AAC Accepts, published online ahead of print on 15 November 2010 Antimicrob. Agents Chemother. doi:10.1128/AAC.01082-10 Copyright © 2010, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

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Herb-drug interaction between Echinacea purpurea and darunavir/ritonavir in

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HIV-infected patients

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José Moltó,1,2 Marta Valle,2,3 Cristina Miranda,1 Samandhy Cedeño,4 Eugenia

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Negredo,1 Manuel José Barbanoj,2,3,5 Bonaventura Clotet1, 2, 4

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Pujol, Badalona, Spain

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Badalona, Spain

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Spain

“Lluita contra la Sida” Foundation, HIV Clinic, Hospital Universitari Germans Trias i

Universitat Autónoma de Barcelona, Barcelona, Spain. CIM-St Pau, Institut de Recerca HSCSP, Barcelona, Spain

“IrsiCaixa” Foundation, HIV Clinic, Hospital Universitari Germans Trias i Pujol,

Clinical Pharmacology department. Hospital de la Santa Creu i Sant Pau, Barcelona,

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Address for correspondence:

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José Moltó, MD, PhD

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Fundació Lluita contra la SIDA

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Hospital Universitari Germans Trias i Pujol.

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Ctra de Canyet, s/n. 08916 Badalona. Barcelona. Spain.

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Telf number: + 34 93 497 88 87

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Fax number: + 34 93 465 76 02

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e-mail: [email protected]

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Running title: Echinacea purpurea and darunavir/ritonavir interaction

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Keywords: Echinacea purpurea; darunavir/ritonavir; herb-drug interaction, HIV

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infection

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ABSTRACT

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The aim of this open-label, fixed-sequence study was to investigate the potential of

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Echinacea purpurea, a commonly used botanical supplement, to interact with the

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boosted protease inhibitor darunavir/ritonavir. Fifteen HIV-infected patients receiving

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antiretroviral therapy including darunavir/ritonavir (600/100 mg twice daily) for at least 4

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weeks were included. E. purpurea root extract capsules were added to the antiretroviral

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treatment (500 mg every 6 hours) from days 1 to 14. Darunavir concentrations in

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plasma were determined by high-performance liquid chromatography immediately

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before and 1, 2, 4, 6, 8, 10 and 12 hours after a morning dose of darunavir/ritonavir on

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days 0 (darunavir/ritonavir) and 14 (darunavir/ritonavir + echinacea).

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darunavir pharmacokinetic parameters were calculated by non-compartmental analysis

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and compared between days 0 and 14 with the geometric mean ratio (GMR) and its

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90% confidence interval (CI). Median (range) age was 49 (43-67) years and body mass

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index was 24.2 (18.7-27.5) kg/m2. Echinacea was well tolerated and all participants

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completed the study. The GMR for darunavir coadministered with echinacea relative to

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darunavir alone was 0.84 (90% CI, 0.63-1.12) for the concentration at the end of the

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dosing interval, 0.90 (90% CI, 0.74-1.10) for the area under the concentration-time

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curve from 0 to 12 hours, and 0.98 (90% CI, 0.82-1.16) for the maximum concentration.

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In summary, coadministration of E. purpurea with darunavir/ritonavir was safe and well

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tolerated. Although not affecting overall darunavir or ritonavir pharmacokinetics,

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individual patients did show a decrease in darunavir concentrations. Although no dose

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adjustment is required, monitoring darunavir concentrations on an individual basis may

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give re-assurance in this setting.

Individual

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INTRODUCTION

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Despite widespread use and proven effectiveness of highly active antiretroviral therapy

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(HAART) for the management of HIV infection, the use of herbal remedies and other

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types complementary and alternative medicine (CAM) is common among HIV-infected

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patients, who often do not report such use to their doctor (14; J. Moltó, C. Miranda, S.

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Malo, M. Valle, A. Andreu, X. Bonafont, and B. Clotet, presented at the 11th

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International Wokshop in Clinical Pharmacology of HIV Therapy, 2010.). Many of these

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remedies are taken as complements rather than as substitutes for HAART. This,

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together with limited evidence to support the safety of many of these combinations,

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makes it possible for potentially significant interactions between certain types of CAM

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and antiretroviral drugs to occur.

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Herbal medicines are often perceived to be innocuous and healthier than manufactured

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medicines even though they can act on the metabolism of antiretroviral agents,

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decreasing or increasing drug concentrations through induction or inhibition of

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metabolic pathways (11, 13). The most widely recognized botanical supplement

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associated with CYP450-mediated herb-drug interaction is St. John’s wort (Hypericum

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perforatum). This herb may induce CYP3A4 activity, decreasing exposure to

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antiretroviral drugs such as to indinavir or nevirapine (6, 18) and putting patients at risk

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of treatment failure and subsequent development of viral resistance to antiretroviral

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drugs. Clinical pharmacokinetic interaction studies between antiretroviral agents and

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botanicals nonetheless remain scarce in the literature.

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Echinacea preparations rank among the top-selling botanical supplements worldwide

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(1, 4) and they are among the herbal medicines most commonly taken by HIV-infected

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patients (12), usually as a self-prescribed remedy and without medical supervision.

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Although the exact mechanism of action of echinacea remains unknown (3, 17, 19, 22,

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23), this substance has been reported to be an immunostimulant and its oral

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administration has been suggested to be beneficial in the early treatment of upper

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respiratory tract infections (3, 21, 24).

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The main constituents of echinacea preparations are caffeic acid derivatives and

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alkamides, which have a potential to interact with cytochrome P450 (1). Gorski et al.

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(10) investigated the in vivo effects of Echinacea purpurea on the activity of several

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CYP

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administration. In that study echinacea selectively modulated the catalytic activity of

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CYP3A4 at both hepatic and intestinal sites. It inhibited intestinal lumen CYP3A4

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activity, increasing the oral bioavailability of midazolam by nearly 50%, but also

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induced hepatic CYP3A4 activity, significantly increasing the systemic clearance of the

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drug (10). This differential effect on CYP3A4 activity at two sites makes it difficult to

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predict potential effects on the disposition of other CYP3A4 substrates such as HIV-

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protease inhibitors.

isozymes,

including

CYP3A4,

after

intravenous

and

oral

midazolam

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Darunavir is a protease inhibitor with demonstrated anti-HIV efficacy in both

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antiretroviral-naïve and treatment-experienced patients.(5, 16) Similarly to other

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protease inhibitors, darunavir undergoes extensive metabolism by the CYP3A4 isoform

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of the cytochrome P450 enzyme family (20). Therefore, in order to enhance its

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pharmacokinetic profile, darunavir must be coadministered with low doses of ritonavir,

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which acts as a potent CYP3A4 inhibitor, thereby boosting other CYP3A4 substrates.

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Thus, at the approved dosage of darunavir/ritonavir, darunavir concentrations at the

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end of the dosing interval remain well above the concentration needed to inhibit

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replication of HIV strains (20; Sekar V, Spinosa-Guzman S, Lefebvre E, Hoetelmans R,

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presented at the 16th International AIDS Conference, 2006.). However, induction or

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inhibition of CYP3A4 activity by other agents might result in inadequately low or in

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excessively high darunavir concentrations, respectively, compromising antiretroviral

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treatment effectiveness.

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The aim of the present study was, therefore, to investigate the potential of this

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commonly used botanical supplement, E. purpurea, to interact with a protease inhibitor

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such as darunavir/ritonavir.

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METHODS

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Study design

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This was an open-label, fixed-sequence study in 15 HIV-infected patients who were

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receiving antiretroviral therapy with darunavir/ritonavir at a dosage of 600/100 mg twice

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daily for at least 4 weeks, and whose HIV-1 RNA load in plasma was