The case of a 32-year-old Caucasian female with multi-drug resistant HIV-1 subtype B infection treated with a salvage regimen including maraviroc, raltegravir, etravirine and unboosted saquinavir who started atovaquone/proguanil prophylaxis, is reported. The potential interactions between atovaquone/proguanil and these anti-retroviral drugs are investigated. Pharmacokinetic analyses documented a marked increase in etravirine and saquinavir plasma concentrations (+55% and +274%, respectively), but not in raltegravir and maraviroc plasma concentrations. The evidence that atovaquone/proguanil significantly interacts with etravirine and saquinavir, but not with raltegravir and maraviroc, suggests that the mechanism of interaction is related to cytochrome P450

A D'Avolio

AK Boggild

Anna L Gallo

Antonio D'Avolio

C Tommasi

CG Lee

Chiara Tommasi

Emanuele Nicastri

Jelena Ivanovic

Leopoldo P Pucillo

M Iwamoto

M Schöller-Gyüre

M van Luin

Massimo Tempestilli

NA Meanwell

Pasquale Narciso

R Srinivas

Rita Bellagamba

S Abel

English

PubMed

Springer - Publisher Connector

CASE REPORT Open Access
Marked increase in etravirine and saquinavir
plasma concentrations during atovaquone/
proguanil prophylaxis
Chiara Tommasi1*, Rita Bellagamba1, Massimo Tempestilli1, Antonio D’Avolio2, Anna L Gallo1, Jelena Ivanovic1,
Emanuele Nicastri1, Leopoldo P Pucillo1 and Pasquale Narciso
Abstract
The case of a 32-year-old Caucasian female with multi-drug resistant HIV-1 subtype B infection treated with a
salvage regimen including maraviroc, raltegravir, etravirine and unboosted saquinavir who started atovaquone/
proguanil prophylaxis, is reported. The potential interactions between atovaquone/proguanil and these anti-
retroviral drugs are investigated. Pharmacokinetic analyses documented a marked increase in etravirine and
saquinavir plasma concentrations (+55% and +274%, respectively), but not in raltegravir and maraviroc plasma
concentrations. The evidence that atovaquone/proguanil significantly interacts with etravirine and saquinavir, but
not with raltegravir and maraviroc, suggests that the mechanism of interaction is related to cytochrome P450.
Background
Atovaquone/proguanil (Malarone®) is a fixed-dose com-
bination of the anti-malarial agents atovaquone and pro-
guanil hydrochloride. HIV-infected travellers in malaria
endemic countries frequently use atovaquone/proguanil
as a prophylaxis.
Atovaquone displays linear pharmacokinetic with a
mean absolute bioavailability of 23%. It is highly pro-
tein-bound (> 99%) but does not displace other highly
protein-bound drugs in vitro [1]. The principal excretion
route is the liver, with the 94% of the drug excreted
unchanged in the faeces. The elimination half-life is 2-3
days in adults [1].
Proguanil is rapidly absorbed from the gastrointestinal
tract and achieves peak plasma concentrations in 2-4
hours, with an absolute bioavailability as high as 60%
[1]. It is 75% protein bound, and this binding is unaf-
fected by the presence of atovaquone and vice versa [1].
Proguanil is metabolized to cycloguanil (primarily
trough CYP2C19) and 4-chlorophenylbiguanide, with
between 40% and 60% of proguanil excreted renally.
The elimination half-life of proguanil is 12-21 hours [1].
Drug interactions between atovaquone/proguanil and
tetracycline, metoclopramide, rifampin, rifabutin and
warfarin have been described. The concomitant adminis-
tration of indinavir is associated with a 23% decrease in
indinavir Cmin (90% CI 8-35%). Potential interactions
between proguanil and other drugs that are CYP2C19
substrates or inhibitors are unknown [1].
Case presentation
A 32-year-old Caucasian female was admitted to the “L.
Spallanzani” National Institute for Infectious Diseases in
Rome for multi-drug resistant HIV-1 subtype B infection
(diagnosed in 1985), beta-thalassaemia, severe pulmonary
hypertension, wasting syndrome and ritonavir allergy. In
October 2007, a genotypic resistance test (GRT) revealed
high-level resistance to all currently available anti-retrovir-
als (ARVs) and a salvage treatment with unboosted daru-
navir (600 mg bid), lamivudine (300 mg qd) and
raltegravir (400 mg bid) was started. Three months later, a
viral rebound occurred; a new GRT evidenced the emer-
gence of primary N155H/N and secondary D232N muta-
tions in integrase gene with no new RT and PR-related
mutations. In March 2008, after the viral tropism assay, a
new ARV regimen including raltegravir (400 mg bid),
saquinavir (1000 mg bid), maraviroc (150 mg bid) and
etravirine (200 mg bid) was started. Viremia immediately
* Correspondence: chiara.tommasi@inmi.it
1“National Institute for Infectious Diseases “L. Spallanzani”, Via Portuense 292,
00149 Rome, Italy
Full list of author information is available at the end of the article
Tommasi et al. Malaria Journal 2011, 10:141
http://www.malariajournal.com/content/10/1/141
© 2011 Tommasi et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
decreased to below the detection limit (50cp/ml) and
remained undetectable. Tolerability was good and no
grade 3/4 adverse events have been reported.
In September 2009, the patient planned to spend a
two-week holiday in Kenya. The CD4 cell count was
334/mmc. Standard malaria prophylaxis with atova-
quone/proguanil fixed-dose combination (250/100 mg)
was prescribed: one tablet daily starting two days before
the journey and ending the treatment seven days after
return to Italy [2]. A 12 hour-PK of anti-retrovirals was
performed before starting prophylaxis with atovaquone/
proguanil (Figure 1). The samples were collected in fast-
ing status following this order: the first sample 12 hours
after the last dose of anti-retrovirals (pre-dose); the sec-
ond sample one hour after breakfast and anti-retrovirals
consumption; the following samples at 2, 4, 6 and 12
hours post anti-retrovirals’ intake. The second PK for
the determination of anti-retrovirals’ plasma concentra-
tions during atovaquone/proguanil prophylaxis was col-
lected at day 20 on prophylaxis with the same timing
plan (Figure 1). In order to avoid any food interference
with the PK results, the same diet was administered in
both the PK sampling days. During the stay in Kenya,
the adherence was monitored by self-reported diary that
documented an adherence level of 100% both for anti-
retroviral and prophylaxis drugs. This data was retro-
spectively confirmed by pills count system.
Twenty days after atovaquone/proguanil was started,
the blood examinations documented a CD4 count of
438 cell/mmc, with undetectable HIV-RNA. Liver and
haematological parameters were normal. No clinical or
laboratory adverse events were reported during or after
the journey.
Conclusions
In a recent study, Van Luin et al demonstrated that geo-
metric mean ratios (95% confidence interval) of the area
under the curve (AUC) of atovaquone in patients on efa-
virenz, lopinavir/ritonavir and atazanavir/ritonavir com-
pared with healthy volunteers were 0.25 (0.16-0.38), 0.26
(0.17-0.41) and 0.54 (0.35-0.83), respectively. Proguanil
plasma concentrations were also significantly lower (38-
43%). No data on anti-retroviral pharmacokinetics during
atovaquone/proguanil prophylaxis were provided. The
authors concluded that physicians should be alert to ato-
vaquone/proguanil prophylaxis failures in patients taking
efavirenz, lopinavir/ritonavir or atazanavir/ritonavir [3].
The anti-retrovirals’ pharmacokinetic during atovaquone/
proguanil prophylaxis were analysed. A marked increase
in etravirine and saquinavir AUC0-12h (+55% and +274%,
respectively) and a slight decrease in raltegravir and mara-
viroc AUC0-12h (-23% and -9%, respectively) were docu-
mented. Although AUCs between pre- and post-
prophylaxis are not very different, in the PK profiles of
 AUC0-12h: -23% 
 AUC0-12h: -9%
 AUC0-12h: +55% 
 AUC0-12h: +274% 
Figure 1 Plasma concentrations of antiretroviral drugs (raltegravir, maraviroc, etravirine and saquinavir) evaluated as Area Under
Curve (AUC) before starting atovaquone/proguanil (pre) and at day 20 of prophylaxis (post). The D AUC0-12h represents the difference
in AUC0-12h (during prophylaxis AUC minus pre-prophylaxis AUC). An HPLC-UV method for the simultaneous quantification of the HIV integrase
inhibitor raltegravir, the new non- nucleoside reverse transcriptase inhibitor etravirine, protease inhibitor saquinavir and CCR-5 inhibitor maraviroc
was used [11,12].
Tommasi et al. Malaria Journal 2011, 10:141
http://www.malariajournal.com/content/10/1/141
Page 2 of 3
maraviroc and raltegravir the Tmax and the Cmax in post-
prophylaxis appear to be earlier than in pre- prophylaxis,
suggesting a more fast absorption of both drugs. Unfortu-
nately, it was not possible to determine atovaquone and
proguanil plasma concentrations. However, the absence of
established minimum effective atovaquone plasma con-
centrations in the setting of malaria prophylaxis makes it
difficult to assess the clinical relevance of dosing atova-
quone and proguanil plasma concentrations, except for
the evaluation of potential interactions with anti-retroviral
drugs [3]. The evidence that atovaquone/proguanil signifi-
cantly interacts with etravirine and saquinavir, but not
with raltegravir and maraviroc, suggests that the mechan-
ism of interaction is related to cytochrome P450. Etravir-
ine is metabolized primarily by hydroxylation through
several cytochrome P-450 isoenzymes (mainly CYP3A,
CYP2C9 and CYP2C19), followed by glucuronidation of
the metabolites. It is also an inducer of CYP3A and a mild
inhibitor of CYP2C9, 2C19 and P-glycoprotein [4]. Saqui-
navir is metabolized by CYP3A4. It is neither an inducer
nor an inhibitor of P450 system, but it is substrate and
inhibitor of P-glycoprotein and MRP1 [5,6]. Raltegravir is
metabolized via UGT1A1-mediated glucuronidation and is
neither an inducer nor an inhibitor of the CYP oxidation
system or P-glycoprotein [7]. Maraviroc is extensively
metabolized by CYP3A4 and it is a substrate for P-glyco-
protein. At higher doses, maraviroc is a potential inhibitor
of CYP2D6 and perhaps of P-glycoprotein [8]. In vitro,
maraviroc was not found to inhibit any major CYP isoen-
zyme, including CYPIA2, CYP2B6, CYP2C8, CYP2C19,
CYP2D6, and CYP3A4 [9]. Basing on the pharmacokinetic
characteristics of these anti-retrovirals, it is supposable
that atovaquone, or more likely proguanil, interferes with
etravirine and saquinavir for CYP450 mediated metabo-
lism (perhaps on the 2C isoenzymes) with a consequent
marked increase in plasma concentrations of both anti-ret-
rovirals. Despite of the clear effect in plasma concentra-
tions of etravirine and saquinavir, in this case the patient
noticed no side effects, and blood examinations during
prophylaxis documented any lab toxicities. It is possible
that, in this case, the absence of drug-related toxicity was
due to the use of unboosted protease inhibitor; while for
etravirine there are no clear data on the correlation
between PK and toxicity [10].
This case should alert the physicians to be cautious
and vigilant when atovaquone/proguanil prophylaxis is
prescribed in patients treated with etravirine and/or
saquinavir (especially if ritonavir-boosted).
Acknowledgements
Written consent was obtained from the patient. All authors contributed to
the management of the patient and to the writing and the revising of the
article. The authors alone are responsible for the content and writing of the
paper. The authors thank Andrea Baker and Eugenio Tommasi for the
language revision.
Author details
1“National Institute for Infectious Diseases “L. Spallanzani”, Via Portuense 292,
00149 Rome, Italy. 2Clinica Universitaria c/o Ospedale Amedeo di Savoia,
University of Turin, Turin - Italy.
Authors’ contributions
CT conceived of the study, performed blood sampling and drafted the
manuscript. RB, JI and EN were responsible for the clinical management of
the patient. MT, ALG and AD carried out the pharmacokinetic studies. LP
and PN participated in study design and coordination. All authors read and
approved the final manuscript.
Competing interests
The authors declare that they have no competing interests.
Received: 23 December 2010 Accepted: 21 May 2011
Published: 21 May 2011
References
1. Boggild AK, Parise ME, Lewis LS, Kain KC: Atovaquone-proguanil: report
from the CDC expert meeting on malaria chemoprophylaxis (II). Am J
Trop Med Hyg 2007, 76:208-223.
2. Centers for Disease Control and Prevention: 2009 [http://wwwnc.cdc.gov/
travel/destinations/kenya.aspx], Travelers’ Health. Yellow book Available at:.
3. van Luin M, Van der Ende ME, Richter C, Visser M, Faraj D, Van der Ven A,
Gelinck L, Kroon F, Wit FW, Van Schaik RH, Kuks PF, Burger DM: Lower
atovaquone/proguanil concentrations in patients taking efavirenz,
lopinavir/ritonavir or atazanavir/ritonavir. AIDS 2010, 24:1223-1226.
4. Schöller-Gyüre M, Kakuda TN, Raoof A, De Smedt G, Hoetelmans RM:
Clinical pharmacokinetics and pharmacodynamics of etravirine. Clin
Pharmacokinet 2009, 48:561-574.
5. Lee CG, Gottesman MM, Cardarelli CO, Ramachandra M, Jeang KT,
Ambudkar SV, Pastan I, Dey S: HIV-1 protease inhibitors are substrates for
the MDR1 multidrug transporter. Biochemistry 1998, 37:3594-3601.
6. Srinivas R, Middlemas D, Flynn P, Fridland A: Human immunodeficiency
virus protease inhibitors serve as substrates for multidrug transporter
proteins MDR1 and MRP1 but retain antiviral efficacy in cell lines
expressing these transporters. Antimicrob Agents Chemother 1998,
42:3157-3162.
7. Iwamoto M, Wenning LA, Petry AS, Laethem M, De Smet M, Kost JT,
Merschman SA, Strohmaier KM, Ramael S, Lasseter KC, Stone JA,
Gottesdiener KM, Wagner JA: Safety, tolerability, and pharmacokinetics of
raltegravir after single and multiple doses in healthy subjects. Clin Pharm
Ther 2008, 83:293-299.
8. Abel S, Back DJ, Vourvahis M: Maraviroc: pharmacokinetics and drug
interactions. Antivir Ther 2009, 14:607-618.
9. Meanwell NA, Kadow JF: Maraviroc, a chemokine CCR5 receptor
antagonist for the treatment of HIV infection and AIDS. Curr Opin Investig
Drugs 2007, 8:669-681.
10. Tommasi C, Tempestilli M, Fezza R, Bellagamba R, Nicastri E, D’offizi G,
Pucillo LP, Narciso P: A rare case of severe myopathy associated with
etravirine use. AIDS 2010, 24:1088-1090.
11. D’Avolio A, Baietto L, Siccardi M, Sciandra M, Simiele M, Oddone V,
Bonora S, Di Perri G: An HPLC-PDA method for the simultaneous
quantification of the HIV integrase inhibitor raltegravir, the new
nonnucleoside reverse transcriptase inhibitor etravirine, and 11 other
anti-retroviral agents in the plasma of HIV-infected patients. Ther Drug
Monit 2008, 30:662-669.
12. D’Avolio A, Simiele M, Baietto L, Siccardi M, Sciandra M, Patanella S,
Bonora S, Di Perri G: A validated high-performance liquid
chromatography-ultraviolet method for quantification of the CCR5
inhibitor maraviroc in plasma of HIV-infected patients. Ther Drug Monit
2010, 32:86-92.
doi:10.1186/1475-2875-10-141
Cite this article as: Tommasi et al.: Marked increase in etravirine and
saquinavir plasma concentrations during atovaquone/proguanil
prophylaxis. Malaria Journal 2011 10:141.
Tommasi et al. Malaria Journal 2011, 10:141
http://www.malariajournal.com/content/10/1/141
Page 3 of 3


Marked increase in etravirine and saquinavir plasma concentrations during atovaquone/proguanil prophylaxis

D'Avolio, Antonio

Institutional Research Information System University of Turin

CASE REPORT Open AccessMarked increase in etravirine and saquinavirplasma concentrations during atovaquone/proguanil prophylaxisChiara Tommasi1*, Rita Bellagamba1, Massimo Tempestilli1, Antonio D’Avolio2, Anna L Gallo1, Jelena Ivanovic1,Emanuele Nicastri1, Leopoldo P Pucillo1 and Pasquale NarcisoAbstractThe case of a 32-year-old Caucasian female with multi-drug resistant HIV-1 subtype B infection treated with asalvage regimen including maraviroc, raltegravir, etravirine and unboosted saquinavir who started atovaquone/proguanil prophylaxis, is reported. The potential interactions between atovaquone/proguanil and these anti-retroviral drugs are investigated. Pharmacokinetic analyses documented a marked increase in etravirine andsaquinavir plasma concentrations (+55% and +274%, respectively), but not in raltegravir and maraviroc plasmaconcentrations. The evidence that atovaquone/proguanil significantly interacts with etravirine and saquinavir, butnot with raltegravir and maraviroc, suggests that the mechanism of interaction is related to cytochrome P450.BackgroundAtovaquone/proguanil (Malarone®) is a fixed-dose com-bination of the anti-malarial agents atovaquone and pro-guanil hydrochloride. HIV-infected travellers in malariaendemic countries frequently use atovaquone/proguanilas a prophylaxis.Atovaquone displays linear pharmacokinetic with amean absolute bioavailability of 23%. It is highly pro-tein-bound (> 99%) but does not displace other highlyprotein-bound drugs in vitro [1]. The principal excretionroute is the liver, with the 94% of the drug excretedunchanged in the faeces. The elimination half-life is 2-3days in adults [1].Proguanil is rapidly absorbed from the gastrointestinaltract and achieves peak plasma concentrations in 2-4hours, with an absolute bioavailability as high as 60%[1]. It is 75% protein bound, and this binding is unaf-fected by the presence of atovaquone and vice versa [1].Proguanil is metabolized to cycloguanil (primarilytrough CYP2C19) and 4-chlorophenylbiguanide, withbetween 40% and 60% of proguanil excreted renally.The elimination half-life of proguanil is 12-21 hours [1].Drug interactions between atovaquone/proguanil andtetracycline, metoclopramide, rifampin, rifabutin andwarfarin have been described. The concomitant adminis-tration of indinavir is associated with a 23% decrease inindinavir Cmin (90% CI 8-35%). Potential interactionsbetween proguanil and other drugs that are CYP2C19substrates or inhibitors are unknown [1].Case presentationA 32-year-old Caucasian female was admitted to the “L.Spallanzani” National Institute for Infectious Diseases inRome for multi-drug resistant HIV-1 subtype B infection(diagnosed in 1985), beta-thalassaemia, severe pulmonaryhypertension, wasting syndrome and ritonavir allergy. InOctober 2007, a genotypic resistance test (GRT) revealedhigh-level resistance to all currently available anti-retrovir-als (ARVs) and a salvage treatment with unboosted daru-navir (600 mg bid), lamivudine (300 mg qd) andraltegravir (400 mg bid) was started. Three months later, aviral rebound occurred; a new GRT evidenced the emer-gence of primary N155H/N and secondary D232N muta-tions in integrase gene with no new RT and PR-relatedmutations. In March 2008, after the viral tropism assay, anew ARV regimen including raltegravir (400 mg bid),saquinavir (1000 mg bid), maraviroc (150 mg bid) andetravirine (200 mg bid) was started. Viremia immediately* Correspondence: chiara.tommasi@inmi.it1“National Institute for Infectious Diseases “L. Spallanzani”, Via Portuense 292,00149 Rome, ItalyFull list of author information is available at the end of the articleTommasi et al. Malaria Journal 2011, 10:141http://www.malariajournal.com/content/10/1/141© 2011 Tommasi et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly cited.decreased to below the detection limit (50cp/ml) andremained undetectable. Tolerability was good and nograde 3/4 adverse events have been reported.In September 2009, the patient planned to spend atwo-week holiday in Kenya. The CD4 cell count was334/mmc. Standard malaria prophylaxis with atova-quone/proguanil fixed-dose combination (250/100 mg)was prescribed: one tablet daily starting two days beforethe journey and ending the treatment seven days afterreturn to Italy [2]. A 12 hour-PK of anti-retrovirals wasperformed before starting prophylaxis with atovaquone/proguanil (Figure 1). The samples were collected in fast-ing status following this order: the first sample 12 hoursafter the last dose of anti-retrovirals (pre-dose); the sec-ond sample one hour after breakfast and anti-retroviralsconsumption; the following samples at 2, 4, 6 and 12hours post anti-retrovirals’ intake. The second PK forthe determination of anti-retrovirals’ plasma concentra-tions during atovaquone/proguanil prophylaxis was col-lected at day 20 on prophylaxis with the same timingplan (Figure 1). In order to avoid any food interferencewith the PK results, the same diet was administered inboth the PK sampling days. During the stay in Kenya,the adherence was monitored by self-reported diary thatdocumented an adherence level of 100% both for anti-retroviral and prophylaxis drugs. This data was retro-spectively confirmed by pills count system.Twenty days after atovaquone/proguanil was started,the blood examinations documented a CD4 count of438 cell/mmc, with undetectable HIV-RNA. Liver andhaematological parameters were normal. No clinical orlaboratory adverse events were reported during or afterthe journey.ConclusionsIn a recent study, Van Luin et al demonstrated that geo-metric mean ratios (95% confidence interval) of the areaunder the curve (AUC) of atovaquone in patients on efa-virenz, lopinavir/ritonavir and atazanavir/ritonavir com-pared with healthy volunteers were 0.25 (0.16-0.38), 0.26(0.17-0.41) and 0.54 (0.35-0.83), respectively. Proguanilplasma concentrations were also significantly lower (38-43%). No data on anti-retroviral pharmacokinetics duringatovaquone/proguanil prophylaxis were provided. Theauthors concluded that physicians should be alert to ato-vaquone/proguanil prophylaxis failures in patients takingefavirenz, lopinavir/ritonavir or atazanavir/ritonavir [3].The anti-retrovirals’ pharmacokinetic during atovaquone/proguanil prophylaxis were analysed. A marked increasein etravirine and saquinavir AUC0-12h (+55% and +274%,respectively) and a slight decrease in raltegravir and mara-viroc AUC0-12h (-23% and -9%, respectively) were docu-mented. Although AUCs between pre- and post-prophylaxis are not very different, in the PK profiles of? AUC0-12h: -23% ? AUC0-12h: -9%? AUC0-12h: +55% ? AUC0-12h: +274% Figure 1 Plasma concentrations of antiretroviral drugs (raltegravir, maraviroc, etravirine and saquinavir) evaluated as Area UnderCurve (AUC) before starting atovaquone/proguanil (pre) and at day 20 of prophylaxis (post). The D AUC0-12h represents the differencein AUC0-12h (during prophylaxis AUC minus pre-prophylaxis AUC). An HPLC-UV method for the simultaneous quantification of the HIV integraseinhibitor raltegravir, the new non- nucleoside reverse transcriptase inhibitor etravirine, protease inhibitor saquinavir and CCR-5 inhibitor maravirocwas used [11,12].Tommasi et al. Malaria Journal 2011, 10:141http://www.malariajournal.com/content/10/1/141Page 2 of 3maraviroc and raltegravir the Tmax and the Cmax in post-prophylaxis appear to be earlier than in pre- prophylaxis,suggesting a more fast absorption of both drugs. Unfortu-nately, it was not possible to determine atovaquone andproguanil plasma concentrations. However, the absence ofestablished minimum effective atovaquone plasma con-centrations in the setting of malaria prophylaxis makes itdifficult to assess the clinical relevance of dosing atova-quone and proguanil plasma concentrations, except forthe evaluation of potential interactions with anti-retroviraldrugs [3]. The evidence that atovaquone/proguanil signifi-cantly interacts with etravirine and saquinavir, but notwith raltegravir and maraviroc, suggests that the mechan-ism of interaction is related to cytochrome P450. Etravir-ine is metabolized primarily by hydroxylation throughseveral cytochrome P-450 isoenzymes (mainly CYP3A,CYP2C9 and CYP2C19), followed by glucuronidation ofthe metabolites. It is also an inducer of CYP3A and a mildinhibitor of CYP2C9, 2C19 and P-glycoprotein [4]. Saqui-navir is metabolized by CYP3A4. It is neither an inducernor an inhibitor of P450 system, but it is substrate andinhibitor of P-glycoprotein and MRP1 [5,6]. Raltegravir ismetabolized via UGT1A1-mediated glucuronidation and isneither an inducer nor an inhibitor of the CYP oxidationsystem or P-glycoprotein [7]. Maraviroc is extensivelymetabolized by CYP3A4 and it is a substrate for P-glyco-protein. At higher doses, maraviroc is a potential inhibitorof CYP2D6 and perhaps of P-glycoprotein [8]. In vitro,maraviroc was not found to inhibit any major CYP isoen-zyme, including CYPIA2, CYP2B6, CYP2C8, CYP2C19,CYP2D6, and CYP3A4 [9]. Basing on the pharmacokineticcharacteristics of these anti-retrovirals, it is supposablethat atovaquone, or more likely proguanil, interferes withetravirine and saquinavir for CYP450 mediated metabo-lism (perhaps on the 2C isoenzymes) with a consequentmarked increase in plasma concentrations of both anti-ret-rovirals. Despite of the clear effect in plasma concentra-tions of etravirine and saquinavir, in this case the patientnoticed no side effects, and blood examinations duringprophylaxis documented any lab toxicities. It is possiblethat, in this case, the absence of drug-related toxicity wasdue to the use of unboosted protease inhibitor; while foretravirine there are no clear data on the correlationbetween PK and toxicity [10].This case should alert the physicians to be cautiousand vigilant when atovaquone/proguanil prophylaxis isprescribed in patients treated with etravirine and/orsaquinavir (especially if ritonavir-boosted).AcknowledgementsWritten consent was obtained from the patient. All authors contributed tothe management of the patient and to the writing and the revising of thearticle. The authors alone are responsible for the content and writing of thepaper. The authors thank Andrea Baker and Eugenio Tommasi for thelanguage revision.Author details1“National Institute for Infectious Diseases “L. Spallanzani”, Via Portuense 292,00149 Rome, Italy. 2Clinica Universitaria c/o Ospedale Amedeo di Savoia,University of Turin, Turin - Italy.Authors’ contributionsCT conceived of the study, performed blood sampling and drafted themanuscript. RB, JI and EN were responsible for the clinical management ofthe patient. MT, ALG and AD carried out the pharmacokinetic studies. LPand PN participated in study design and coordination. All authors read andapproved the final manuscript.Competing interestsThe authors declare that they have no competing interests.Received: 23 December 2010 Accepted: 21 May 2011Published: 21 May 2011References1. Boggild AK, Parise ME, Lewis LS, Kain KC: Atovaquone-proguanil: reportfrom the CDC expert meeting on malaria chemoprophylaxis (II). Am JTrop Med Hyg 2007, 76:208-223.2. Centers for Disease Control and Prevention: 2009 [http://wwwnc.cdc.gov/travel/destinations/kenya.aspx], Travelers’ Health. Yellow book Available at:.3. van Luin M, Van der Ende ME, Richter C, Visser M, Faraj D, Van der Ven A,Gelinck L, Kroon F, Wit FW, Van Schaik RH, Kuks PF, Burger DM: Loweratovaquone/proguanil concentrations in patients taking efavirenz,lopinavir/ritonavir or atazanavir/ritonavir. AIDS 2010, 24:1223-1226.4. Schöller-Gyüre M, Kakuda TN, Raoof A, De Smedt G, Hoetelmans RM:Clinical pharmacokinetics and pharmacodynamics of etravirine. ClinPharmacokinet 2009, 48:561-574.5. Lee CG, Gottesman MM, Cardarelli CO, Ramachandra M, Jeang KT,Ambudkar SV, Pastan I, Dey S: HIV-1 protease inhibitors are substrates forthe MDR1 multidrug transporter. Biochemistry 1998, 37:3594-3601.6. Srinivas R, Middlemas D, Flynn P, Fridland A: Human immunodeficiencyvirus protease inhibitors serve as substrates for multidrug transporterproteins MDR1 and MRP1 but retain antiviral efficacy in cell linesexpressing these transporters. Antimicrob Agents Chemother 1998,42:3157-3162.7. Iwamoto M, Wenning LA, Petry AS, Laethem M, De Smet M, Kost JT,Merschman SA, Strohmaier KM, Ramael S, Lasseter KC, Stone JA,Gottesdiener KM, Wagner JA: Safety, tolerability, and pharmacokinetics ofraltegravir after single and multiple doses in healthy subjects. Clin PharmTher 2008, 83:293-299.8. Abel S, Back DJ, Vourvahis M: Maraviroc: pharmacokinetics and druginteractions. Antivir Ther 2009, 14:607-618.9. Meanwell NA, Kadow JF: Maraviroc, a chemokine CCR5 receptorantagonist for the treatment of HIV infection and AIDS. Curr Opin InvestigDrugs 2007, 8:669-681.10. Tommasi C, Tempestilli M, Fezza R, Bellagamba R, Nicastri E, D’offizi G,Pucillo LP, Narciso P: A rare case of severe myopathy associated withetravirine use. AIDS 2010, 24:1088-1090.11. D’Avolio A, Baietto L, Siccardi M, Sciandra M, Simiele M, Oddone V,Bonora S, Di Perri G: An HPLC-PDA method for the simultaneousquantification of the HIV integrase inhibitor raltegravir, the newnonnucleoside reverse transcriptase inhibitor etravirine, and 11 otheranti-retroviral agents in the plasma of HIV-infected patients. Ther DrugMonit 2008, 30:662-669.12. D’Avolio A, Simiele M, Baietto L, Siccardi M, Sciandra M, Patanella S,Bonora S, Di Perri G: A validated high-performance liquidchromatography-ultraviolet method for quantification of the CCR5inhibitor maraviroc in plasma of HIV-infected patients. Ther Drug Monit2010, 32:86-92.doi:10.1186/1475-2875-10-141Cite this article as: Tommasi et al.: Marked increase in etravirine andsaquinavir plasma concentrations during atovaquone/proguanilprophylaxis. Malaria Journal 2011 10:141.Tommasi et al. Malaria Journal 2011, 10:141http://www.malariajournal.com/content/10/1/141Page 3 of 3

Marked increase in etravirine and saquinavir plasma concentrations during atovaquone/proguanil prophylaxis.

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Malaria Journal

Abstract The case of a 32-year-old Caucasian female with multi-drug resistant HIV-1 subtype B infection treated with a salvage regimen including maraviroc, raltegravir, etravirine and unboosted saquinavir who started atovaquone/proguanil prophylaxis, is reported. The potential interactions between atovaquone/proguanil and these anti-retroviral drugs are investigated. Pharmacokinetic analyses documented a marked increase in etravirine and saquinavir plasma concentrations (+55% and +274%, respectively), but not in raltegravir and maraviroc plasma concentrations. The evidence that atovaquone/proguanil significantly interacts with etravirine and saquinavir, but not with raltegravir and maraviroc, suggests that the mechanism of interaction is related to cytochrome P450.</p

Ivanovic Jelena

Gallo Anna L

D'Avolio Antonio

Tempestilli Massimo

Bellagamba Rita

Tommasi Chiara

Nicastri Emanuele

Pucillo Leopoldo P

Narciso Pasquale

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a chemokine CCR5 receptor antagonist for the treatment of HIV infection and AIDS. Curr Opin Investig Drugs

A rare case of severe myopathy associated with etravirine use. AIDS

An HPLC-PDA method for the simultaneous quantification of the HIV integrase inhibitor raltegravir, the new nonnucleoside reverse transcriptase inhibitor etravirine, and 11 other anti-retroviral agents in the plasma of HIV-infected patients. Ther Drug Monit

Dey S: HIV-1 protease inhibitors are substrates for the MDR1 multidrug transporter. Biochemistry

Disease Control and Prevention:

DM: Lower atovaquone/proguanil concentrations in patients taking efavirenz, lopinavir/ritonavir or atazanavir/ritonavir. AIDS

Fridland A: Human immunodeficiency virus protease inhibitors serve as substrates for multidrug transporter proteins MDR1 and MRP1 but retain antiviral efficacy in cell lines expressing these transporters. Antimicrob Agents Chemother

Hoetelmans RM: Clinical pharmacokinetics and pharmacodynamics of etravirine. Clin Pharmacokinet

KC: Atovaquone-proguanil: report from the CDC expert meeting on malaria chemoprophylaxis (II). Am J Trop Med Hyg

Maraviroc: pharmacokinetics and drug interactions. Antivir Ther

Perri G: A validated high-performance liquid chromatography-ultraviolet method for quantification of the CCR5 inhibitor maraviroc in plasma of HIV-infected patients. Ther Drug Monit

Safety, tolerability, and pharmacokinetics of raltegravir after single and multiple doses in healthy subjects. Clin Pharm Ther

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Marked increase in etravirine and saquinavir plasma concentrations during atovaquone/proguanil prophylaxis

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