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.
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Keywords:© 2008 Lippincott Williams & Wilkins, Inc.
interaction; lopinavir/ritonavir; pharmacokinetics; organic anion transporting polypeptide 1B1; rosuvastatin; SLCO1B1