Abacavir Plasma Pharmacokinetics in the Absence and Presence of Atazanavir/Ritonavir Or Lopinavir/ Ritonavir and Vice Versa in HIV-Infected Patients

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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*

1St. Stephen’s Centre, Chelsea and Westminster Hospital, London, UK 2University of Turin, Turin, Italy 3University of Liverpool, Liverpool, UK

Corresponding author: Tel: +44 20 8846 6507; Fax: +44 20 8746 5628; E-mail: [email protected]

Background: Significant interactions between abacavir and pharmacokinetic assessment repeated. Within-subject other antiretrovirals have not been reported. This study changes in drug exposure were evaluated by geometric investigated the steady-state plasma pharmacokinetics of mean (GM) ratios and 95% confidence intervals (CI). abacavir when co-administered with atazanavir/ritonavir or Results: Twenty-four patients completed the study. GM lopinavir/ritonavir in HIV-infected individuals. (95% CI) abacavir area under the curve (AUC) was 18,621 Methods: HIV-infected subjects on abacavir (600 mg once (15,900–21,807) and 15,136 (13,339–17,174) ng.h/ml daily) plus two nucleoside reverse transcriptase inhibitors without and with atazanavir/ritonavir and 15,136 (NRTIs) (excluding tenofovir) underwent a 24 h pharmaco- (12,298–18,628) and 10,471 (9,270–11,828) ng.h/ml kinetic assessment for plasma abacavir concentrations. without and with lopinavir/ritonavir. GM (95% CI) Atazanavir/ritonavir (300/100 mg once daily; arm 1) or atazanavir AUC without and with abacavir was 26,915 lopinavir/ritonavir (400/100 mg twice daily; arm 2) were (13,252–54,666) and 28,840 (19,213–43,291) ng.h/ml; then added and the 24 h pharmacokinetic assessment lopinavir AUC without and with abacavir was 60,253 repeated. Arm 3 included subjects stable on (48,084–75,509) and 63,096 (48,128–82,718) ng.h/ml. atazanavir/ritonavir or lopinavir/ritonavir and two NRTIs Conclusions: No changes in atazanavir or lopinavir (excluding tenofovir or abacavir). These patients underwent exposures were observed following the addition of a pharmacokinetic assessment for atazanavir/ritonavir or abacavir; however, decreases in abacavir plasma exposure lopinavir/ritonavir concentrations on day 1, abacavir of 17% and 32% were observed following the addition of (600 mg once daily) was then added to the regimen and the atazanavir/ritonavir or lopinavir/ritonavir, respectively.

Introduction

It is now clear that effective antiretroviral therapy plasma concentrations and, consequently, to virological has transformed the course of HIV infection, from a failure or toxicity, respectively [3]. lethal illness to a chronic condition. Despite the Abacavir is a synthetic guanosine analogue approved benefits of antiretroviral combination therapy on for the treatment of HIV infection. It is converted inside HIV-associated morbidity and mortality, its use is cells to an active metabolite, carbovir 5′-triphosphate, complicated by a number of factors, short- and long- which is a potent inhibitor of the HIV reverse tran- term adverse events, adherence challenges, scriptase [4,5]. Abacavir oral bioavailability is greater drug–drug interactions, and the selection of drug- than 80% regardless of food intake. It is eliminated resistant virus [1]. following transformation to inactive compounds by Guidelines for the treatment of HIV infection recom- alcohol dehydrogenase and by glucuronidation [6]. A mend that initial therapy should include two nucleo- study by Kearney and colleagues showed that, although side/nucleotide reverse transcriptase inhibitors (RTIs) the introduced dose of abacavir was 300 mg twice daily, plus one non-nucleoside RTI or ritonavir-boosted carbovir triphosphate (the abacavir intracellular active protease inhibitor (PI) [2]. When drugs are combined, metabolite) accumulated inside the cell and had a

however, clinically important drug–drug interactions reported elimination half-life (t1/2) of up to 20 h [7]. can occur and lead to a decrease or an increase in drug Subsequent clinical investigations demonstrated the

LJ Waters et al.

non-inferior efficacy of once daily 600 mg abacavir to NRTIs (excluding tenofovir DF or abacavir). Exclusion twice daily 300 mg abacavir in combination with once criteria were active HIV replication (viral load >400 daily lamivudine and efavirenz [8]. copies/ml), the presence of active clinically significant Abacavir has not been associated with any clinically disease or any grade 3/4 toxicity according to the AIDS significant pharmacokinetic interaction; however, high Clinical Trial Group (ACTG) grading severity list doses of ethanol have been shown to increase abacavir (other than grade 3/4 asymptomatic triglyceride/choles- plasma area under the curve (AUC) by 41% and to terol elevations). Subjects were also not eligible if they

lengthen its plasma elimination t1/2 [9]. Furthermore, had taken systemic corticosteroids or drugs known to concurrent use of abacavir and the PI tipranavir in the induce or inhibit hepatic enzymes within 14 days of presence of ritonavir, caused a 40% decrease in study entry. Approval for the study was obtained from abacavir total plasma exposure. The clinical impor- the Hammersmith Research Ethics Committee, tance of the decrease in abacavir AUC is not estab- London, UK, and all subjects gave written informed lished, and dose adjustments of abacavir cannot be consent to participate in the study. recommended at this time [10]. Atazanavir is a once daily administered azapeptide Study design PI active against HIV-1 and HIV-2. It undergoes This was an open-label, multiple dose, two-period oxidative metabolism in the liver primarily by (without and with addition of study drug), three arm, cytochrome P450 (CYP450) 3A4, which accounts for pharmacokinetic study. Arms 1 and 2 comprised HIV- most of the elimination of the drug. Ritonavir signifi- infected subjects who had been on abacavir for at least cantly increases atazanavir AUC and reduces its 2 weeks prior to screening. For the purposes of the systemic clearance [11]. Therefore, a dose of study, these were patients on Trizivir® atazanavir/ritonavir (300/100 mg once daily) is (abacavir/lamivudine/zidovudine) who were switched approved for the treatment of HIV infection. to Combivir® (lamivudine/zidovudine) twice daily and Lopinavir is a peptidomimetic HIV PI co-formu- abacavir 600 mg once daily at least 2 weeks prior to lated with low-dose ritonavir; ritonavir is used to day 1. Tenofovir DF, non-nucleoside RTIs and PIs were inhibit CYP450 3A4 metabolism and to increase not allowed as part of the baseline regimens, as they lopinavir concentrations [12]. When combined, might have altered the pharmacokinetics of the studied lopinavir and ritonavir have been shown to modestly agents. After a 24 h pharmacokinetic assessment (day induce CYP450 1A2 and 2C9, potently induce 2C19 1), arm 1 and 2 patients had atazanavir/ritonavir activity, and inhibit intestinal 3A to a greater extent (300/100 mg once daily) and lopinavir/ritonavir than hepatic 3A activity [13]. (400/100 mg twice daily) added to their regimen, Drug interactions involving nucleoside/nucleotide respectively. A second pharmacokinetic assessment was RTIs and PIs have been reported [3], most notably the performed 14 days later, on day 15; following this reduction in concentrations of atazanavir (both with and assessment, atazanavir/ritonavir and lopinavir/riton- without ritonavir boosting) during co-administration avir were discontinued. with tenofovir disoproxil fumarate (DF) [14]. In addition, Arm 3 consisted of HIV-infected subjects who had when tenofovir DF and lopinavir/ritonavir are co-admin- been on regimens containing either atazanavir/ritonavir istered, although no changes are observed in the lopinavir (300/100 mg once daily) or lopinavir/ritonavir or ritonavir concentrations tenofovir plasma exposure is (400/100 mg twice daily), but not including abacavir or increased by 32% [15]. The potential clinical relevance of tenofovir DF for at least 2 weeks prior to screening. increased tenofovir exposure remains unclear. After a 24 h and 12 h pharmacokinetic assessment of The aim of this study was to investigate the steady- atazanavir/ritonavir and lopinavir/ritonavir, respec- state plasma pharmacokinetics of abacavir when tively, abacavir 600 mg was added to the regimen and a co-administered with atazanavir/ritonavir or lopinavir second pharmacokinetic assessment of atazanavir/riton- /ritonavir and vice versa in HIV-1 infected individuals. avir and lopinavir/ritonavir was performed 14 days later, on day 15. Thereafter, abacavir was either discon- Patients and methods tinued or the subject remained on abacavir at the discretion of their physician. Subjects On pharmacokinetic assessment days drugs were Subjects eligible for this study were HIV-1 antibody- administered within 15 min of a standardized breakfast seropositive adults (18 to 65 years of age), receiving (16 g of fat, 626 kcal) along with 240 ml of water. ongoing treatment with: i) abacavir 600 mg once daily Serial pharmacokinetic blood samples were taken pre- plus two NRTIs (excluding tenofovir DF); ii) dose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10 and 12 h post- atazanavir/ritonavir plus two NRTIs (excluding teno- dose for lopinavir/ritonavir and a 24 h sample was fovir DF or abacavir); iii) lopinavir/ritonavir plus two taken for abacavir and atazanavir/ritonavir.

Abacavir and protease inhibitors

Pharmacokinetic blood samples were collected into Data analysis heparinized tubes, centrifuged, and plasma was stored Statistical calculations were performed and analysed at -70˚C until analysis. using SPSS (version 12.0; SPSS Inc., Chicago, IL, USA). Geometric mean ratios (GMRs) and associated Safety assessment 95% confidence intervals (CIs) were constructed for The safety and tolerability of the study medications the abacavir, atazanavir/ritonavir and lopinavir/ riton-

were evaluated at each study visit on the basis of clin- avir pharmacokinetic parameters AUC, Cmax, Ctrough

ical adverse events (using the ACTG toxicity grading and t1/2, using the values observed when the drugs were scale to characterize abnormal findings), clinical not co-administered as references. The CIs were first laboratory tests, vital signs and physical examina- determined using logarithms of the individual GMR tions. The severity of adverse events and the investi- values and then expressed as linear values. The gator’s assessment of their causality to study drugs changes in pharmacokinetic parameters were consid- were recorded. ered significant when the CI for the GMR did not As the most important adverse effect of abacavir is a cross the value of one. potentially fatal hypersensitivity syndrome caused by a The distribution of the data did not exhibit any genetically mediated immune response linked to the evidence of non-normality (Shapiro–Wilkes test) hence HLA-B*5701 locus, all subjects in arm 3 underwent a paired t-test was performed to confirm the presence HLA-B*5701 testing at screening. Those testing posi- or absence of statistical significance when comparing tive were excluded. the pharmacokinetic parameters measured on the different study days. Analytical and pharmacokinetic methods The coefficient of variation (CV) was calculated to Abacavir plasma concentrations were analysed by a express inter-individual variability in the pharmaco- sensitive and selective analytical high-performance kinetic parameters of all the drugs studied ([standard liquid chromatography (HPLC) method at the deviation/mean] × 100). University of Turin, Italy, with detection carried out by UV spectrophotometry at 260 nm [16]. Results The limit of quantification for abacavir was 30 ng/ml. All analyses were performed in duplicate and Twenty-six HIV-1-infected subjects were screened, 24 the inter- and intra-day precision ranged between 1.1 were enrolled and completed all phases of the study. and 1.9% and 0.2 and 2.3%, respectively. One subject withdrew for personal reasons and one Atazanavir, lopinavir and ritonavir were quantified had a positive HLA-B*5701 test and was not included using a fully validated HPLC tandem mass spectrom- in the study. The demographic and baseline clinical etry (HPLC-MS/MS) method [17] at the University of characteristics of the study subjects are summarized in Liverpool. The lower limit of quantification was 62, Table 1. Concurrent antiretroviral medications admin- 95 and 26 ng/ml for atazanavir, lopinavir and riton- istered with the study medications included zidovudine avir, respectively, and inter-assay and intra-assay vari- (n=16), lamivudine (n=17) and didanosine (n=1). ability did not exceed 10% for all three drugs. The Study medications were generally well tolerated. No laboratory participates in an external quality assur- grade 3 or 4 adverse events or changes in laboratory ance program twice yearly (International parameters were reported during the study period. Of Interlaboratory Quality Control Program for the 26 patients screened 18 (69.2%) experienced at Therapeutic Drug Monitoring in HIV Infection, least one adverse event. There were reported to be 53 Nijmegen, The Netherlands). adverse events in total, 28 (52.8%) were considered The pharmacokinetic parameters determined for mild (grade 1) and 25 (47.2%) moderate (grade 2). abacavir, atazanavir, lopinavir and ritonavir were the Most common adverse events observed throughout the

maximum observed plasma concentration (Cmax), the three arms were diarrhoea, nausea, and dizziness. trough plasma concentration observed 12 h Abacavir pharmacokinetic parameters assessed on (lopinavir/ritonavir) or 24 h (abacavir, atazanavir/ riton- the sampling days and changes in abacavir plasma

avir) after ingestion (Ctrough), the elimination half-life exposures following the addition of atazanavir/ritonavir

(t1/2), and total drug exposure, measured as the area or lopinavir/ritonavir are summarized in Table 2. under the concentration–time curve over the dosing Although the addition of atazanavir/ritonavir to stable

interval (AUC0–12 for lopinavir/ritonavir and AUC0–24 for abacavir-containing therapy resulted in only a 17% abacavir and atazanavir/ritonavir). Noncompartmental (range 7–26%) reduction in abacavir plasma exposure,

analyses were used to derive the AUC and t1/2 for each a slightly higher decrease in abacavir exposure was patient over the dosing interval using WinNonlin soft- observed following the addition of lopinavir/ritonavir ware (version 3.1; Pharsight Corporation, CA). (32%, range 6–44%).

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Table 1. Summary of patient baseline characteristics Phase IV drug development. This is largely because of Characteristic Value the speed at which new antiretroviral drugs are introduced into clinical care, usually through expanded Male, n 21 access programs and clinical trials for treatment-expe- Female, n 3 rienced subjects with limited treatment options who are Age, years 43 on salvage regimens. As a result, the use of new anti- Median (range) (31–62) retrovirals often exceeds our knowledge of how these Ethnicity agents might be best used and how they may interact White, n 18 with other drugs. Black, n 4 Atazanavir and lopinavir are commonly administered Other, n 2 boosted PIs and are metabolized by CYP450, mainly the Baseline CD4+ cell count, cells/mm3 525 Median (range) (144–1181) isoform 3A4 [3]. Baseline viral load, copies/ml <200 In terms of Phase II metabolic reactions, few data on the effect of ritonavir on glucuronidation, a commonly used drug elimination pathway are available [18]. Furthermore, although there are no available data Table 2 illustrates all pharmacokinetic parameters about the effect of lopinavir on glucuronidation, assessed for atazanavir and lopinavir. No changes in atazanavir inhibits uridine 5′-diphospho-glucuronosyl- atazanavir or lopinavir exposures were observed transferase 1A1 (UGT1A1) activity [19]. following the addition of abacavir to stable therapy. Therefore, there is the potential for drug–drug Moreover, no significant changes in ritonavir pharmaco- interactions to occur when drugs that share the same kinetic parameters were observed for patients in arm 3 metabolic pathway are co-administered [3]. following the addition of abacavir to the antiretroviral Abacavir is not a substrate for, nor does it inhibit or regimen (data not shown). induce, CYP isoenzymes in vitro [6]. The potential for The inter-individual variability in abacavir pharmaco- CYP-mediated drug interactions between abacavir and kinetic parameters was less than 40%, with the excep- other medications is therefore low. However, as the

tion of abacavir Ctrough in the presence of primary routes of elimination of abacavir are metabo-

atazanavir/ritonavir (88%), and abacavir Ctrough and t1/2 lism by alcohol dehydrogenase and glucuronyl trans- in the presence of lopinavir/ritonavir (58% and 49%, ferase [6], abacavir plasma concentrations might be respectively) (Table 2). However, it should be noted that altered in the presence of other drugs that undergo,

several abacavir Ctrough values were close to the limit of inhibit or induce the same metabolic pathways. This is quantification and hence there is the potential for highlighted by the fact that drug–drug pharmacokinetic increased variability. There was marked inter-individual interactions described between abacavir and variability in all atazanavir and lopinavir pharmaco- tipranavir/ritonavir [10] probably result from the kinetic parameters (Table 2). induction of abacavir glucuronidation. However, whether this induction is caused by ritonavir only or by Discussion both tipranavir and ritonavir remains unclear. The induction of abacavir glucuronidation by low- We report here the steady-state plasma pharmacokinetics dose ritonavir, and possibly by lopinavir, is the of abacavir (600 mg taken once daily) in the absence and proposed mechanism of the interaction observed in presence of the PIs atazanavir/ritonavir (300/100 mg our study. However, whether the different changes in once daily) or lopinavir/ritonavir (400/100 mg twice abacavir plasma exposure in the presence of daily). The plasma exposure of the two PIs measured atazanavir/ritonavir or lopinavir/ritonavir are due to without and with abacavir was also reported. an additional inducing effect on glucuronidation of Although abacavir plasma exposure was significantly lopinavir on top of ritonavir or due to the higher decreased in the presence of atazanavir/ritonavir or ritonavir dose administered in combination with lopinavir/ritonavir, the pharmacokinetics of neither lopinavir (100 mg twice daily, 200 mg daily in total) atazanavir nor lopinavir were affected by the addition of versus the dose given with atazanavir (100 mg daily) abacavir to the antiretroviral regimen. The combinations is uncertain. of abacavir and atazanavir/ritonavir or lopinavir/riton- Several studies have shown that ritonavir (at avir were well tolerated, with adverse events limited to a different doses ranging from 200 mg to 1200 mg small number of study subjects who reported grade 1/2 daily) decreases the exposure of drugs that are metab- diarrhoea, nausea, and dizziness during the study period. olized by glucuronidation [20–23]. Additionally, Drug–drug interactions involving antiretroviral lopinavir could affect abacavir glucuronidation as the medications are frequently not recognised until after reduction in abacavir concentrations was greater with

Abacavir and protease inhibitors

Table 2. Pharmacokinetic parameters of abacavir in the absence and presence of atazanavir/ritonavir or lopinavir/ritonavir

AUC0–24, ng.h/ml Cmax, ng/ml Ctrough, ng/ml t1/2, h

ABC in the presence and absence of ATV/r ABC (day 1) 18621 (15900–21807) 4266 (3313–5492) 25 (21–30) 4.79 (4.24–5.41) ABC+ATV/r (day 15) 15136 (13339–17174) 3467 (2767–4345) 26 (14–48) 5.50 (4.33–6.98) GMR 0.83 (0.78–0.88) 0.81 (0.67–0.98) 1.04 (0.59–1.82) 1.13 (0.85–1.49) P-value 0.002 0.073 0.541 0.399 CV% (day 1–day 15) 18–15 26–28 24–88 16–32 ABC in the presence and absence of LTV/r ABC (Day 1) 15136 (12298–18628) 4571 (3378–6185) 22 (16-29) 6.03 (4.90–7.42) ABC+LTV/r (day 15) 10471 (9270–11828) 3020 (2476–3683) 8 (5-12) 4.68 (3.35–6.53) GMR 0.68 (0.59–0.78) 0.66 (0.53–0.82) 0.35 (0.27-0.47) 0.78 (0.64–0.95) P-value 0.005 0.037 0.003 0.147 CV% (day 1–day 15) 24–15 40–27 33–58 26–49 ATV/r in the presence and absence of ABC ATV (day 1) 26915 (13252–54666) 2692 (1437–5040) 427 (172-1057) 10.0 (7.06–14.2) ATV+ABC (day 15) 28840 (19213–43291) 2818 (1929–4118) 468 (257-852) 9.93 (7.21–13.7) GMR 1.09 (0.74–1.60) 1.04 (0.72–1.51) 1.11 (0.75-1.64) 0.99 (0.88–1.12) P-value 0.558 0.529 0.458 0.685 CV% (day 1–day 15) 100–60 83–54 125–81 47–45 LPV/r in the presence and absence of ABC LPV (day 1) 60253 (48084–75509) 7762 (5921–10177) 2818 (1878–4231) 5.75 (4.20–7.89) LPV+ABC (day 15) 63096 (48128–82718) 8318 (6637–10423) 3236 (2255–4643) 5.89 (3.75–9.25) GMR 1.05 (0.80–1.31) 1.10 (0.80–1.44) 1.12 (0.86–1.34) 1.02 (0.66–1.38) P-value 0.691 0.487 0.437 0.748 CV% (day 1–day 15) 31–39 34–32 50–51 44–52

Pharmacokinetic parameters, geometric mean ratios (GMR) and 95% confidence intervals (CI) measured during the study of abacavir (ABC) in the absence and presence of atazanavir/ritonavir (ATV/r), ABC in the absence and presence of lopinavir/ritonavir (LPV/r), ATV/r in the absence and presence of ABC, and LPV/r in the

absence and presence of ABC. Day 1 values were used as references. CV, coefficient of variation; AUC, area under the curve; Cmax, maximum concentration; Ctrough, trough concentration; t1/2, half-life.

lopinavir/ritonavir than with atazanavir/ritonavir. Acknowledgements However, it is unclear whether this difference is secondary to an additional induction effect of The authors would like to thank St. Stephen’s AIDS lopinavir on glucuronidation or whether the inhibi- Trust Charity for allowing us to undertake the study, tion of glucuronidation caused by atazanavir limits GlaxoSmithKline, Glaxo Wellcome UK Ltd, for the impact of ritonavir on abacavir concentrations. providing an unrestricted educational grant to allow The clinical significance of the changes in the running of the study, and Mauro Sciandra, HIV abacavir concentrations observed during the Pharmacology Laboratory, Turin, Italy, for his labora- co-administration with lopinavir/ritonavir in this tory expertise. study and previously with tipranavir/ritonavir [10] is still unclear. However, clinical data from 444 References subjects randomized to receive abacavir/lamivudine 1. Palella Jr FJ, Chmiel JS, Moorman AC, Holmberg SD. co-administered with lopinavir/ritonavir in the Durability and predictors of success of highly active anti- KLEAN study clearly showed that the regimen was retroviral therapy for ambulatory HIV-infected patients. effective [24]. As with all other nucleoside/ AIDS 2002; 16:1617–1626. nucleotide RTIs approved for the treatment of HIV 2. Gazzard B, Bernard AJ, Boffito M, et al. British HIV Association (BHIVA) guidelines for the treatment of HIV- infection, abacavir is a prodrug that is phosphory- infected adults with antiretroviral therapy (2006). HIV lated at the intracellular level to obtain the active Med 2006; 7:487–503. moiety, carbovir triphosphate. Data on the relation- 3. Boffito M, Acosta E, Burger D, et al. Therapeutic drug monitoring and drug–drug interactions involving antiretro- ship between drug intracellular concentrations, viral drugs. Antivir Ther 2005; 10:469–477. abacavir plasma concentrations, and antiretroviral 4. Piliero PJ. Pharmacokinetic properties of efficacy are conflicting [25,26] and further study is nucleoside/nucleotide reverse transcriptase inhibitors. J warranted. Acquir Immune Defic Syndr 2004; 37(Suppl 1):S2–S12.

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