JAIDS Journal of Acquired Immune Deficiency Syndromes:
Drug/Drug Interaction Between Lopinavir/Ritonavir and Rosuvastatin in Healthy Volunteers
Kiser, Jennifer J PharmD*; Gerber, John G MD†; Predhomme, Julie A RN, MS, C-ANP*; Wolfe, Pamela MS‡; Flynn, Devon M PharmD§; Hoody, Dorie W PharmD§
From the *Department of Pharmaceutical Sciences, University of Colorado Denver, Denver, CO; †Divisions of Pharmacology and Toxicology and Infectious Diseases, University of Colorado Denver, Denver, CO; ‡Department of Preventive Medicine and Biometrics, University of Colorado Denver, Denver, CO; and the §Department of Pharmacy, University of Colorado Hospital, Denver, CO.
Received for publication June 29, 2007; accepted October 30, 2007.
Research supported by a grant from the Investigators-Sponsored Study Program of Astra Zeneca and grant M01 RR00051 from the NIH General Clinical Research Center.
Data were presented as a poster at the 14th Conference on Retroviruses and Opportunistic Infections, February 25-28, 2007, Los Angeles, CA (abstract 564).
Correspondence to: Dorie W. Hoody, PharmD, University of Colorado Hospital, Health Sciences Library, 12950 E. Montview Blvd., CB A003, PO Box 6508, Aurora, CO 80045 (e-mail: firstname.lastname@example.org).
Objectives: This open-label, single-arm, pharmacokinetic (PK) study in HIV-seronegative volunteers evaluated the bioequivalence of rosuvastatin and lopinavir/ritonavir when administered alone and in combination. Tolerability and lipid changes were also assessed.
Methods: Subjects took 20 mg of rosuvastatin alone for 7 days, then lopinavir/ritonavir alone for 10 days, and then the combination for 7 days. Intensive PK sampling was performed on days 7, 17, and 24.
Results: Twenty subjects enrolled, and PK data were available for 15 subjects. Geometric mean (±SD) rosuvastatin area under the concentration time curve (AUC)[0,τ] and maximum concentration (Cmax) were 47.6 ng·h/mL (±15.3) and 4.34 ng/mL (±1.8), respectively, when given alone versus 98.8 ng·h/mL (±65.5) and 20.2 ng/mL (±16.9) when combined with lopinavir/ritonavir (P < 0.0001). The geometric mean ratio was 2.1 (90% confidence interval [CI]: 1.7 to 2.6) for rosuvastatin AUC[0,τ] and 4.7 (90% CI: 3.4 to 6.4) for rosuvastatin Cmax with lopinavir/ritonavir versus rosuvastatin alone (P < 0.0001). There was 1 asymptomatic creatine phosphokinase elevation 17 times the upper limit of normal (ULN) and 1 liver function test elevation between 1.1 and 2.5 times the ULN with the combination.
Conclusions: 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. Rosuvastatin and lopinavir/ritonavir should be used with caution until the safety, efficacy, and appropriate dosing of this combination have been demonstrated in larger populations.
In the developed world, the HIV infection has transformed from a fatal to a chronic illness secondary to potent antiretroviral therapies. Improved survival rates have led to more HIV-infected persons being susceptible to age-associated comorbidities, including hypertension, diabetes, and hyperlipidemia.1 HIV disease itself2,3 and antiretroviral therapies4,5 also contribute to the problem. Several protease inhibitors have been linked to metabolic disturbances, including hyperlipidemia.4-9 Even low pharmacologic “boosting” doses of ritonavir have increased lipids in healthy volunteers after just 14 days.10 As many as 50% of HIV-infected patients experience lipid abnormalities throughout the course of their disease.11-13 The extent that these metabolic disturbances lead to the development of cardiovascular disease is an intense area of debate and research, but several studies have found combination antiretroviral therapy to be an independent risk factor for the development of myocardial infarction.14-18 Additionally, cardiovascular disease is a leading non-AIDS-related cause of death among persons with HIV.19,20 Based on these data, treatment guidelines recommend that patients with HIV receiving antiretroviral therapy be systematically assessed for the risk of cardiovascular disease and that interventions be implemented to reduce the risk in the same manner as in persons without HIV.21,22
3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are first-line therapy for persons with elevated low-density lipoprotein (LDL) cholesterol regardless of HIV status.21,22 Statin selection is limited in persons with HIV, however, because of significant drug-drug interactions with antiretroviral drugs, particularly protease inhibitors. The inactive lactone prodrugs, simvastatin and lovastatin, are highly dependent on intestinal and hepatic cytochrome P450 (CYP) 3A4 for metabolism.23 Ritonavir and other protease inhibitors are potent inhibitors of CYP 3A4.24 An increase in plasma statin concentrations carries the risk of life-threatening rhabdomyolysis, causing myalgias and pigmenturia and leading to acute oliguric renal failure.25-28 Therefore, treatment guidelines currently advocate only pravastatin, fluvastatin, and low-dose atorvastatin in HIV-infected patients on antiretroviral therapy including a protease inhibitor.22,29 Success rates with these agents are variable,30-37 however, rarely achieving adequate LDL reductions as recommended in guidelines.21 Thus, potent drugs to treat dyslipidemia without major interactions with antiretroviral agents are urgently needed.
Rosuvastatin produces significant reductions in LDL cholesterol38 and improvements in other lipid measures,39 with a safety profile consistent with other HMG-CoA reductase inhibitors.40 The LDL-lowering effects of rosuvastatin exceed those achieved with atorvastatin, simvastatin, and pravastatin.41 Less than 10% of a dose of rosuvastatin undergoes metabolism by CYP enzymes, and the remainder is eliminated unchanged. Therefore, rosuvastatin would be a welcome addition to our armamentarium of agents for the treatment of dyslipidemia in patients with HIV disease because of its limited potential for CYP-mediated drug interactions. Not all drug-drug interactions are easily predicted, however; thus, there is a need for pharmacokinetic (PK) data to ensure the lack of a clinically significant drug interaction with protease inhibitors before it can safely be recommended in the HIV-infected patient population.
The primary objective of this study was to determine the bioequivalence of rosuvastatin and lopinavir/ritonavir when used alone and in combination in HIV-seronegative healthy volunteers. Secondary objectives included assessments of safety and tolerability and changes in lipid levels throughout the course of the study.
Healthy HIV-1-seronegative men and nonpregnant women between 18 and 60 years of age who weighed ≥50 kg and were within 30% (±) of their ideal body weight were eligible. Subjects had to have hematologic, metabolic, renal, and hepatic function test results all within normal limits and a creatine phosphokinase (CPK) level <195 U/L. Subjects were instructed not to consume alcohol for 48 hours before lipid profile testing and on PK sampling days. The following were criteria for exclusion from study participation: allergy/sensitivity to rosuvastatin (or any other statin) or lopinavir/ritonavir; active drug or alcohol abuse or dependence; active cardiovascular, renal, hematologic, hepatic, neurologic, gastrointestinal, psychiatric, endocrine, or immunologic disease(s); any chronic gastrointestinal conditions that might interfere with drug absorption; and the use of investigational, prescription, or over-the-counter medications within 14 days of study entry with the exception of aspirin, acetaminophen, diphenhydramine, multivitamins, mineral supplements, or hormonal contraceptives. Postmenopausal women requiring hormone replacement therapy were excluded from participation in this study. Women who were pregnant or breast-feeding and women and men of reproductive potential actively engaging in sexual activity or assisted reproductive technology with the intent of pregnancy were also excluded. Men and women of reproductive potential were required to use at least 2 contraceptive methods during the course of this study and for 4 weeks after its completion. Because of the potential effects of lopinavir/ritonavir on oral contraceptive concentrations, all participants were required to use a barrier method (condoms, diaphragm, female condom, or cervical cap) during the study and for at least 4 weeks after the last dose of study drug.
This study was approved by the Colorado Multiple Institutional Review Board. All participants provided written informed consent. All study procedures were in accordance with the Helsinki Declaration of 1975, as revised in 2000.
This was an open-label, single-arm, 3-phase PK study designed to determine the effects of lopinavir/ritonavir on the area under the concentration time curve (AUC[0,τ]) over the dosing interval and maximum concentration (Cmax) of rosuvastatin in HIV-1-seronegative subjects. Subjects were given 20 mg of rosuvastatin once daily on study days 1 to 7 (phase 1). Subjects took the rosuvastatin in the morning. On study days 8 to 17, study participants were instructed to take 2 lopinavir/ritonavir tablets (400 mg/100 mg) orally twice daily (phase 2). On days 18 to 24, the lopinavir/ritonavir was continued and the 20 mg of rosuvastatin taken once daily in the morning was reintroduced (phase 3). Participants underwent intensive 24-, 12-, and 24-hour PK visits on study days 7, 17, and 24, respectively. Blood samples for PK analysis of rosuvastatin were collected before dosing and at the following times after an observed dose of study drug(s) on days 7 and 24: 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24 hours. Blood samples for PK analysis of lopinavir/ritonavir were collected before dosing and at the following times after an observed dose of study drugs on days 17 and 24: 1, 2, 3, 4, 5, 6, 8, and 12 hours. A single blood sample was also drawn to check for residual rosuvastatin in the bloodstream on study day 17. For all 3 intensive PK study visits, subjects consumed a nonstandardized breakfast immediately before taking study medications. Adherence was assessed using a standardized questionnaire. The rosuvastatin and lopinavir/ritonavir were given simultaneously in the morning on the day of the phase 3 intensive PK visit, and the evening dose of lopinavir/ritonavir was given 12 hours after the morning dose.
Lopinavir/Ritonavir in Plasma
Blood for determination of lopinavir and ritonavir was processed by centrifugation with the plasma stored (−70°C) within 30 minutes of collection. Lopinavir and ritonavir plasma concentrations were determined using a simultaneous validated high-performance liquid chromatography (HPLC) ultraviolet (UV) method (Antiviral Pharmacology Laboratory, University of Colorado, Denver, CO). Briefly, after addition of internal standard, a liquid-liquid extraction procedure with t-butylmethylether at basic pH was used to prepare the samples. The chromatographic separation of the compounds and the internal standard was accomplished on a Waters YMC HPLC 100-mm × 4.6-mm reversed-phase octyl column with a 3-μm particle size (Waters Corporation, Milford, MA). The mobile phase consisted of 54.7% 20-mM acetate buffer/45.3% acetonitrile, pH 4.9, with an isocratic flow rate of 1 mL/min. Detection and quantification of the drugs were at 212 nm. The assay was linear over the range of 20 to 20,000 ng/mL, with a minimum limit of quantification (LOQ) of 20 ng/mL using 0.2 mL of human plasma. The standard curves generated had coefficients of determination (r2) >0.9988. Precision and accuracy were measured in quality controls at 75, 750, and 7500 ng/mL, and all accuracies were within 15% of the nominal concentration with percent relative standard deviation of <10%.
Rosuvastatin in Plasma
Blood samples for rosuvastatin quantitation were protected from light and cooled to approximately 4°C in an ice bath and then centrifuged within 30 minutes of collection. After centrifugation, 1.5 mL of plasma was transferred to a separate tube and 1.5 mL of 0.1-M acetate buffer, pH 4.0, was added. The samples were thoroughly mixed, and 1.5-mL aliquots of the buffered plasma were then transferred to separate tubes, frozen (−70°C), and protected from light. Rosuvastatin in plasma was determined by a validated method (Covance Laboratories, Madison, WI). Rosuvastatin and the internal standard were extracted from human plasma by a robotic liquid handling system in which plasma proteins were precipitated by the addition of an ethanol solution containing the internal standard. After evaporation under nitrogen, the residue was reconstituted and analyzed by liquid chromatography tandem mass spectometry (LC/MS/MS). This method's lower LOQ for rosuvastatin was 0.05 ng/mL using a 0.2-mL aliquot of plasma. The upper LOQ in undiluted samples was 100 ng/mL. Plasma dilutions of 1:10 have been validated to extend the working range for quantitation to 1000 ng/mL.
Rosuvastain, lopinavir, and ritonavir PK analyses were determined by noncompartmental methods (WinNonLin, v5.0.1; Pharsight Corporation, Mountain View, CA). Cmax, time to Cmax (Tmax), and concentration at 24 hours after dose (C24) were determined visually. AUC[0,τ] was determined using the linear-log trapezoidal rule. Total apparent oral clearance (CL/F) was determined as dose divided by AUC[0,τ]. Half-lives were calculated as 0.693 divided by λz, where λz is the terminal elimination rate constant.
Safety and Tolerability Assessments
Clinical adverse effects were assessed using a questionnaire. Subjects were asked to grade the severity of their adverse effect as mild (does not interfere with normal activities), moderate (interferes with normal activities to some extent), or serious (life threatening, requiring hospitalization, or persistent or significant disability/incapacity). Laboratory tests were performed at baseline and on all 3 intensive PK study visits. Clinical and laboratory adverse events were graded by study investigators using the 1992 Division of AIDS table for grading the severity of adult and pediatric adverse experiences.42
Each subject's fasting total cholesterol, high-density lipoprotein (HDL), and triglycerides were measured at baseline and on study days 7, 17, and 24. LDL was calculated as previously described.43
The primary endpoint for this study was rosuvastatin and lopinavir/ritonavir AUC[0,τ] and Cmax bioequivalence when given alone and in combination. The study was powered based on the expectation that 18 subjects would provide complete data, with 98% and 84% power for rosuvastatin AUC[0,τ] and Cmax, respectively, such that the 90% confidence interval for the geometric least square (GLS) means ratio would be contained within the interval of 0.7 to 1.43. This interval was used in several previous drug-drug interaction studies with rosuvastatin.44-48 The GLS means (and 90% confidence intervals) were determined for rosuvastatin, lopinavir, and ritonavir PK parameters. Paired t tests were done to clarify results.
Paired t tests were used to compare the percent change in lipids from baseline to phase 1 and the percent change from phase 2 to phase 3.
No adjustments were made for multiple comparisons. SAS version 9.1 (SAS Institute, Cary, NC) was used for data analyses.
Twenty subjects enrolled, and 15 completed all 3 phases of the study. Of the 5 subjects who were not included in PK analyses, 1 withdrew consent on day 10 because of personal reasons, 1 discontinued because of neutropenia, 1 was nonadherent with lopinavir/ritonavir, 1 discontinued because of rash, and 1 subject's rosuvastatin samples from day 7 were lost and thus unable to be quantified. Among the 15 volunteers who were eligible for PK analyses, 9 were female and 7 were on oral contraceptives. Three subjects were Hispanic, and all 3 were male. The remaining subjects were white. 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 rosuvastatin PK during phase 1 (monotherapy) and phase 3 (in combination with lopinavir/ritonavir) are shown in Table 1. Rosuvastatin AUC[0,τ] and Cmax were significantly increased with lopinavir/ritonavir (Fig. 1). All 15 patients had an increase in rosuvastatin Cmax (treatment ratios ranged from 1.83- to 20-fold for Cmax), and 14 of 15 had an increase in rosuvastatin AUC[0,τ] (treatment ratios ranged from 0.88- to 5.32-fold for AUC[0,τ]) with the addition of lopinavir/ritonavir. Rosuvastatin minimum concentration (Cmin) and half-life were unchanged by the addition of lopinavir/ritonavir. All 18 subjects who underwent intensive PK sampling on day 17 (for lopinavir/ritonavir) had rosuvastatin levels less than the lower LOQ of the assay (<0.05 ng/mL).
The lopinavir and ritonavir PK during phase 2 (monotherapy) and phase 3 (in combination with rosuvastatin) are shown in Table 2. The 90% confidence intervals for the AUC[0,τ] and Cmax of lopinavir were within the bioequivalence range of the US Food and Drug Administration (FDA). The Cmin of lopinavir decreased by 22% from phase 2 to phase 3 (P = 0.04). The AUC[0,τ] and Cmax of ritonavir were bioequivalent when given with or without rosuvastatin.
Safety and Tolerability
Clinical and laboratory adverse events are highlighted in Table 3. All clinical adverse events as graded by study subjects were considered mild or moderate in severity. The most commonly reported adverse effects were nausea/vomiting/abdominal pain and diarrhea reported during lopinavir/ritonavir monotherapy or with the combination. “Other” symptoms included 1 patient each with numbness and swollen eyes during phase 1 and with weakness and dark urine during phase 2 and 2 subjects with fatigue during phase 3.
Increases in total bilirubin were the most commonly observed laboratory abnormality, noted during all 3 phases of the study. Four study subjects experienced graded increases in CPK, including 1 Hispanic man with a CPK of 3300 U/L (16.9 × upper limit of normal [ULN]) on day 24. He was not symptomatic, he denied engaging in strenuous exercise, and his previous CPK values had been within normal limits. The value was repeated and confirmed.
As previously described, 2 subjects discontinued the study because of adverse events and were not included in PK analysis. One subject, a black woman, had severe neutropenia (absolute neutrophil count [ANC] of 600 cells/mm3) and a white blood cell (WBC) count of 2.5 cells/mm3 during the phase 2 intensive PK visit (day 17). Within 5 days of study discontinuation, her WBC count was 4.2 cells/mm3 and her ANC count was 1300 cells/mm3. Another subject, a white woman, developed a papular rash on the sides of her face, upper back, thorax, buttocks, and anterior and posterior portions of upper legs and arms on day 15.
The median (± interquartile range [IQR]) lipid values throughout the course of the study are shown in Figure 2. The median (range) baseline LDL for study subjects was 88 mg/dL (61 to 143 mg/dL [2.29 mmol/L: 1.58 to 3.7 mmol/L]). LDL 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).
This study found a 4.7- and 2.1-fold increase in rosuvastatin Cmax and AUC[0,τ], respectively, when given with lopinavir/ritonavir. This interaction was unexpected, and the mechanism(s) has yet to be determined.
AIDS Clinical Trials Group study A5047 showed that in healthy volunteers, simvastatin acid, atorvastatin, and total active atorvastatin AUCs were increased 3059%, 347%, and 79%, respectively, when combined with 400 mg/400 mg of saquinavir/ritonavir given twice daily.49 Atorvastatin and simvastatin are highly dependent on CYP3A4 for metabolism; thus, in the presence of ritonavir, a potent CYP3A4 inhibitor, they accumulate. Unlike simvastatin and atorvastatin, rosuvastatin does not undergo a significant amount of CYP-mediated metabolism. Less than 10% of a dose is metabolized, primarily by CYP2C9 and to a lesser extent by CYP2C19 and CYP3A4, to N-desmethyl rosuvastatin (active) and rosuvastatin-5S-lactone (inactive).50 Most (∼90%) of an orally administered dose of rosuvastatin is excreted in urine and feces as unchanged drug. Previous drug interaction studies with CYP enzyme inhibitors support the minimal contribution of metabolism to the disposition of rosuvastatin. For example, coadministration of fluconazole (a potent CYP2C9 inhibitor) produces only slight increases in rosuvastatin AUC and Cmax.44 Concomitant administration of ketoconazole (a potent CYP3A4 inhibitor) does not alter rosuvastatin concentrations.48 Thus, it is unlikely that the inhibition of CYP3A4 (or another CYP enzyme) by lopinavir or ritonavir led to the elevated concentrations of rosuvastatin observed in this study.
Compounds that have been shown to interact with rosuvastatin (and other statins) significantly are gemfibrozil47 and cyclosporine.51 Gemfibrozil increased rosuvastatin AUC and Cmax 1.88- and 2.21-fold, respectively, after 80 mg of rosuvastatin.47 Cyclosporine increased rosuvastatin AUC and Cmax 7.1- and 10.6-fold, respectively, after 10 mg of rosuvastatin in heart transplant recipients compared with historical values.51 Gemfibrozil and cyclosporine are weak CYP2C9 and CYP3A4 inhibitors, respectively; thus, these interactions with rosuvastatin are not likely mediated by CYP. It is likely that these interactions are mediated by drug transporters. Cyclosporine and gemfibrozil are inhibitors of the hepatic human organic anion transporting polypeptide 1B1 (OATP1B1), also known as OAPTC or OATP2. Shitara and colleagues52 previously demonstrated that cyclosporine inhibition of OATP1B1 was the major mechanism for an interaction with another statin. Cyclosporine has also been shown in vitro to inhibit breast cancer resistance protein (BCRP).53,54
OATP1B1 is a liver-specific transporter localized to the basolateral membrane of the hepatocytes. OATP1B1 plays a pivotal role in the distribution, elimination, and clinical efficacy of statins. Rosuvastatin is a high-affinity substrate for OATP1B1 (km = 7.3 μM),55-57 and genetic polymorphisms in the SLCO1B1 gene (which encodes OATP1B1) have been shown to alter rosuvastatin PK significantly.58,59 Rosuvastatin is also a substrate for BCRP (km = 10.3 μM).60 BCRP is localized to the apical side of many tissues, including the small intestine and the liver. Genetic polymorphisms in BCRP have also been shown to alter rosuvastatin PK.61
In our study, lopinavir/ritonavir did not alter rosuvastatin's plasma half-life. This is evidence that this drug-drug interaction is not secondary to an inhibition of metabolism. As shown in Table 1, this interaction is most likely attributable to a change in bioavailability, because rosuvastatin clearance and volume of distribution decreased to a similar extent with the addition of lopinavir/ritonavir. The same phenomenon occurred with the interactions between cyclosporine and rosuvastatin and between gemfibrozil and rosuvastatin.47,51 It is uncertain whether it is the lopinavir, ritonavir, or both drugs that are responsible for inhibiting rosuvastatin transport. Interaction data with pravastatin, another statin with similar physiochemical properties to rosuvastatin, does not shed light on the potential mechanism(s). Pravastatin AUC is reduced 50% with saquinavir/ritonavir at a dose of 400 mg/400 mg twice daily.49 Conversely, when pravastatin is given with lopinavir/ritonavir at a dose of 400 mg/100 mg twice daily, pravastatin exposure is not significantly altered.62 Darunavir/ritonavir at a dose of 600 mg/100 mg has also been shown to increase pravastatin AUC and Cmax 81% and 63%, respectively.63
It is not possible to ascertain from our study the precise mechanism for this interaction. The interaction observed in our study may be mediated by the inhibition by lopinavir and/or ritonavir of rosuvastatin uptake at the level of absorption by BCRP or at the level of uptake into the hepatocytes by OATP1B1, by both, or by neither. Ritonavir has been shown to inhibit the transport of 17β-estradiol glucuronide, an OATP1B1 substrate, in vitro.64,65 To our knowledge, there are no data on lopinavir's potential to inhibit OATP1B1. Ritonavir has also been shown to inhibit BCRP.66 Ritonavir is also an inhibitor of P-glycoprotein (P-gp).67 Although atorvastatin and simvastatin are P-gp substrates rosuvastatin is not.60 This is confirmed by the fact that digoxin, a P-gp inhibitor, does not significantly increase rosuvastatin concentrations.68 Rosuvastatin is also a substrate for other basolaterally located hepatic transporters, including OATP1B3, OATP2B1, OATP1A2, and sodium-dependent taurocholate cotransporting polypeptide.69 Our lipid findings suggest that this interaction is most likely mediated by OATP1B1. The potential implications of the observed interaction occurring by means of the inhibition of OATP1B1 by lopinavir and/or ritonavir are that much of rosuvastatin may not reach the hepatocyte, its site of action, and elimination; thus, rosuvastatin plasma concentrations rise but with attenuated lipid-lowering effects. This phenomenon has been previously observed in transplant patients on cyclosporine and pravastatin.70-72 Although our study was not powered to examine the effect of this combination on serum lipids, when rosuvastatin was given in combination with lopinavir/ritonavir, the LDL-lowering effects of rosuvastatin were attenuated as compared to when rosuvastatin was given alone. Because the therapeutic effects of rosuvastatin seem to be diminished despite elevated plasma concentrations, lowering the rosuvastatin dosage in combination with lopinavir/ritonavir may not alleviate this interaction. This strategy may still be worthy of investigation, however, because our study included HIV-seronegative healthy volunteers with normal lipids on rosuvastatin for only 7 days when fasting lipids were determined. After 1 week of statin therapy only 70% of the maximal lipid-lowering effect is expected to be achieved.73 Furthermore, our data suggest that higher rosuvastatin doses would produce extremely high rosuvastatin concentrations.
Rosuvastatin may also have a different benefit-to-risk ratio in patients on lopinavir/ritonavir than in those on rosuvastatin monotherapy.74 Increased plasma exposures to statins, including rosuvastatin, have been shown to lead to adverse effects, including serum CPK elevations with myalgias or rhabdomyolysis with renal failure.40 All clinical adverse events in our study were scored as mild to moderate in severity by the participants. The most concerning laboratory abnormality was an asymptomatic CPK elevation 17 times the ULN in 1 Hispanic man receiving the combination of rosuvastatin and lopinavir/ritonavir. In contrast, in an observational study in 16 HIV-infected patients receiving 10 mg of rosuvastatin once daily in combination with antiretroviral drugs, including 7 patients on lopinavir/ritonavir, neither myalgias nor myositis was observed and no significant laboratory adverse events, including CPK elevations, were reported.75
Additional protease inhibitor-rosuvastatin interaction and in vitro studies are needed to establish the precise mechanism of this interaction. These in vitro studies should determine the potential for protease inhibitors to inhibit OATP1B1 and other transporters. Studies to ascertain the safety, efficacy, and appropriate dosing of the combination of rosuvastatin and lopinavir/ritonavir are also warranted. In the meantime, the combination of rosuvastatin and lopinavir/ritonavir should be administered with caution.
The authors acknowledge the study participants and the nurses and staff of the University of Colorado Hospital General Clinical Research Center; Thomas Delahunty, PhD, University of Colorado Antiviral Pharmacology Laboratory (Courtney V. Fletcher, PharmD, Director), for analyzing the lopinavir and ritonavir concentrations; Connie Azumaya, MS, Astra Zeneca, for supplying the rosuvastatin concentrations; and Susan Trieu, PharmD, for her assistance with and support of this project.
1. Aberg JA. The changing face of HIV care: common things really are common. Ann Intern Med
2. Riddler SA, Smit E, Cole SR, et al. Impact of HIV infection and HAART on serum lipids in men. JAMA
3. Grunfeld C, Pang M, Doerrler W, et al. Lipids, lipoproteins, triglyceride clearance, and cytokines in human immunodeficiency virus infection and the acquired immunodeficiency syndrome. J Clin Endocrinol Metab
4. Carr A, Samaras K, Burton S, et al. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS
5. Sadler BM, Piliero PJ, Preston SL, et al. Pharmacokinetics and safety of amprenavir and ritonavir following multiple-dose, co-administration to healthy volunteers. AIDS
6. Purnell JQ, Zambon A, Knopp RH, et al. Effect of ritonavir on lipids and post-heparin lipase activities in normal subjects. AIDS
7. Periard D, Telenti A, Sudre P, et al. Atherogenic dyslipidemia in HIV-infected individuals treated with protease inhibitors. The Swiss HIV Cohort Study. Circulation
8. Levy AR, McCandless L, Harrigan PR, et al. Changes in lipids over twelve months after initiating protease inhibitor therapy among persons treated for HIV/AIDS. Lipids Health Dis
9. Lee GA, Seneviratne T, Noor MA, et al. The metabolic effects of lopinavir/ritonavir in HIV-negative men. AIDS
10. Shafran SD, Mashinter LD, Roberts SE. The effect of low-dose ritonavir monotherapy on fasting serum lipid concentrations. HIV Med
11. Carr A, Samaras K, Chisholm DJ, et al. Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance. Lancet
12. Calza L, Manfredi R, Farneti B, et al. Incidence of hyperlipidaemia in a cohort of 212 HIV-infected patients receiving a protease inhibitor-based antiretroviral therapy. Int J Antimicrob Agents
13. Grinspoon S, Carr A. Cardiovascular risk and body-fat abnormalities in HIV-infected adults. N Engl J Med
14. Holmberg SD, Moorman AC, Williamson JM, et al. Protease inhibitors and cardiovascular outcomes in patients with HIV-1. Lancet
15. Mary-Krause M, Cotte L, Simon A, et al. Increased risk of myocardial infarction with duration of protease inhibitor therapy in HIV-infected men. AIDS
16. Friis-Moller N, Sabin CA, Weber R, et al. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med
17. Currier JS, Taylor A, Boyd F, et al. Coronary heart disease in HIV-infected individuals. J Acquir Immune Defic Syndr
18. Barbaro G, Di Lorenzo G, Cirelli A, et al. An open-label, prospective, observational study of the incidence of coronary artery disease in patients with HIV infection receiving highly active antiretroviral therapy. Clin Ther
19. Sackoff JE, Hanna DB, Pfeiffer MR, et al. Causes of death among persons with AIDS in the era of highly active antiretroviral therapy: New York City. Ann Intern Med
20. Lewden C, Salmon D, Morlat P, et al. Causes of death among human immunodeficiency virus (HIV)-infected adults in the era of potent antiretroviral therapy: emerging role of hepatitis and cancers, persistent role of AIDS. Int J Epidemiol
21. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. J Am Coll Cardiol
22. Dube MP, Stein JH, Aberg JA, et al. 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 Dis
23. Fichtenbaum CJ, Gerber JG. Interactions between antiretroviral drugs and drugs used for the therapy of the metabolic complications encountered during HIV infection. Clin Pharmacokinet
24. Hsu A, Granneman GR, Bertz RJ. Ritonavir. Clinical pharmacokinetics and interactions with other anti-HIV agents. Clin Pharmacokinet
25. Kantola T, Kivisto KT, Neuvonen PJ. Effect of itraconazole on the pharmacokinetics of atorvastatin. Clin Pharmacol Ther
26. Aboulafia DM, Johnston R. Simvastatin-induced rhabdomyolysis in an HIV-infected patient with coronary artery disease. AIDS Patient Care STDS
27. Mah Ming JB, Gill MJ. Drug-induced rhabdomyolysis after concomitant use of clarithromycin, atorvastatin, and lopinavir/ritonavir in a patient with HIV. AIDS Patient Care STDS
28. Hare CB, Vu MP, Grunfeld C, et al. Simvastatin-nelfinavir interaction implicated in rhabdomyolysis and death. Clin Infect Dis
30. Mallon PW, Miller J, Kovacic JC, et al. Effect of pravastatin on body composition and markers of cardiovascular disease in HIV-infected men-a randomized, placebo-controlled study. AIDS
31. Moyle GJ, Lloyd M, Reynolds B, et al. Dietary advice with or without pravastatin for the management of hypercholesterolaemia associated with protease inhibitor therapy. AIDS
32. Benesic A, Zilly M, Kluge F, et al. Lipid lowering therapy with fluvastatin and pravastatin in patients with HIV infection and antiretroviral therapy: comparison of efficacy and interaction with indinavir. Infection
33. Stein JH, Merwood MA, Bellehumeur JL, et al. Effects of pravastatin on lipoproteins and endothelial function in patients receiving human immunodeficiency virus protease inhibitors. Am Heart J
34. Murillas J, Martin T, Ramos A, et al. Atorvastatin for protease inhibitor-related hyperlipidaemia. AIDS
35. Calza L, Manfredi R, Chiodo F. Statins and fibrates for the treatment of hyperlipidaemia in HIV-infected patients receiving HAART. AIDS
36. Doser N, Kubli S, Telenti A, et al. Efficacy and safety of fluvastatin in hyperlipidemic protease inhibitor-treated HIV-infected patients. AIDS
37. Baldini F, Di Giambenedetto S, Cingolani A, et al. Efficacy and tolerability of pravastatin for the treatment of HIV-1 protease inhibitor-associated hyperlipidaemia: a pilot study. AIDS
38. Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA
39. Ballantyne CM, Bertolami M, Hernandez Garcia HR, et al. Achieving LDL cholesterol, non-HDL cholesterol, and apolipoprotein B target levels in high-risk patients: Measuring Effective Reductions in Cholesterol Using Rosuvastatin therapY (MERCURY) II. Am Heart J
40. Davidson MH, Clark JA, Glass LM, et al. Statin safety: an appraisal from the adverse event reporting system. Am J Cardiol
41. Jones PH, Davidson MH, Stein EA, et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial). Am J Cardiol
43. Stone NJ, Bilek S, Rosenbaum S. Recent National Cholesterol Education Program Adult Treatment Panel III update: adjustments and options. Am J Cardiol
44. Cooper KJ, Martin PD, Dane AL, et al. The effect of fluconazole on the pharmacokinetics of rosuvastatin. Eur J Clin Pharmacol
45. Cooper KJ, Martin PD, Dane AL, et al. Effect of itraconazole on the pharmacokinetics of rosuvastatin. Clin Pharmacol Ther
46. Cooper KJ, Martin PD, Dane AL, et al. The effect of erythromycin on the pharmacokinetics of rosuvastatin. Eur J Clin Pharmacol
47. Schneck DW, Birmingham BK, Zalikowski JA, et al. The effect of gemfibrozil on the pharmacokinetics of rosuvastatin. Clin Pharmacol Ther
48. Cooper KJ, Martin PD, Dane AL, et al. Lack of effect of ketoconazole on the pharmacokinetics of rosuvastatin in healthy subjects. Br J Clin Pharmacol
49. Fichtenbaum CJ, Gerber JG, Rosenkranz SL, et al. Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers: ACTG Study A5047. AIDS
50. Martin PD, Warwick MJ, Dane AL, et al. Metabolism, excretion, and pharmacokinetics of rosuvastatin in healthy adult male volunteers. Clin Ther
51. Simonson SG, Raza A, Martin PD, et al. Rosuvastatin pharmacokinetics in heart transplant recipients administered an antirejection regimen including cyclosporine. Clin Pharmacol Ther
52. Shitara Y, Itoh T, Sato H, et al. Inhibition of transporter-mediated hepatic uptake as a mechanism for drug-drug interaction between cerivastatin and cyclosporin A. J Pharmacol Exp Ther
53. Gupta A, Dai Y, Vethanayagam RR, et al. Cyclosporin A, tacrolimus and sirolimus are potent inhibitors of the human breast cancer resistance protein (ABCG2) and reverse resistance to mitoxantrone and topotecan. Cancer Chemother Pharmacol
54. Xia CQ, Liu N, Miwa GT, et al. Interactions of cyclosporin a with breast cancer resistance protein. Drug Metab Dispos
55. Hsiang B, Zhu Y, Wang Z, et al. A novel human hepatic organic anion transporting polypeptide (OATP2). Identification of a liver-specific human organic anion transporting polypeptide and identification of rat and human hydroxymethylglutaryl-CoA reductase inhibitor transporters. J Biol Chem
56. McTaggart F. Comparative pharmacology of rosuvastatin. Atheroscler Suppl
57. Brown CD, Windass AS, Bleasby K, et al. Rosuvastatin is a high affinity substrate of hepatic organic anion transporter OATP-C [abstract P174]. Atheroscler Suppl
58. Lee E, Ryan S, Birmingham B, et al. Rosuvastatin pharmacokinetics and pharmacogenetics in white and Asian subjects residing in the same environment. Clin Pharmacol Ther
59. Pasanen MK, Fredrikson H, Neuvonen PJ, et al. Different effects of SLCO1B1 polymorphism on the pharmacokinetics of atorvastatin and rosuvastatin. Clin Pharmacol Ther
60. Huang L, Wang Y, Grimm S. ATP-dependent transport of rosuvastatin in membrane vesicles expressing breast cancer resistance protein. Drug Metab Dispos
61. Zhang W, Yu BN, He YJ, et al. Role of BCRP 421C>A polymorphism on rosuvastatin pharmacokinetics in healthy Chinese males. Clin Chim Acta
62. Carr RA, Andre AK, Bertz RJ. Concomitant administration of ABT-378/ritonavir results in a clinically important pharmacokinetic interaction with atorvastatin but not pravastatin [abstract 1644]. Presented at: 40th Conference on Antimicrobial Agents and Chemotherapy; 2000; Toronto.
63. Sekar VJ, Spinosa-Guzman S, Marien K, et al. Pharmacokinetic drug-drug interaction between the new HIV protease inhibitor darunavir (TMC114) and the lipid-lowering agent pravastatin [abstract 54]. Presented at: Eight International Workshop on Clinical Pharmacology of HIV Therapy; 2007; Budapest.
64. Tirona RG, Leake BF, Wolkoff AW, et al. Human organic anion transporting polypeptide-C (SLC21A6) is a major determinant of rifampin-mediated pregnane X receptor activation. J Pharmacol Exp Ther
65. Smith NF, Figg WD, Sparreboom A. Role of the liver-specific transporters OATP1B1 and OATP1B3 in governing drug elimination. Expert Opin Drug Metab Toxicol
66. Gupta A, Zhang Y, Unadkat JD, et al. HIV protease inhibitors are inhibitors but not substrates of the human breast cancer resistance protein (BCRP/ABCG2). J Pharmacol Exp Ther
67. Gutmann H, Fricker G, Drewe J, et al. Interactions of HIV protease inhibitors with ATP-dependent drug export proteins. Mol Pharmacol
68. Martin PD, Kemp J, Dane AL, et al. No effect of rosuvastatin on the pharmacokinetics of digoxin in healthy volunteers. J Clin Pharmacol
69. Ho RH, Tirona RG, Leake BF, et al. Drug and bile acid transporters in rosuvastatin hepatic uptake: function, expression, and pharmacogenetics. Gastroenterology
70. Hedman M, Neuvonen PJ, Neuvonen M, et al. Pharmacokinetics and pharmacodynamics of pravastatin in pediatric and adolescent cardiac transplant recipients on a regimen of triple immunosuppression. Clin Pharmacol Ther
71. Asberg A, Hartmann A, Fjeldsa E, et al. Bilateral pharmacokinetic interaction between cyclosporine A and atorvastatin in renal transplant recipients. Am J Transplant
72. Olbricht C, Wanner C, Eisenhauer T, et al. Accumulation of lovastatin, but not pravastatin, in the blood of cyclosporine-treated kidney graft patients after multiple doses. Clin Pharmacol Ther
73. Schneck DW, Knopp RH, Ballantyne CM, et al. Comparative effects of rosuvastatin and atorvastatin across their dose ranges in patients with hypercholesterolemia and without active arterial disease. Am J Cardiol
74. Neuvonen PJ, Niemi M, Backman JT. Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther
75. Calza L, Colangeli V, Manfredi R, et al. Rosuvastatin for the treatment of hyperlipidaemia in HIV-infected patients receiving protease inhibitors: a pilot study. AIDS
This article has been cited 25 time(s).
Aaps JournalDrug-Drug Interaction Studies: Regulatory Guidance and An Industry PerspectiveAaps Journal
Expert Opinion on Drug Metabolism & ToxicologyModel-based approaches to predict drug-drug interactions associated with hepatic uptake transporters: preclinical, clinical and beyondExpert Opinion on Drug Metabolism & Toxicology
Expert Opinion on Drug Metabolism & ToxicologyEffect of the ATP-binding cassette transporter ABCG2 on pharmacokinetics: experimental findings and clinical implicationsExpert Opinion on Drug Metabolism & Toxicology
Biopharmaceutics & Drug DispositionInteraction between HIV protease inhibitors (PIs) and hepatic transporters in sandwich cultured human hepatocytes: implication for PI-based DDIsBiopharmaceutics & Drug Disposition
Drug Metabolism and PharmacokineticsAnalysis of the Pharmacokinetic Boosting Effects of Ritonavir on Oral Bioavailability of Drugs in MiceDrug Metabolism and Pharmacokinetics
Expert Opinion on PharmacotherapyRosuvastatin: efficacy, safety and clinical effectivenessExpert Opinion on Pharmacotherapy
Journal of Clinical Endocrinology & MetabolismApproach to the human immunodeficiency virus-infected patient with lipodystrophyJournal of Clinical Endocrinology & Metabolism
Nature Reviews Drug DiscoveryMembrane transporters in drug developmentNature Reviews Drug Discovery
American Journal of Cardiovascular Drugs
Rosuvastatin-Associated Adverse Effects and Drug-Drug Interactions in the Clinical Setting of Dyslipidemia
American Journal of Cardiovascular Drugs, 10(1):
Endocrinology and Metabolism Clinics of North AmericaLipid Management in Patients Who Have HIV and Are Receiving HIV TherapyEndocrinology and Metabolism Clinics of North America
British Journal of PharmacologyEffects of cytochrome P450 3A (CYP3A) and the drug transporters P-glycoprotein (MDR1/ABCB1) and MRP2 (ABCC2) on the pharmacokinetics of lopinavirBritish Journal of Pharmacology
Antiviral TherapyPrevalence of comedications and effect of potential drug-drug interactions in the Swiss HIV Cohort StudyAntiviral Therapy
Expert Opinion on Drug SafetyNephrotoxicity associated with antiretroviral therapy in HIV-infected patientsExpert Opinion on Drug Safety
XenobioticaInteraction of HIV protease inhibitors with OATP1B1, 1B3, and 2B1Xenobiotica
Antimicrobial Agents and ChemotherapyDifferential Effects of Tipranavir plus Ritonavir on Atorvastatin or Rosuvastatin Pharmacokinetics in Healthy VolunteersAntimicrobial Agents and Chemotherapy
Journal of Antimicrobial ChemotherapyAntiretroviral drug interactions: often unrecognized, frequently unavoidable, sometimes unmanageableJournal of Antimicrobial Chemotherapy
Molecular PharmaceuticsScientific and Regulatory Perspectives on Metabolizing Enzyme-Transporter Interplay and Its Role in Drug Interactions: Challenges in Predicting Drug InteractionsMolecular Pharmaceutics
European Journal of Clinical PharmacologySuccessful strategy to improve the specificity of electronic statin-drug interaction alertsEuropean Journal of Clinical Pharmacology
Current Medical Research and OpinionA study of the pharmacokinetic interactions of the direct renin inhibitor aliskiren with metformin, pioglitazone and fenofibrate in healthy subjectsCurrent Medical Research and Opinion
Toxicology and Applied PharmacologyDrug interactions evaluation: An integrated part of risk assessment of therapeuticsToxicology and Applied Pharmacology
Drug Metabolism and DispositionIn Vitro Assessment of Drug-Drug Interaction Potential of Boceprevir Associated with Drug Metabolizing Enzymes and TransportersDrug Metabolism and Disposition
High-throughput Screening of Inhibitory Effects of Bo-yang-hwan-o-tang on Human Cytochrome P450 Isoforms in vitro Using UPLC/MS/MS
Analytical Sciences, 28():
Cardiology in ReviewAntiretroviral and Statin Drug-Drug InteractionsCardiology in Review
JAIDS Journal of Acquired Immune Deficiency SyndromesCardiovascular Complications in HIV Management: Past, Present, and FutureJAIDS Journal of Acquired Immune Deficiency Syndromes
JAIDS Journal of Acquired Immune Deficiency SyndromesGemfibrozil Concentrations Are Significantly Decreased in the Presence of Lopinavir-RitonavirJAIDS Journal of Acquired Immune Deficiency Syndromes
interaction; lopinavir/ritonavir; pharmacokinetics; organic anion transporting polypeptide 1B1; rosuvastatin; SLCO1B1
© 2008 Lippincott Williams & Wilkins, Inc.
Highlight selected keywords in the article text.