Lopinavir / ritonavir

Rosuvastatin

Dosage adjustment may be necessary.

No pharmaceutical opinion available for this interaction.

Mechanism

Lopinavir / ritonavir may inhibit hepatic transports OATP1B1/B3 and BCRP and increase plasma concentration of Rosuvastatin.

Furthermore, inhibition of these transports may prevent the action of statin into the hepatic cell and potentially decrease clinical efficacy .

Lopinavir / ritonavir

Pharmacodynamic effects

Recommendations

Alternative solution(s)

Rosuvastatin

Pharmacodynamic effects

Possible increased risk of hypolipidemic agents toxicity due to the increase in rosuvastatin AUC.

Also possible decrease of clinical efficacy due to reduced liver transport of the statin.

Recommendations

Start with the lowest dose possible, or in patients already on treatment, a dose reduction may be necessary.

Carefully increase the dose as tolerated by the patient.

We do not recommend more than 10 mg per day (U.S. guidelines) and 20 mg per day (European guidelines).

Or choose an alternative.

Alternative solution(s)

Pravastatin or ezetimibe.

Monitor

Symptoms of toxicity associated with hypolipidemic agents : gastrointestinal effects, fatigue and muscular weaknesses, myalgias, muscular cramps, myopathies, rhabdomyolysis and myoglobinuria leading to renal insufficiency.

Tests

AST

ALT

CK

Lipidic profile

Pharmacokinetic parameters
Parameters
Reference number
# patients
HIV
Cmin
Dose
Frequency
Duration (days)
Cmax
AUC
Tmax
Cl
T1/2
Lopinavir / ritonavir
2117 1955 1955 1955
15 22    
- + + +
- 22% +/- 0% +/- 0% +/- 0%
400/100 mg 400/100 mg    
BID      
17      
+/- 0%      
       
       
       
       
Rosuvastatin
2117 1955 1955 1955
15 22    
- + + +
+ 4% + 50% ** + 60% ** + 90% **
20 mg 5-10 mg 20 mg 10 mg *
QD QD QD QD
7 84    
+ 366% (4.7x) + 60%    
+ 110% (2.1x)      
- 31%      
- 52%      
- 8%      
Comment

Ref #1955 : * Dose adjusted according to lipid targets. If therapeutic goals are not reached, increase the dosage to 20mg (after week 4) and then to 40mg (after week 8)
** Compared to historical controls.
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. 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. Lopinavir/ritonavir concentrations were not influenced by rosuvastatin.
Author’s conclusion: 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.

Ref #2117 : Author’s conclusion : Rosuvastatin low-density lipoprotein reduction was attenuated with lopinavir/ritonavir. Rosuvastatin AUC and Cmax were unexpectedly increased 2.1- and 4.7-fold in combination with lopinavir/ritonavir. There was 1 asymptomatic creatinine phosphokinase elevation 17 times the upper limit of normal and 1 liver function test elevation between 1.1 to 2.5 times the upper limit normal with the combination.
Rosuvastatin and lopinavir/ritonavir should be used with caution until the safety, efficacy, and appropriate dosing of this combination have been demonstrated in larger study.

Ref #2210 : Studied on 16 positive HIV patients (rosuvastatine 10mg/d + Saquinavir/r, lopinavir /r or nelfinavir) : no serious adverse events.

Ref #2117, #2378 and #2364 : Other studies with rosuvastatin 10 mg dose showed increases in AUC with atazanavir/ritonavir 300/100 mg QD by 3.1-fold, with darunavir/ritonavir 600/100 mg BID by 1.5-fold and with tipranavir/ritonavir 500/200 mg BID by 1.4-fold. However with fosamprenavir/ritonavir 700/100 mg QD, there was no significant change in rosuvastatin AUC.

Ref #2596: Case report of rhabdomyolysis. A combination of many factors might have contributed to the development of a rhabdomyolysis in this case. This illustrates that it can be challenging to use statins in an HIV-infected patient with co-morbidities and organ failure because statins as well antiretroviral therapy are susceptible to drug-drug or drug-disease interactions.

For these reasons, US and European guidelines recommend to reduce the dose of rosuvastatin when it is combined with PIs. US guidelines recommend no more than 10 mg per day while European guidelines recommend no more than 20 mg per day.

Ref #1490: Rosuvastatin Canadian product monograph makes specific recommendations for some PIs. Indeed, rosuvastatin dose administered with atazanavir/ritonavir should not exceed 10 mg daily and with lopinavir/ritonavir, darunavir/ritonavir and tipranavir/ritonavir it should not exceed 20 mg daily.

Reference
  • 2596
    de Kanter, C, Keuter, M. van der Lee M.J., Koopmans, P.P. and Burger D.M. Rhabdomyolysis in an HIV-infected patient with impaired renal function concomitanly treated with rosuvastatin and lopinavir/ritonavir. Antiviral Therapy 2011; 16:435-437.
  • 3151
    U.S. Department of Health and Human services (DHHS) : Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. Disponible : https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/whats-new-guidelines. Publié le 16 août 2021. Consulté le 16 septembre 2021.
  • 2904
    European AIDS Clinical Society (EACS) Guidelines 7.1, Nov 2014. [En ligne]. Disponible : http://www.eacsociety.org.
  • 2364
    Pham PA, la Porte CJ, Lee LS, et al. Differential effects of tipranavir plus ritonavir on atorvastatin or rosuvastatin pharmacokinetics in healthy volunteers. Antimicrob Agents Chemother, 2009, 53(10): 4385-4392.
  • 2378
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  • 2794
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  • 1490
    Rosuvastatin (Crestor), AstraZeneca, Ontario, Canada, 21 avril 2015.
  • 2268
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  • 2211
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  • 2210
    Calza L, Colangeli V, Manfredi R et al. Rosuvastatine for the traitement of hyperlipideamia in HIV-infected patients receiving protease inhibitors: a pilot study. AIDS 2005;19:1103-1105.
  • 2117
    Kiser JJ, Gerber JG, Predhomme JA, Wolfe PR, Flynn DM, Hoody DW. Drug/drug interaction between lopinavir/ritonavir and rosuvastatin in healthy volunteers. JAIDS Journal of Acquired Immune Deficiency Syndromes 2008; 47(5): 570-8.
  • 1955
    Van der Lee M, Sankatsing R, Schippers E, Vogel M, Fätkenheuer G, van der Ven A, Kroon F, Rockstroh J, Wyen C, Bäumer A, de Groot E, Koopmans P, Stroes E, Reiss P, Burger D. Pharmacokinetics and pharmacodynamics of combined use of lopinavir/ritonavir and rosuvastatin in HIV-infected patients. Antiviriral Therapy. 2007;12(7):1127-32.
  • 1681
    Van der Lee MJ, Schippers E, Koopmans PP, et al. Pharmacokinetics of combined use of lopinavir/ritonavir and rosuvastatin in HIV-infected patients. 6th International Workshop on Clinical Pharmacology of HIV Therapy, 28-30 April 2005, Québec, Canada. Abstract 25.