An interaction between lopinavir/ritonavir (Kaletra) and rosuvastatin (Crestor) can boost peak rosuvastatin levels nearly fivefold, according to a pharmacokinetic study in HIV-negative individuals. Despite the increased levels of rosuvastatin, the interaction may actually hamper the drug's effectiveness at decreasing cholesterol levels in the blood. The results were published in the April 15 issue of Journal of Acquired Immune Deficiency Syndromes.
Statin drugs such as rosuvastatin are often used to control high levels of low-density lipoprotein (LDL) cholesterol. Rosuvastatin, in particular, is one of the more effective and frequently-used statins, and has previously been found to be safe and effective for treating elevated lipids in HIV-positive individuals on HAART (see here). Also, rosuvastatin is only minimally metabolised using the cytochrome P450 pathway that is extensively involved with protease inhibitor metabolism, and it has been surmised that there would therefore be a low risk of interaction with protease inhibitors.
Investigators at the University of Colorado have now found that an interaction apparently occurs independently of the P450 pathway. This was an open-label, single-arm pharmacokinetic (PK) study in healthy, HIV-negative men and women between 18 and 60 years of age, with normal metabolic function, who weighed ≥ 50 kg, and were within 30% of their ideal body weight.
There were three phases to the study: in phase 1, participants were given 20 mg rosuvastatin once daily for seven days. In phase 2 (study days 8 to 17), participants stopped rosuvastatin and took a standard dose of Kaletra: two tablets (400 mg lopinavir / 100 mg ritonavir) twice daily. In phase 3 (study days 18 to 24), the participants took both drugs. Intensive PK analysis was done on the final day of each phase. On study days 7 and 24, blood samples were collected over a 24-hour period, and on study day 17, over 12 hours. Participants ate a (non-standardised) breakfast just before dosing on each of these days.
Of 20 subjects who enrolled, 15 completed all three study phases: nine women and six men. Twelve were white, and three were Hispanic males. The median (range) age, weight, height, and body surface area of volunteers were 27 years (23 to 40 years), 71 kg (54 to 103 kg), 176 cm (158 to 196 cm), and 1.8 m2 (1.5 to 2.3 m2), respectively.
The study found a 4.7-fold increase in rosuvastatin Cmax and a 2.1-fold increase in rosuvastatin AUC (area under the concentration curve) when given with Kaletra, but no increase in the rosuvastatin half-life. Rosuvastatin PK parameters were as follows for phase 1 (given alone) versus phase 3 (given with Kaletra): Cmin, 0.74 vs. 0.77 ng/ml; Cmax, 4.34 vs. 20.2 ng/ml (4.7-fold increase, 90% confidence interval [CI], 3.4-6.4, p<.0001 auc="" ci="" difference="" half-life="" hours="" increase="" ng-h="" p="" vs.="">
A comparison of the rosuvastatin concentration curves showed a dramatic increase in the first seven hours, with rosuvastatin levels with and without Kaletra becoming similar from eight hours post-dose onward. None of the PK parameters for lopinavir or ritonavir were significantly affected.
Given that less than 10% of rosuvastatin doses are metabolised by CYP (P450) enzymes, and previous studies have shown little interaction, the reason for these findings is not fully understood. Moreover, despite the increase in rosuvastatin concentrations, its lipid-lowering effect was actually found to be diminished in combination: LDL cholesterol was reduced 31% with rosuvastatin alone versus 26% with the combination (P = 0.01). Total cholesterol was also reduced 27% with rosuvastatin alone versus 21% with the combination (P = 0.03). (The median baseline LDL for study subjects was 88 mg/dl [2.29 mmol/l].)
While the mechanism of this interaction is not known, the researchers speculate it is "most likely" due to the action of lopinavir and/or ritonavir on another enzyme involved in statin metabolism, the human organic anion transporting polypeptide 1B1 (OATP1B1), also known as OAPTC or OATP2. Such an interaction would prevent much of the rosuvastatin from reaching its site of action, leading to the observed increases in levels while lessening its lipid-lowering effects. Additional studies of protease inhibitor-rosuvastatin interactions, including further analyses of the safety and efficacy of rosuvastatin with Kaletra, are warranted. "In the meantime," the researchers note, "the combination of rosuvastatin and lopinavir/ritonavir should be administered with caution."
References:
Kiser JJ et al. Drug/drug interaction between lopinavir/ritonavir and rosuvastatin in healthy volunteers. J Acquir Immune Defic Syndr 47: 570-578, 2008.