Darunavir / ritonavir

Rosuvastatin

Dosage adjustment may be necessary.

No pharmaceutical opinion available for this interaction.

Mechanism

Darunavir / 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 .

Darunavir / 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
Dose
Frequency
AUC
Cmax
Duration (days)
Rosuvastatin
2378
12
-
10 mg
QD
+ 48% (1.5x)
+144% (2.5x)
 
Darunavir / ritonavir
2378
12
-
600/100 mg
BID
+/- 0%
+/- 0%
7
Comment

Ref #2269, #2117, #2378 and #2364 : One study showed that rosuvastatin AUC with a 20 mg dose increased by 2.1-fold when coadministered lopinavir/ritonavir 400/100 mg BID. 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: A case of rhabdomyolysis has been reported in a patient with renal failure and the combination of lopinavir/ritonavir and rosuvastatin.

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
  • 2211
    Burger D, Stroes E, Reiss P et al. Drug interactions between statins and antiretroviral agents. Current opinion in HIV and AIDS 2008;3:247-251.
  • 2212
    Neuvonen PJ, Niem M and Backman JT. Drug interaction with lipid-lowering drugs: mecanisms and clinical relevance. Clin Pharmacol Ther 2006;80:565-581
  • 2268
    Bottaro EG, Cravello O, Scapellanto PG et al. Rosuvastatine for treatment of dyslipidemia in HIV-infected patients receiving highly active antiretroviral therapy. Enferm Infecc Microbiol Clin. 2008 Jun-Jul;26(6):325-9.
  • 2378
    Samineni D, Desai P, Sallans L and Fichtenbaum C. Steady-State Pharmacokinetic Interactions of Darunavir/Ritonavir With Lipid-Lowering Agent Rosuvastatin. The Journal of Clinical Pharmacology. 2012; 52(6): 922-931.
  • 1490
    Rosuvastatin (Crestor), AstraZeneca, Ontario, Canada, 21 avril 2015.
  • 2794
    Kitamura S, Maeda K, Wang Y, Sugiyama Y. Involvement of Multiple Transporters in the Hepatobiliary Transport of Rosuvastatin. Drug Metab Dispos 2008; 36 : 2014-2023.
  • 2795
    Martin PD, Warwick MJ, Dane AL, et al. Metabolism, Excretion and Pharmacokinetics of Rosuvastatin in Healthy Adult Male Volunteers. Clin Ther 2003; 25 : 2822-2835.
  • 2983
    Chauvin B, Drouot S, Barrail-Tran A and Taburet AM. Drug-Drug Interactions between HMG-coA reductase inhibitors (Statins) and Antiretroviral Protease Inhibitors. Clin Pharmacokinet 2013; 52: 815-831.
  • 2269
    Busti AJ, Bain AM, Hall RG, et al. Effects of atazanavir/ritonavir or fosamprenavir/ritonavir on the pharmacokinetics of rosuvastatin. J Cardiovasc Pharmacol, 2008, 51(6): 605-610.
  • 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.
  • 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.
  • 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.
  • 2904
    European AIDS Clinical Society (EACS) Guidelines 7.1, Nov 2014. [En ligne]. Disponible : http://www.eacsociety.org.
  • 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/hiv-clinical-guidelines-adult-and-adolescent-arv/whats-new. Publié le 6 décembre 2023. Consulté le 20 février 2024.
  • 2573
    Ritonavir (Norvir), Corporation AbbVie, Quebec, Canada, 5 juillet 2021.