Lower atovaquone/proguanil concentrations in patients taking efavirenz, lopinavir/ritonavir or atazanavir/ritonavir
Van Luin, Matthijsa,b,c; Van der Ende, Marchina Ed; Richter, Clemense; Visser, Mirjamb; Faraj, Diarif; Van der Ven, Andrec,g; Gelinck, Luch,i; Kroon, Franki; Wit, Ferdinand Wj; Van Schaik, Ron HNk; Kuks, Paul FMb; Burger, David Ma,c
aDepartment of Clinical Pharmacy, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
bDepartment of Clinical Pharmacy, Rijnstate Hospital, Arnhem, The Netherlands
cNijmegen Institute for Infection, Inflammation and Immunity (N4i), Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
dDepartment of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands
eDepartment of Internal Medicine, Rijnstate Hospital, Arnhem, The Netherlands
fDepartment of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
gDepartment of Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
hDepartment of Medical Microbiology and Infectious Diseases, Erasmus Medical Centre, Rotterdam, The Netherlands
iDepartment of Infectious Diseases, Leiden University Medical Centre, Leiden, The Netherlands
jCentre for Poverty-related Communicable Diseases, Academic Medical Centre, Amsterdam, The Netherlands
kDepartment of Clinical Chemistry, Erasmus Medical Centre, Rotterdam, The Netherlands.
Received 26 November, 2009
Revised 11 December, 2009
Accepted 9 February, 2010
Correspondence to Matthijs van Luin, Department of Clinical Pharmacy, 864 Radboud University Nijmegen Medical Centre, Geert Grooteplein 10, 6525 GA Nijmegen, The Netherlands. Tel: +31 24 3616405; fax: +31 24 3668755; e-mail: firstname.lastname@example.org
HIV-infected travellers frequently use atovaquone/proguanil as malaria prophylaxis. We compared atovaquone/proguanil pharmacokinetics between healthy volunteers and HIV-infected patients taking efavirenz, lopinavir/ritonavir or atazanavir/ritonavir. The geometric mean ratio (95% confidence interval) area under the curve (AUC)0→t for atovaquone relative to the healthy volunteers was 0.25 (0.16–0.38), 0.26 (0.17–0.41) and 0.54 (0.35–0.83) for patients on efavirenz, lopinavir/ritonavir and atazanavir/ritonavir, respectively. Proguanil plasma concentrations were also significantly lower (38–43%). Physicians should be alert for atovaquone/proguanil prophylaxis failures in patients taking efavirenz, lopinavir/ritonavir or atazanavir/ritonavir.
HIV-infected travellers frequently use atovaquone/proguanil as malaria prophylaxis. Nonetheless, there are indications for drug–drug interactions between these agents and antiretroviral drugs. The summary of product characteristics of lopinavir/ritonavir warns that, theoretically, coadministration may lead to decreased atovaquone plasma concentrations . The postulated mechanism for this theoretical drug–drug interaction is enhanced glucuronidation of atovaquone [2,3]. In addition, there is a potential for decreased atovaquone concentrations in patients treated with other boosted protease inhibitors, such as atazanavir/ritonavir, or nonnucleoside reverse transcriptase inhibitors (NNRTIs), such as efavirenz, because these drugs may induce glucuronidation as well [4,5].
Therefore, we designed the current open-label, multicentre, phase I, single-dose study to compare single-dose atovaquone/proguanil pharmacokinetics between healthy volunteers and HIV-infected patients who were on stable antiretroviral treatment with regimens containing efavirenz, lopinavir/ritonavir or atazanavir/ritonavir. We did not choose for a design in which untreated HIV-infected patients served as a reference group because, at the time of study design, the HIV physicians at our clinics felt it would be very difficult to motivate this group of patients to participate in the trial.
The study was conducted in five Dutch HIV treatment centres from May 2007 until December 2008. All HIV-infected patients had CD4 cell counts higher than 200 cells/μl and were stable for at least 1 month on antiretroviral regimens that contained efavirenz 600 mg once daily (q.d.), atazanavir/ritonavir 300/100 mg q.d. or lopinavir/ritonavir in a dosage of 400/100 mg twice daily or 800/200 mg q.d. Patients suspected of nonadherence to antiretroviral medication were excluded. Both patients and healthy volunteers had to be 18–65 years old and had BMIs between 18 and 30 kg/m2. Subjects who used medication known to interfere with the pharmacokinetics of atovaquone or proguanil were excluded.
On day 1, subjects received one single dose of atovaquone/proguanil 250/100 mg with a strictly fat-standardized breakfast at their clinic. Blood samples for pharmacokinetics were collected throughout a 168-h period [0, 0.5, 1, 2, 3, 4, 5, 6, 8, 24, 48, 72 and 168 h (7 days)] after intake of atovaquone/proguanil. In addition, all patients were tested for the presence of *2, *3, and *17 alleles of CYP2C19, which is a key enzyme involved in proguanil metabolism.
Plasma concentrations of atovaquone and proguanil were determined with a validated HPLC method for the simultaneous quantitative analysis of atovaquone and proguanil, as described by Lindegardh et al. . Pharmacokinetic parameters for atovaquone and proguanil were calculated by noncompartmental methods using the WinNonlin software package (version 5.2; Pharsight, Mountain View, California, USA). We used multiple variable linear regression models to assess the effect of efavirenz, lopinavir/ritonavir and atazanavir/ritonavir on the area under the curve (AUC)0→t and Cmax of atovaquone and proguanil. Potential confounding parameters that were assessed were race, age, smoking behaviour, body weight, CYP2C19 genotype and body height. We used a stepwise selection procedure, by which a parameter was identified as a confounder if its addition to the model resulted in more than 10% change of the regression coefficient of efavirenz, lopinavir/ritonavir or atazanavir/ritonavir. Statistical evaluations were carried out with SPSS for Windows, version 16.0.1 (SPSS Inc., Chicago, Illinois, USA).
A total of 76 participants were evaluable for statistical evaluation: 18 healthy volunteers and 58 HIV-infected patients who were treated with efavirenz (n = 20), lopinavir/ritonavir (n = 19) or atazanavir/ritonavir (n = 19). Baseline characteristics were well balanced except that the HIV-infected patient group as a whole was older (median 48 versus 23 years) and included a higher proportion of men (88 versus 56%) and a higher proportion of smokers (45 versus 11%) compared with the healthy volunteers.
Figure 1(a) shows the atovaquone plasma concentration–time curves after a single dose of atovaquone/proguanil. Atovaquone plasma concentrations were considerably lower in HIV-infected patients treated with efavirenz or lopinavir/ritonavir, and modestly lower in those treated with atazanavir/ritonavir. After adjustment for confounders in the multiple linear regression analysis, the geometric mean ratio (GMR) [95% confidence interval (CI) AUC0→t for atovaquone relative to the healthy volunteers was 0.25 (0.16–0.38)] for patients on efavirenz, 0.26 (0.17–0.41) for patients on lopinavir/ritonavir and 0.54 (0.35–0.83) for patients on atazanavir/ritonavir. The adjusted GMR (95% CI) Cmax for atovaquone was 0.56 (0.39–0.80) for patients on efavirenz, 0.56 (0.39–0.82) for patients on lopinavir/ritonavir and 0.51 (0.36–0.73) for patients on atazanavir/ritonavir.
Proguanil plasma concentrations were modestly lower in all groups of HIV-infected patients (Fig. 1b). After adjustment for confounders, including the CYP2C19 genotype, the GMR (95% CI) AUC0→t for proguanil relative to the healthy volunteers was 0.57 (0.35–0.93) for patients on efavirenz, 0.62 (0.39–0.99) for patients on lopinavir/ritonavir and 0.59 (0.38–0.93) for patients on atazanavir/ritonavir. The Cmax for proguanil was not significantly lower in the three groups of HIV-infected patients versus the healthy controls.
It is not possible to establish from our study the exact mechanism behind the lower atovaquone plasma concentrations in the three groups of HIV-infected patients. The mechanism might be increased atovaquone glucuronidation . The lower atovaquone exposure in patients treated with lopinavir/ritonavir compared with those treated with atazanavir/ritonavir is in line with such a mechanism because lopinavir/ritonavir seems to have stronger inductive effects on glucuronidation enzymes than atazanavir/ritonavir [3,5,7]. Proguanil, which bolsters atovaquone activity , is predominantly metabolized by CYP2C19. Lopinavir/ritonavir, efavirenz, [9,10] and possibly atazanavir/ritonavir may induce CYP2C19, which may explain the lower proguanil exposure in these groups.
Despite the lower atovaquone/proguanil plasma exposure observed in our study, no clinical reports have been published so far that describe atovaquone/proguanil chemoprophylaxis failure in HIV-infected travellers treated with ritonavir-boosted protease inhibitors or NNRTIs. In addition, there are no established minimum effective atovaquone plasma concentrations in the setting of malaria prophylaxis, which makes it difficult to assess the precise clinical relevance of decreased atovaquone plasma concentrations. Nevertheless, the difference in atovaquone/proguanil plasma exposure with the healthy volunteers was substantial. Therefore, physicians should be alert for atovaquone/proguanil prophylaxis failures in HIV-infected patients treated with efavirenz, lopinavir/ritonavir or atazanavir/ritonavir. We recommend emphasizing adherence to atovaquone/proguanil in HIV-infected travellers treated with these drugs, that is, strict daily intake during the main meal. In addition, an increase of the dose of atovaquone/proguanil should be considered in patients treated with efavirenz or lopinavir/ritonavir.
We thank all participants who participated in the trial. Iman Padmos, Laura van Zonneveld, Nienke Langebeek, Petra van Bentum, Gerjanne ter Beest, Marjolein Bosch, Willemien Dorama, Conny Moons and Marien Kuipers are kindly acknowledged for their enthusiasm and their help with the data collection. Angela Colbers and Anita Huisman are kindly acknowledged for all their indispensable work. Technicians of the Department of Clinical Pharmacy, Rijnstate Hospital, Arnhem, The Netherlands, are kindly acknowledged for processing and analysing the samples for atovaquone and proguanil. Technicians of the Department of Clinical Pharmacy, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands, are kindly acknowledged for analysing the samples for lopinavir, atazanavir and efavirenz. Martin van Vliet is kindly acknowledged for DNA isolations and CYP2C19 genotyping.
Clinical trial registration: NCT00421473.
There are no conflicts of interest.
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