Lopinavir/ritonavir-containing antiretro-viral therapy can cause hyperlipidaemia. However, most statins are contraindicated due to drug-drug interactions. Rosuvastatin undergoes minimal metabolism by CYP450, so no CYP450-based interaction with lopinavir/ritonavir is expected. This study explored the lipid-lowering effect of rosuvastatin and assessed the effect of lopinavir/ritonavir on the pharmacokinetics of rosuvastatin and vice versa.
Methods
HIV-infected patients on lopinavir/ritonavir (viral load <400 copies/ml) with total cholesterol (TC) >6.2 mmol/l were treated with rosuvastatin for 12 weeks, starting on 10 mg once daily. If fasting target values (TC<5.0 mmol/l, high-density lipoprotein-cholesterol >1.0 mmol/l, low-density lipoprotein-cholesterol [LDL-c] <2.6 mmol/l and triglycerides <2.0 mmol/l) were not reached, rosuvastatin was escalated to 20 mg or 40 mg at week 4 and 8, respectively. Plasma lopinavir/ritonavir trough levels (Cmin) were determined at week 0, 4, 8 and 12 and rosuvastatin Cmin, at week 4, 8 and 12.
Results
Twenty-two patients completed the study. Mean reductions in TC and LDL-c from baseline to week 4 (on rosuvastatin 10 mg once a day) were 27.6% and 31.8%, respectively. Lopinavir/ritonavir concentrations were not influenced by rosuvastatin (P=0.44 and 0.26, repeated-measures analysis). Median (interquartile range) rosuvastatin Cmin for 10 mg, 20 mg and 40 mg once daily were 0.97 (0.70–1.5), 2.5 (1.3–3.3) and 5.5 (3.3–8.8) ng/ml, respectively.
Conclusions
Rosuvastatin appeared to be an effective statin in hyperlipidaemic HIV-infected patients. Lopinavir/ritonavir levels were not affected by rosuvastatin, but rosuvastatin levels unexpectedly appeared to be increased 1.6-fold compared with data from healthy volunteers. Until safety and efficacy have been confirmed in larger studies, the combination of rosuvastatin and lopinavir/ritonavir should be used with caution.
References
1.
CalzaL., ManfrediR., ChiodoF.Hyperlipidaemia in patients with HIV-1 infection receiving highly active antiretroviral therapy: epidemiology, pathogenesis, clinical course and management.Int J Antimicrob Agents2003; 22: 89–99.
2.
de JonghS., LilienM.R., op't RoodtJ., StroesE.S., BakkerH.D., KasteleinJ.J.Early statin therapy restores endothelial function in children with familial hypercholesterolemia.J Am Coll Cardiol2002; 40: 2117–2121.
3.
CalzaL., ManfrediR., ChiodoF.Statins and fibrates for the treatment of hyperlipidaemia in HIV-infected patients receiving HAART.AIDS2003; 17: 851–859.
4.
SchambelanM., BensonC.A., CarrA.Management of metabolic complications associated with antiretroviral therapy for HIV-1 infection: recommendations of an International AIDS Society-USA panel.J Acquir Immune Defic Syndr2002; 31: 257–275.
MartinP.D., WarwickM.J., DaneA.L.Metabolism, excretion, and pharmacokinetics of rosuvastatin in healthy adult male volunteers.Clin Ther2003; 25: 2822–2835.
7.
McCormickA.D., McKillopD., ButtersC.J.ZD-4522: an HMG-CoA reductase inhibitor free of metabolically mediated drug interactions: metabolic studies in human in vitro systems.J Clin Pharmacol2000; 40: 1045–1067.
8.
JonesP.H., DavidsonM.H., SteinE.A.Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial).Am J Cardiol2003; 92: 152–160.
9.
Crestor. Summary of product characteristics. In: SmPC Crestor. The Medicines Evaluation Board the Netherlands.2006. CBG-MEB.
10.
DubeM.P., SteinJ.H., AbergJ.A.Guidelines for the evaluation and management of dyslipidemia in human immunodeficiency virus (HIV)-infected adults receiving antiretroviral therapy: recommendations of the HIV Medical Association of the Infectious Disease Society of America and the Adult AIDS Clinical Trials Group.Clin Infect Dis2003; 37: 613–627.
11.
FriedewaldW.T., LevyR.I., FredricksonD.S.Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge.Clin Chem1972; 18: 499–502.
12.
DrosteJ.A.H., Verweij-van WissenC.P., BurgerD.M.Simultaneous determination of the HIV drugs indinavir, amprenavir, saquinavir, ritonavir, lopinavir, nelfinavir, the nelfinavir hydroxymetabolite M8 and nevirapine in human plasma by reversed phase high performance liquid chromatography.Ther Drug Monit2003; 25: 393–399.
13.
HullC.K., PenmanA.D., SmithC.K., MartinP.D.Quantification of rosuvastatin in human plasma by automated solid-phase extraction using tandem mass spectrometric detection.J Chromatogr B Analyt Technol Biomed Life Sci2002; 772: 219–228.
14.
MartinP.D., MtchellP.D., SchneckD.W.Pharmacodynamic effects and pharmacokinetics of a new HMG-CoA reductase inhibitor, rosuvastatin, after morning or evening administration in healthy volunteers.Br J Clin Pharmacol2002; 54: 472–477.
15.
MartinP.D., DaneA.L., SchneckD.W., WarwickM.J.An open-label, randomized, three-way crossover trial of the effects of coadministration of rosuvastatin and fenofibrate on the pharmacokinetic properties of rosuvastatin and fenofibric acid in healthy male volunteers.Clin Ther2003; 25: 459–471.
16.
SimonsonS.G., MartinP.D., MitchellP.D., LasseterK., GibsonG., SchneckD.W.Effect of rosuvastatin on warfarin pharmacodynamics and pharmacokinetics.J Clin Pharmacol2005; 45: 927–934.
17.
CalzaL., ColangeliV., ManfrediR.Rosuvastatin for the treatment of hyperlipidaemia in HIV-infected patients receiving protease inhibitors: a pilot study.AIDS2005; 19: 1103–1105.
18.
ChengJ.W.Rosuvastatin in the management of hyperlipidemia.Clin Ther2004; 26: 1368–1387.
Kaletra.Summary of Product Characteristics. 16 April 2007. EMEA.
21.
CvetkovicR., GoaK.Lopinavir/Ritonavir: A Review of its Use in the Management of HIV Infection.Drugs2003; 63: 769–802.
22.
Norvir. Summary of Product Characteristics. 16 March 2007. EMEA.
23.
McTaggartF., BuckettL., DavidsonR.Preclinical and clinical pharmacology of Rosuvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor.Am J Cardiol.2001; 87: 28B–32B.
24.
CooperK.J., MartinP.D., DaneA.L., WarwickM.J., SchneckD.W., CantariniM.V.The effect of fluconazole on the pharmacokinetics of rosuvastatin.Eur J Clin Pharmacol2002; 58: 527–531.
25.
CooperK.J., MartinP.D., DaneA.L., WarwickM.J., RazaA., SchneckD.W.Lack of effect of ketoconazole on the pharmacokinetics of rosuvastatin in healthy subjects.Br J Clin Pharmacol2003; 55: 94–99.
26.
CooperK.J., MartinP.D., DaneA.L., WarwickM.J., RazaA., SchneckD.W.The effect of erythromycin on the pharmacokinetics of rosuvastatin.Eur J Clin Pharmacol2003; 59: 51–56.
27.
CooperK.J., MartinP.D., DaneA.L., WarwickM.J., SchneckD.W., CantariniM.V.Effect of itraconazole on the pharmacokinetics of rosuvastatin.Clin Pharmacol Ther2003; 73: 322–329.
28.
SimonsonS.G., RazaA., MartinP.D.Rosuvastatin pharmacokinetics in heart transplant recipients administered an antirejection regimen including cyclosporine.Clin Pharmacol Ther2004; 76: 167–177.
29.
KonigJ., CuiY., NiesA.T., KepplerD.A novel human organic anion transporting polypeptide localized to the basolateral hepatocyte membrane.Am J Physiol Gastrointest Liver Physiol2000; 278: G156–G164.
30.
BrownC.D.A., WindassA., BleasbyK., LauffartB.Rosuvastatin is a high affinity substrate of hepatic organic anion transporter OATP-C.Atherosclerosis Supplements2002; 2: 90.
31.
NeuvonenP.J., NiemiM., BackmanJ.T.Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance.Clin Pharmacol Ther2006; 80: 565–581.
32.
HiranoM., MaedaK., ShitaraY., SugiyamaY.Drug-drug interaction between pitavastatin and various drugs via OATP1B1.Drug Metab Dispos2006; 34: 1229–1236.
33.
HoodyD., KiserJ., PredhommeJ., FlynnD., GerberJ.Drug-drug interaction between lopinavir/ritonavir and rosuvastatin.14th Conference on Retroviruses and Opportunistic Infections, 25–28 February 2007, Los Angeles, CA, USA. Abstract 564.
34.
CarrR.A., AndreA.K., BetzR.J.Concommitant administration of ABT-378/ritonavir (ABT-378/r) results in a clinically important pharmacokintics (PK) interaction with atorvastatin (ATO) but not pravastatin (PRA).40th Interscience Conference on Antimicrobial Agents and Chemotherapy. 17–20 September 2000, Toronto, Canada. Abstract 1644.
35.
FichtenbaumC.J., GerberJ.G., RosenkranzS.L.Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers: ACTG Study A5047.AIDS2002; 16: 569–577.
36.
HsyuP.H., Schultz-SmithM.D., LillibridgeJ.H., LewisR.H., KerrB.M.Pharmacokinetic interactions between nelfinavir and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors atorvastatin and simvastatin.Antimicrob Agents Chemother2001; 45: 3445–3450.
