BoffitoNEW
17/7/07
15:47
Page 825
Antiviral Therapy 12:825–830
Abacavir plasma pharmacokinetics in the absence and presence of atazanavir/ritonavir or lopinavir/ ritonavir and vice versa in HIV-infected patients Laura J Waters1, Graeme Moyle1, Stefano Bonora2, Antonio D’Avolio2, Laura Else3, Sundhiya Mandalia1, Anton Pozniak1, Mark Nelson1, Brian Gazzard1, David Back3 and Marta Boffito1* 1
St. Stephen’s Centre, Chelsea and Westminster Hospital, London, UK University of Turin, Turin, Italy 3 University of Liverpool, Liverpool, UK 2
Corresponding author: Tel: +44 20 8846 6507; Fax: +44 20 8746 5628; E-mail:
[email protected]
Background: Significant interactions between abacavir and other antiretrovirals have not been reported. This study investigated the steady-state plasma pharmacokinetics of abacavir when co-administered with atazanavir/ritonavir or lopinavir/ritonavir in HIV-infected individuals. Methods: HIV-infected subjects on abacavir (600 mg once daily) plus two nucleoside reverse transcriptase inhibitors (NRTIs) (excluding tenofovir) underwent a 24 h pharmacokinetic assessment for plasma abacavir concentrations. Atazanavir/ritonavir (300/100 mg once daily; arm 1) or lopinavir/ritonavir (400/100 mg twice daily; arm 2) were then added and the 24 h pharmacokinetic assessment repeated. Arm 3 included subjects stable on atazanavir/ritonavir or lopinavir/ritonavir and two NRTIs (excluding tenofovir or abacavir). These patients underwent a pharmacokinetic assessment for atazanavir/ritonavir or lopinavir/ritonavir concentrations on day 1, abacavir (600 mg once daily) was then added to the regimen and the
pharmacokinetic assessment repeated. Within-subject changes in drug exposure were evaluated by geometric mean (GM) ratios and 95% confidence intervals (CI). Results: Twenty-four patients completed the study. GM (95% CI) abacavir area under the curve (AUC) was 18,621 (15,900–21,807) and 15,136 (13,339–17,174) ng.h/ml without and with atazanavir/ritonavir and 15,136 (12,298–18,628) and 10,471 (9,270–11,828) ng.h/ml without and with lopinavir/ritonavir. GM (95% CI) atazanavir AUC without and with abacavir was 26,915 (13,252–54,666) and 28,840 (19,213–43,291) ng.h/ml; lopinavir AUC without and with abacavir was 60,253 (48,084–75,509) and 63,096 (48,128–82,718) ng.h/ml. Conclusions: No changes in atazanavir or lopinavir exposures were observed following the addition of abacavir; however, decreases in abacavir plasma exposure of 17% and 32% were observed following the addition of atazanavir/ritonavir or lopinavir/ritonavir, respectively.
Introduction It is now clear that effective antiretroviral therapy has transformed the course of HIV infection, from a lethal illness to a chronic condition. Despite the benefits of antiretroviral combination therapy on HIV-associated morbidity and mortality, its use is complicated by a number of factors, short- and longterm adverse events, adherence challenges, drug–drug interactions, and the selection of drugresistant virus [1]. Guidelines for the treatment of HIV infection recommend that initial therapy should include two nucleoside/nucleotide reverse transcriptase inhibitors (RTIs) plus one non-nucleoside RTI or ritonavir-boosted protease inhibitor (PI) [2]. When drugs are combined, however, clinically important drug–drug interactions can occur and lead to a decrease or an increase in drug © 2007 International Medical Press 1359-6535
plasma concentrations and, consequently, to virological failure or toxicity, respectively [3]. Abacavir is a synthetic guanosine analogue approved for the treatment of HIV infection. It is converted inside cells to an active metabolite, carbovir 5′-triphosphate, which is a potent inhibitor of the HIV reverse transcriptase [4,5]. Abacavir oral bioavailability is greater than 80% regardless of food intake. It is eliminated following transformation to inactive compounds by alcohol dehydrogenase and by glucuronidation [6]. A study by Kearney and colleagues showed that, although the introduced dose of abacavir was 300 mg twice daily, carbovir triphosphate (the abacavir intracellular active metabolite) accumulated inside the cell and had a reported elimination half-life (t1/2) of up to 20 h [7]. Subsequent clinical investigations demonstrated the 825
BoffitoNEW
17/7/07
15:47
Page 826
LJ Waters et al.
non-inferior efficacy of once daily 600 mg abacavir to twice daily 300 mg abacavir in combination with once daily lamivudine and efavirenz [8]. Abacavir has not been associated with any clinically significant pharmacokinetic interaction; however, high doses of ethanol have been shown to increase abacavir plasma area under the curve (AUC) by 41% and to lengthen its plasma elimination t1/2 [9]. Furthermore, concurrent use of abacavir and the PI tipranavir in the presence of ritonavir, caused a 40% decrease in abacavir total plasma exposure. The clinical importance of the decrease in abacavir AUC is not established, and dose adjustments of abacavir cannot be recommended at this time [10]. Atazanavir is a once daily administered azapeptide PI active against HIV-1 and HIV-2. It undergoes oxidative metabolism in the liver primarily by cytochrome P450 (CYP450) 3A4, which accounts for most of the elimination of the drug. Ritonavir significantly increases atazanavir AUC and reduces its systemic clearance [11]. Therefore, a dose of atazanavir/ritonavir (300/100 mg once daily) is approved for the treatment of HIV infection. Lopinavir is a peptidomimetic HIV PI co-formulated with low-dose ritonavir; ritonavir is used to inhibit CYP450 3A4 metabolism and to increase lopinavir concentrations [12]. When combined, lopinavir and ritonavir have been shown to modestly induce CYP450 1A2 and 2C9, potently induce 2C19 activity, and inhibit intestinal 3A to a greater extent than hepatic 3A activity [13]. Drug interactions involving nucleoside/nucleotide RTIs and PIs have been reported [3], most notably the reduction in concentrations of atazanavir (both with and without ritonavir boosting) during co-administration with tenofovir disoproxil fumarate (DF) [14]. In addition, when tenofovir DF and lopinavir/ritonavir are co-administered, although no changes are observed in the lopinavir or ritonavir concentrations tenofovir plasma exposure is increased by 32% [15]. The potential clinical relevance of increased tenofovir exposure remains unclear. The aim of this study was to investigate the steadystate plasma pharmacokinetics of abacavir when co-administered with atazanavir/ritonavir or lopinavir /ritonavir and vice versa in HIV-1 infected individuals.
Patients and methods Subjects Subjects eligible for this study were HIV-1 antibodyseropositive adults (18 to 65 years of age), receiving ongoing treatment with: i) abacavir 600 mg once daily plus two NRTIs (excluding tenofovir DF); ii) atazanavir/ritonavir plus two NRTIs (excluding tenofovir DF or abacavir); iii) lopinavir/ritonavir plus two 826
NRTIs (excluding tenofovir DF or abacavir). Exclusion criteria were active HIV replication (viral load >400 copies/ml), the presence of active clinically significant disease or any grade 3/4 toxicity according to the AIDS Clinical Trial Group (ACTG) grading severity list (other than grade 3/4 asymptomatic triglyceride/cholesterol elevations). Subjects were also not eligible if they had taken systemic corticosteroids or drugs known to induce or inhibit hepatic enzymes within 14 days of study entry. Approval for the study was obtained from the Hammersmith Research Ethics Committee, London, UK, and all subjects gave written informed consent to participate in the study.
Study design This was an open-label, multiple dose, two-period (without and with addition of study drug), three arm, pharmacokinetic study. Arms 1 and 2 comprised HIVinfected subjects who had been on abacavir for at least 2 weeks prior to screening. For the purposes of the study, these were patients on Trizivir® (abacavir/lamivudine/zidovudine) who were switched to Combivir® (lamivudine/zidovudine) twice daily and abacavir 600 mg once daily at least 2 weeks prior to day 1. Tenofovir DF, non-nucleoside RTIs and PIs were not allowed as part of the baseline regimens, as they might have altered the pharmacokinetics of the studied agents. After a 24 h pharmacokinetic assessment (day 1), arm 1 and 2 patients had atazanavir/ritonavir (300/100 mg once daily) and lopinavir/ritonavir (400/100 mg twice daily) added to their regimen, respectively. A second pharmacokinetic assessment was performed 14 days later, on day 15; following this assessment, atazanavir/ritonavir and lopinavir/ritonavir were discontinued. Arm 3 consisted of HIV-infected subjects who had been on regimens containing either atazanavir/ritonavir (300/100 mg once daily) or lopinavir/ritonavir (400/100 mg twice daily), but not including abacavir or tenofovir DF for at least 2 weeks prior to screening. After a 24 h and 12 h pharmacokinetic assessment of atazanavir/ritonavir and lopinavir/ritonavir, respectively, abacavir 600 mg was added to the regimen and a second pharmacokinetic assessment of atazanavir/ritonavir and lopinavir/ritonavir was performed 14 days later, on day 15. Thereafter, abacavir was either discontinued or the subject remained on abacavir at the discretion of their physician. On pharmacokinetic assessment days drugs were administered within 15 min of a standardized breakfast (16 g of fat, 626 kcal) along with 240 ml of water. Serial pharmacokinetic blood samples were taken predose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10 and 12 h postdose for lopinavir/ritonavir and a 24 h sample was taken for abacavir and atazanavir/ritonavir. © 2007 International Medical Press
BoffitoNEW
17/7/07
15:47
Page 827
Abacavir and protease inhibitors
Pharmacokinetic blood samples were collected into heparinized tubes, centrifuged, and plasma was stored at -70˚C until analysis.
Safety assessment The safety and tolerability of the study medications were evaluated at each study visit on the basis of clinical adverse events (using the ACTG toxicity grading scale to characterize abnormal findings), clinical laboratory tests, vital signs and physical examinations. The severity of adverse events and the investigator’s assessment of their causality to study drugs were recorded. As the most important adverse effect of abacavir is a potentially fatal hypersensitivity syndrome caused by a genetically mediated immune response linked to the HLA-B*5701 locus, all subjects in arm 3 underwent HLA-B*5701 testing at screening. Those testing positive were excluded.
Analytical and pharmacokinetic methods Abacavir plasma concentrations were analysed by a sensitive and selective analytical high-performance liquid chromatography (HPLC) method at the University of Turin, Italy, with detection carried out by UV spectrophotometry at 260 nm [16]. The limit of quantification for abacavir was 30 ng/ml. All analyses were performed in duplicate and the inter- and intra-day precision ranged between 1.1 and 1.9% and 0.2 and 2.3%, respectively. Atazanavir, lopinavir and ritonavir were quantified using a fully validated HPLC tandem mass spectrometry (HPLC-MS/MS) method [17] at the University of Liverpool. The lower limit of quantification was 62, 95 and 26 ng/ml for atazanavir, lopinavir and ritonavir, respectively, and inter-assay and intra-assay variability did not exceed 10% for all three drugs. The laboratory participates in an external quality assurance program twice yearly (International Interlaboratory Quality Control Program for Therapeutic Drug Monitoring in HIV Infection, Nijmegen, The Netherlands). The pharmacokinetic parameters determined for abacavir, atazanavir, lopinavir and ritonavir were the maximum observed plasma concentration (Cmax), the trough plasma concentration observed 12 h (lopinavir/ritonavir) or 24 h (abacavir, atazanavir/ ritonavir) after ingestion (Ctrough), the elimination half-life (t1/2), and total drug exposure, measured as the area under the concentration–time curve over the dosing interval (AUC0–12 for lopinavir/ritonavir and AUC0–24 for abacavir and atazanavir/ritonavir). Noncompartmental analyses were used to derive the AUC and t1/2 for each patient over the dosing interval using WinNonlin software (version 3.1; Pharsight Corporation, CA). Antiviral Therapy 12:5
Data analysis Statistical calculations were performed and analysed using SPSS (version 12.0; SPSS Inc., Chicago, IL, USA). Geometric mean ratios (GMRs) and associated 95% confidence intervals (CIs) were constructed for the abacavir, atazanavir/ritonavir and lopinavir/ ritonavir pharmacokinetic parameters AUC, Cmax, Ctrough and t1/2, using the values observed when the drugs were not co-administered as references. The CIs were first determined using logarithms of the individual GMR values and then expressed as linear values. The changes in pharmacokinetic parameters were considered significant when the CI for the GMR did not cross the value of one. The distribution of the data did not exhibit any evidence of non-normality (Shapiro–Wilkes test) hence a paired t-test was performed to confirm the presence or absence of statistical significance when comparing the pharmacokinetic parameters measured on the different study days. The coefficient of variation (CV) was calculated to express inter-individual variability in the pharmacokinetic parameters of all the drugs studied ([standard deviation/mean] × 100).
Results Twenty-six HIV-1-infected subjects were screened, 24 were enrolled and completed all phases of the study. One subject withdrew for personal reasons and one had a positive HLA-B*5701 test and was not included in the study. The demographic and baseline clinical characteristics of the study subjects are summarized in Table 1. Concurrent antiretroviral medications administered with the study medications included zidovudine (n=16), lamivudine (n=17) and didanosine (n=1). Study medications were generally well tolerated. No grade 3 or 4 adverse events or changes in laboratory parameters were reported during the study period. Of the 26 patients screened 18 (69.2%) experienced at least one adverse event. There were reported to be 53 adverse events in total, 28 (52.8%) were considered mild (grade 1) and 25 (47.2%) moderate (grade 2). Most common adverse events observed throughout the three arms were diarrhoea, nausea, and dizziness. Abacavir pharmacokinetic parameters assessed on the sampling days and changes in abacavir plasma exposures following the addition of atazanavir/ritonavir or lopinavir/ritonavir are summarized in Table 2. Although the addition of atazanavir/ritonavir to stable abacavir-containing therapy resulted in only a 17% (range 7–26%) reduction in abacavir plasma exposure, a slightly higher decrease in abacavir exposure was observed following the addition of lopinavir/ritonavir (32%, range 6–44%). 827
BoffitoNEW
17/7/07
15:47
Page 828
LJ Waters et al.
Table 1. Summary of patient baseline characteristics Characteristic
Value
Male, n Female, n Age, years Median (range) Ethnicity White, n Black, n Other, n Baseline CD4+ cell count, cells/mm3 Median (range) Baseline viral load, copies/ml
21 3 43 (31–62) 18 4 2 525 (144–1181)
