , Alice K Pau  3 , Parag Kumar  1 , Maryellen McManus  2 , Raul M Alfaro  1 , Joseph A Kovacs  4
Affiliations
Clinical Trial

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

Mónica M Calderón et al. Clin Infect Dis. .

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 (C avg) 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 C avg>15 µg/mL, which has previously been associated with successful treatment of Pneumocystis jirovecipneumonia. 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 C avg>18.5 µg/mL, a concentration that has previously been associated with successful treatment of Toxoplasmaencephalitis (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.

Clinical trials registration: NCT01479361.

Keywords: Pneumocystis jiroveci pneumonia; atovaquone; drug interaction; efavirenz; toxoplasma encephalitis.

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Figures

Figure 1.
Figure 1.
Steady-state atovaquone plasma concentration-time curves in human immunodeficiency virus-infected subjects receiving efavirenz (EFV), atazanavir/ritonavir (ATV/r), or no combination antiretroviral therapy (cART) in combination with atovaquone 750 mg twice daily for 14 days (A) or 1500 mg twice daily for 14 days (B). Solid diamonds and shorter dashed line: no cART; solid triangles and solid line: ATV/r; open squares and longer dashed line: EFV. Error bars represent standard error of the mean.
Figure 2.
Figure 2.
Average atovaquone plasma concentrations (Cavg) in human immunodeficiency virus-infected patients receiving no antiretroviral therapy (no ARVs), atazanavir/ritonavir (ATV/r), or efavirenz (EFV) in combination with atovaquone 750 mg twice daily for 14 days (A) or 1500 mg twice daily for 14 days (B). Horizontal lines: solid line represents the Cavg previously associated with successful treatment of Pneumocystis jiroveci pneumonia (15 µg/mL); the dashed line represents the Cavg previously associated with successful treatment of toxoplasma encephalitis (18.5 µg/mL).
Figure 3.
Figure 3.
Atovaquone plasma concentration-time curves in human immunodeficiency virus-infected subjects receiving atovaquone 750 mg and 1500 mg twice daily for 14 days without concurrent antiretroviral therapy: dose proportionality comparison under steady-state conditions. Solid diamonds and solid line: atovaquone 750-mg regimen; solid squares and solid line: 1500-mg atovaquone regimen; open triangles and dashed line: the concentration-time curve that would be expected for the 1500-mg atovaquone regimen if it were proportional to the 750-mg atovaquone regimen (ie, plasma concentrations for the 750-mg atovaquone regimen multiplied by 2).
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References

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