Pharmacokinetics and pharmacodynamics of combined use of lopinavir/ritonavir and rosuvastatin in HIV-infected patients.
BACKGROUND
Lopinavir/ritonavir-containing antiretroviral 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 (C(min)) were determined at week 0, 4, 8 and 12 and rosuvastatin C(min), 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 C(min) 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.
van der Lee
Manon
M
Department of Clinical Pharmacy, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. m.vanderlee@akf.umcn.nl
Sankatsing
Raaj
R
Schippers
Emile
E
Vogel
Martin
M
Fätkenheuer
Gerd
G
van der Ven
Andre
A
Kroon
Frank
F
Rockstroh
Jürgen
J
Wyen
Christoph
C
Bäumer
Anselm
A
de Groot
Eric
E
Koopmans
Peter
P
Stroes
Erik
E
Reiss
Peter
P
Burger
David
D
D000293:Adolescent; D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D005464:Fluorobenzenes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D006937:Hypercholesterolemia / Q000139:chemically induced / Q000188:drug therapy*; D061466:Lopinavir; D008875:Middle Aged; D010865:Pilot Projects; D011743:Pyrimidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011744:Pyrimidinones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019438:Ritonavir / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*
D019380:Anti-HIV Agents; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D011744:Pyrimidinones; D013449:Sulfonamides; D061466:Lopinavir; D000068718:Rosuvastatin Calcium; D019438:Ritonavir