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.
References
1.
PalellaF.J.Jr, ChmielJ.S., MoormanA.C., HolmbergS.D.Durability and predictors of success of highly active anti-retroviral therapy for ambulatory HIV-infected patients.AIDS2002; 16: 1617–1626.
2.
GazzardB., BernardA.J., BoffitoM.British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy (2006).HIV Med2006; 7: 487–503.
3.
BoffitoM., AcostaE., BurgerD.Therapeutic drug monitoring and drug-drug interactions involving antiretroviral drugs.Antivir Ther2005; 10: 469–477.
KewnS., HoggardP.G., SalesS.D.Development of enzymatic assays for quantification of intracellular lamivudine and carbovir triphosphate levels in peripheral blood mononuclear cells from human immunodeficiency virus-infected patients.Antimicrob Agents Chemother2002; 46: 135–143.
6.
Ziagen® [abacavir]. Summary of Product Characteristics. GlaxoSmithKline, Research Triangle Park, NC 27709, USA. October 2006.
7.
HawkinsT., VeikleyW., St ClaireR.L.III, GuyerB., ClarkN., KearneyB.P.Intracellular pharmacokinetics of tenofovir diphosphate, carbovir triphosphate, and lamivudine triphosphate in patients receiving triple-nucleoside regimens.J Acquir Immune Defic Syndr2005; 39: 406–411.
8.
MoyleG.J., DeJesusE., CahnP., CastilloZiagen Once-Daily in Antiretroviral Combination Therapy (CNA30021) Study Team. Abacavir once or twice daily combined with once-daily lamivudine and efavirenz for the treatment of antiretroviral-naive HIV-infected adults: results of the Ziagen Once Daily in Antiretroviral Combination Study.J Acquir Immune Defic Syndr2005; 38: 417–425.
9.
McDowellJ.A., ChittickG.E., StevensC.P., EdwardsK.D., SteinD.S.Pharmacokinetic interaction of abacavir (1592U89) and ethanol in human immunodeficiency virus-infected adults.Antimicrob Agents Chemother2000; 44: 1686–1690.
10.
Aptivus® [tipranavir]. Summary of Product Characteristics.Boehringer Ingelheim Pharmaceuticals, Inc.Ridgefield, CT 06877, USA. June 2006.
11.
Swainston HarrisonT., ScottL.J.Atazanavir: a review of its use in the management of HIV infection.Drugs2005; 65: 2309–2336.
12.
OldfieldV., PloskerG.L.Lopinavir/ritonavir: a review of its use in the management of HIV infection.Drugs2006; 66: 1275–1299.
13.
YehR.F., GaverV.E., PattersonK.B.Lopinavir/ritonavir induces the hepatic activity of cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP1A2 but inhibits the hepatic and intestinal activity of CYP3A as measured by a phenotyping drug cocktail in healthy volunteers.J Acquir Immune Defic Syndr2006; 42: 52–60.
14.
AgarwalaS., EleyT., VillegasC.Pharmacokinetic interaction between tenofovir and atazanavir coadministered with ritonavir in healthy subjects.6th International Workshop on Clinical Pharmacology of HIV Therapy. 28–30 April 2005, Quebec City, Quebec, Canada. Abstract 16.
15.
KearneyB.P., MathiasA., MittanA., SayreJ., EbrahimiR., ChengA.K.Pharmacokinetics and safety of tenofovir disoproxil fumarate on coadministration with lopinavir/ritonavir.J Acquir Immune Defic Syndr2006; 43: 278–283.
16.
Verweij-van WissenC.P., AarnoutseR.E., BurgerD.M.Simultaneous determination of the HIV nucleoside analogue reverse transcriptase inhibitors lamivudine, didanosine, stavudine, zidovudine and abacavir in human plasma by reversed phase high performance liquid chromatography.J Chromatogr B Analyt Technol Biomed Life Sci2005; 816: 121–129.
17.
DickinsonL., RobinsonL., TjiaJ., KhooS., BackD.Simultaneous determination of HIV protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir and saquinavir in human plasma by high performance liquid chromatography-tandem mass spectrometry.J Chromatogr B Analyt Technol Biomed Life Sci2005; 829: 82–90.
18.
SmithC.M., FaucetteS.R., WangH., LeCluyseE.L.Modulation of UDP-glucuronosyltransferase 1A1 in primary human hepatocytes by prototypical inducers.J Biochem Mol Toxicol2005; 19: 96–108.
19.
ZhangD., ChandoT.J., EverettD.W., PattenC.J., DehalS.S., HumphreysW.G.In vitro inhibition of UDP glucuronosyl-transferases by atazanavir and other HIV protease inhibitors and the relationship of this property to in vivo bilirubin glucuronidation.Drug Metab Dispos2005; 33: 1729–1739.
20.
OuelletD., HsuA., QianJ.Effect of ritonavir on the pharmacokinetics of ethinyl oestradiol in healthy female volunteers.Br J Clin Pharmacol1998; 46: 111–116.
21.
FichtenbaumC.J., GerberJ.G., RosenkranzS.L.Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers: ACTG Study A5047.AIDS2002; 16: 569–577.
22.
TsengA., FletcherD.Interaction between ritonavir and levothyroxine.AIDS1998; 12: 2235–2236.
23.
van der LeeM.J., DawoodL., ter HofstedeH.J.Lopinavir/ritonavir reduces lamotrigine plasma concentrations in healthy subjects.Clin Pharmacol Ther2006; 80: 159–168.
24.
EronJ., YeniP., GatheJ.The KLEAN study of fosam-prenaivr-ritonavir versus lopinavir-ritonavir, each in combination with abacavir-lamivudine, for the initial treatment of HIV infection over 48 weeks: a randomized non-inferiority trial.Lancet2006; 368: 476–482.
25.
HoggardP.G., BackD.J.Intracellular pharmacology of nucleoside analogues and protease inhibitors: role of transporter molecules.Curr Opin Infect Dis2002; 15: 3–8.
26.
JullienV., TreluyerJ.M., ChappuyH.Weight related differences in the pharmacokinetics of abacavir in HIV-infected patients.Br J Clin Pharmacol2005; 59: 183–188.
