Evaluation of the pharmacokinetics and drug interactions of the two recently developed statins, rosuvastatin and pitavastatin.

INTRODUCTION: Statins are the cornerstone of lipid-lowering therapy to reduce the risk of coronary heart disease. Rosuvastatin and pitavastatin are the two recently developed statins with less potential for drug interaction resulting in improved safety profiles. AREAS COVERED: This review summarizes the pharmacokinetics and drug interactions of rosuvastatin and pitavastatin. The materials reviewed were identified by searching PubMed for publications using 'rosuvastatin', 'pitavastatin', 'statins', 'pharmacokinetics' and 'drug interaction' as the search terms. EXPERT OPINION: Rosuvastatin and pitavastatin have favorable pharmacokinetic and safety profiles as their disposition does not depend on or is only marginally influenced by cytochrome P450 (CYP) enzymes, thus potentially reducing the risk of drug-drug interactions of these two statins with other drugs known to inhibit CYP enzymes. However, drug transporters play a significant role in the disposition of rosuvastatin and pitavastatin and drug interactions may occur through these. Genetic polymorphisms in drug transporters may also affect the pharmacokinetics, drug interactions and/or the lipid-lowering effect of these statins to a different extent.

Model-based approaches to predict drug-drug interactions associated with hepatic uptake transporters: preclinical, clinical and beyond.

INTRODUCTION: Membrane transporters have been recognized to play a key role in determining the absorption, distribution and elimination processes of drugs. The organic anion-transporting polypeptide (OATP)1B1 and OATP1B3 isoforms are selectively expressed in the human liver and are known to cause significant drug-drug interactions (DDIs), as observed with an increasing number of drugs. It is evident that DDIs involving hepatic transporters are capable of altering systemic, as well as tissue-specific, exposure of drug substrates resulting in marked differences in drug safety and/or efficacy. It is therefore essential to quantitatively predict such interactions early in the drug development to mitigate clinical risks. AREAS COVERED: The role of hepatic uptake transporters in drug disposition and clinical DDIs has been reviewed with an emphasis on the current state of the models applicable for quantitative predictions. The readers will also gain insight into the in vitro experimental tools available to characterize transport kinetics, while appreciating the knowledge gaps in the in vitro-in vivo extrapolation (IVIVE), which warrant further investigation. EXPERT OPINION: Static and dynamic models can be convincingly applied to quantitatively predict drug interactions, early in drug discovery, to mitigate clinical risks as well as to avoid unnecessary clinical studies. Compared to basic models, which focus on individual processes, mechanistic models provide the ability to assess DDI potential for compounds with systemic disposition determined by both transporters and metabolic enzymes. However, complexities in the experimental tools and an apparent disconnect in the IVIVE of transport kinetics have limited the physiologically based pharmacokinetic modeling strategies. Emerging data on the expression of transporter proteins and tissue drug concentrations are expected to help bridge these gaps. In addition, detailed characterization of substrate kinetics can facilitate building comprehensive mechanistic models.

Effects of piperine, cinnamic acid and gallic acid on rosuvastatin pharmacokinetics in rats.

The purpose of this study was to investigate the potential pharmacokinetic interactions with natural products (such as piperine (PIP), gallic acid (GA) and cinnamic acid (CA)) and rosuvastatin (RSV) (a specific breast cancer resistance protein, BCRP substrate) in rats. In Caco2 cells, the polarized transport of RSV was effectively inhibited by PIP, CA and GA at concentration of 50 µM. After per oral (p.o.) coadministration of PIP, CA and GA (10 mg/kg) significantly increased intravenous exposure (AUC(last)) of RSV (1 mg/kg) by 73.5%, 62.9% and 53.3% (p < 0.05), respectively than alone group (control). Compared with the control (alone) group, p.o. coadministration of PIP, CA and GA (10 mg/kg) significantly increased the oral exposure (AUC(last)) of RSV (5 mg/kg) by 2.0-fold, 1.83-fold (p < 0.05) and 2.34 -fold (p < 0.05), respectively. Moreover, the cumulative biliary excretion of RSV (5 mg/kg, p.o.) was significantly decreased by 53.3, 33.4 and 39.2% at the end of 8 h after p.o. co-administration of PIP, CA and GA (10 mg/kg), respectively. Taken together, these results indicate that the natural products such as PIP, CA and GA significantly inhibit RSV transport in to bile and increased the plasma exposure (AUC(last)) of RSV.

The effect of herbal medicine danshensu and ursolic acid on pharmacokinetics of rosuvastatin in rats.

The aim of this study was to explore potential herb-drug interaction between danshensu or ursolic acid and rosuvastatin. Compared to the control group given rosuvastatin alone, the concurrent use of danshensu (46 mg/kg) or ursolic acid (80 mg/kg) prior to the oral administration of rosuvastatin (100 mg/kg) increased the systemic exposure of rosuvastatin more than twofold. The plasma clearance of rosuvastatin was reduced to more than 57% in the presence of danshensu or ursolic acid. Rosuvastatin is minimally metabolized in the CYP2C9 isoenzyme pathway and to an even lesser extent in the CYP2C19 isoenzyme pathway. Rosuvastatin is a substrate of drug transporters such as human OATP1B1, OATP 1B3, OATP 1A2, BCRP and NTCP. Therefore, the present results suggested that the potential drug interaction between danshensu or ursolic acid and rosuvastatin may be mediated by one or more transporters (OATP1B1, OATP 1B3, OATP 1A2, BCRP and NTCP) and/or CYPs.

Race differences: modeling the pharmacodynamics of rosuvastatin in Western and Asian hypercholesterolemia patients.

AIM: To evaluate race differences in the pharmacodynamics of rosuvastatin in Western and Asian hypercholesterolemia patients using a population pharmacodynamic (PPD) model generated and validated using published clinical efficacy trials. METHODS: Published studies randomized trials with rosuvastatin treatment for at least 4 weeks in hypercholesterolemia patients were used for model building and validation. Population pharmacodynamic analyses were performed to describe the dose-response relationship with the mean values of LDL-C reduction (%) from dose-ranging trials using NONMEM software. Baseline LDL-C and race were analyzed as the potential covariates. Model robustness was evaluated using the bootstrap method and the data-splitting method, and Monte Carlo simulation was performed to assess the predictive performance of the PPD model with the mean effects from the one-dose trials. RESULTS: Of the 36 eligible trials, 14 dose-ranging trials were used in model development and 22 one-dose trials were used for model prediction. The dose-response of rosuvastatin was successfully described by a simple E(max) model with a fixed E(0), which provided a common E(max) and an approximate twofold difference in ED(50) for Westerners and Asians. The PPD model was demonstrated to be stable and predictive. CONCLUSION: The race differences in the pharmacodynamics of rosuvastatin are consistent with those observed in the pharmacokinetics of the drug, confirming that there is no significant difference in the exposure-response relationship for LDL-C reduction between Westerners and Asians. The study suggests that for a new compound with a mechanism of action similar to that of rosuvastatin, its efficacy in Western populations plus its pharmacokinetics in bridging studies in Asian populations may be used to support a registration of the new compound in Asian countries.

Aleglitazar, a balanced PPARα/γ agonist, has no clinically relevant pharmacokinetic interaction with high-dose atorvastatin or rosuvastatin.

BACKGROUND: Aleglitazar, a dual PPAR-α/γ agonist, combines the lipid benefits of fibrates and the insulin-sensitizing benefits of thiazolidinediones. OBJECTIVE: To investigate the pharmacokinetic effects of co-administration of atorvastatin or rosuvastatin with aleglitazar. RESEARCH DESIGN AND METHODS: In a two-cohort, open-label, randomised, three-period crossover study, 44 healthy subjects received once-daily oral doses of aleglitazar 300 µg, statin (atorvastatin 80 mg or rosuvastatin 40 mg) and aleglitazar co-administered with each statin for 7 days. Plasma concentrations of each drug were measured and pharmacokinetic parameters determined on day 7 in each period. MAIN OUTCOME MEASURES: Peak observed plasma concentration (C(max)) and total exposures (AUC(0 - 24)) of aleglitazar, atorvastatin and rosuvastatin. RESULTS: C(max) and AUC(0 - 24) to aleglitazar were similar, whether administered alone or in combination with a statin. Total exposure to either statin was unaffected by co-administration with aleglitazar. C(max) treatment ratios for both statins exceeded the conventional no-effect boundary (1.25) when administered with aleglitazar. CONCLUSIONS: Co-administration of aleglitazar with a statin does not alter the pharmacokinetic profile of either drug.

Rosuvastatin-associated adverse effects and drug-drug interactions in the clinical setting of dyslipidemia.

HMG-CoA reductase inhibitors (statins) are the mainstay in the pharmacologic management of dyslipidemia. Since they are widely prescribed, their safety remains an issue of concern. Rosuvastatin has been proven to be efficacious in improving serum lipid profiles. Recently published data from the JUPITER study confirmed the efficacy of this statin in primary prevention for older patients with multiple risk factors and evidence of inflammation. Rosuvastatin exhibits high hydrophilicity and hepatoselectivity, as well as low systemic bioavailability, while undergoing minimal metabolism via the cytochrome P450 system. Therefore, rosuvastatin has an interesting pharmacokinetic profile that is different from that of other statins. However, it remains to be established whether this may translate into a better safety profile and fewer drug-drug interactions for this statin compared with others. Herein, we review evidence with regard to the safety of this statin as well as its interactions with agents commonly prescribed in the clinical setting. As with other statins, rosuvastatin treatment is associated with relatively low rates of severe myopathy, rhabdomyolysis, and renal failure. Asymptomatic liver enzyme elevations occur with rosuvastatin at a similarly low incidence as with other statins. Rosuvastatin treatment has also been associated with adverse effects related to the gastrointestinal tract and central nervous system, which are also commonly observed with many other drugs. Proteinuria induced by rosuvastatin is likely to be associated with a statin-provoked inhibition of low-molecular-weight protein reabsorption by the renal tubules. Higher doses of rosuvastatin have been associated with cases of renal failure. Also, the co-administration of rosuvastatin with drugs that increase rosuvastatin blood levels may be deleterious for the kidney. Furthermore, rhabdomyolysis, considered a class effect of statins, is known to involve renal damage. Concerns have been raised by findings from the JUPITER study suggesting that rosuvastatin may slightly increase the incidence of physician-reported diabetes mellitus, as well as the levels of glycated hemoglobin in older patients with multiple risk factors and low-grade inflammation. Clinical trials proposed no increase in the incidence of neoplasias with rosuvastatin treatment compared with placebo. Drugs that antagonize organic anion transporter protein 1B1-mediated hepatic uptake of rosuvastatin are more likely to interact with this statin. Clinicians should be cautious when rosuvastatin is co-administered with vitamin K antagonists, cyclosporine (ciclosporin), gemfibrozil, and antiretroviral agents since a potential pharmacokinetic interaction with those drugs may increase the risk of toxicity. On the other hand, rosuvastatin combination treatment with fenofibrate, ezetimibe, omega-3-fatty acids, antifungal azoles, rifampin (rifampicin), or clopidogrel seems to be safe, as there is no evidence to support any pharmacokinetic or pharmacodynamic interaction of rosuvastatin with any of these drugs. Rosuvastatin therefore appears to be relatively safe and well tolerated, sharing the adverse effects that are considered class effects of statins. Practitioners of all medical practices should be alert when rosuvastatin is prescribed concomitantly with agents that may increase the risk of rosuvastatin-associated toxicity.

ABT-335, the choline salt of fenofibric acid, does not have a clinically significant pharmacokinetic interaction with rosuvastatin in humans.

ABT-335 is the choline salt of fenofibric acid under clinical development as a combination therapy with rosuvastatin for the management of dyslipidemia. ABT-335 and rosuvastatin have different mechanisms of actions and exert complementary pharmacodynamic effects on lipids. The current study assessed the pharmacokinetic interaction between the 2 drugs following a multiple-dose, open-label, 3-period, randomized, crossover design. Eighteen healthy men and women received 40 mg rosuvastatin alone, 135 mg ABT-335 alone, and the 2 drugs in combination once daily for 10 days. Blood samples were collected prior to dosing on multiple days and up to 120 hours after day 10 dosing for the measurements of fenofibric acid and rosuvastatin plasma concentrations. Coadministering 40 mg rosuvastatin had no significant effect on the steady-state Cmax, Cmin, or AUC24 of fenofibric acid (P > .05). Coadministering ABT-335 had no significant effect on the steady-state Cmin or AUC24 of rosuvastatin (P > .05) but increased Cmax by 20% (90% confidence interval: 12%-28%). All 3 regimens were generally well tolerated with no clinically significant changes in clinical laboratory values, vital signs, or electrocardiograms during the study. Results from this study demonstrate no clinically significant pharmacokinetic interaction between ABT-335 at the full clinical dose and rosuvastatin at the highest approved dose.

Effect of silymarin supplement on the pharmacokinetics of rosuvastatin.

OBJECTIVES: To evaluate the effect of silymarin on the pharmacokinetics of rosuvastatin in systems overexpressing OATP1B1 or BCRP transporters and in healthy subjects. MATERIALS AND METHODS: The concentration-dependent transport of rosuvastatin and the inhibitory effect of silymarin were examined in vitro in OATP1B1-expressing oocytes and MDCKII-BCRP cells. For in vivo assessment, eight healthy male volunteers, divided into two groups, were randomly assigned to receive placebo or silymarin (140 mg) three times per day for 5 days. On day 4, all subjects received rosuvastatin (10 mg, 8 AM: ) 1 h after the placebo or silymarin administration. A series of blood samples were collected for 72 h, and the plasma concentration of rosuvastatin was determined using LC-MS/MS. RESULTS: Based on the concentration dependency of rosuvastatin transport in the OATP1B1 and BCRP overexpression systems, rosuvastatin is a substrate for both transporters. Silymarin inhibited both OATP1B1- and BCRP-mediated rosuvastatin transport in vitro (K (i) 0.93 microM and 97 microM, respectively). However, no significant changes in AUC, half-life, Vd/F, or Cl/F of rosuvastatin were observed in human subjects following pretreatment with silymarin. CONCLUSIONS: Silymarin does not appear to affect rosuvastatin pharmacokinetics in vivo, suggesting that silymarin, administered according to a recommended supplementation regimen, is not a potent modulator of OATP1B1 or BCRP in vivo.

The effect of herbal medicine baicalin on pharmacokinetics of rosuvastatin, substrate of organic anion-transporting polypeptide 1B1.

The aim of this study was to explore potential herb-drug interaction between baicalin and rosuvastatin, a typical substrate for organic anion-transporting polypeptide 1B1 (OATP1B1) related to different OATP1B1 haplotype groups. Eighteen unrelated healthy volunteers who were CYP2C9*1/*1 with different OATP1B1 haplotypes (six OATP1B1*1b/*1b, six OATP1B1*1b/*15, and six OATP1B1*15/*15) were selected to participate in this study. Rosuvastatin (20 mg orally) pharmacokinetics after coadministration of placebo and 50-mg baicalin tablets (three times daily orally for 14 days) were measured for up to 72 h by liquid chromatography-mass spectrometry in a two-phase randomized crossover study. After baicalin treatment, the area under the plasma concentration-time curve (AUC)(0-72) and AUC(0-infinity) of rosuvastatin decreased by 47.0+/-11.0% (P=0.001) and 41.9+/-7.19% (P=0.001) in OATP1B1*1b/*1b, 21.0+/-20.6% (P=0.035) and 23.9+/-8.66% (P=0.004) in OATP1B1*1b/*15, and 9.20+/-11.6% (P=0.077) and 1.76+/-4.89% (P=0.36) in OATP1B1*15/*15, respectively. Moreover, decreases of both AUC(0-72) and AUC(0-infinity) of rosuvastatin among different haplotype groups were significantly different (P=0.002 and <0.001). Baicalin reduces plasma concentrations of rosuvastatin in an OATP1B1 haplotype-dependent manner.

Use of LC/MS to assess brain tracer distribution in preclinical, in vivo receptor occupancy studies: dopamine D2, serotonin 2A and NK-1 receptors as examples.

High performance liquid chromatography combined with either single quad or triple quad mass spectral detectors (LC/MS) was used to measure the brain distribution of receptor occupancy tracers targeting dopamine D2, serotonin 5-HT2A and neurokinin NK-1 receptors using the ligands raclopride, MDL-100907 and GR205171, respectively. All three non-radiolabeled tracer molecules were easily detectable in discrete rat brain areas after intravenous doses of 3, 3 and 30 microg/kg, respectively. These levels showed a differential brain distribution caused by differences in receptor density, as demonstrated by the observation that pretreatment with compounds that occupy these receptors reduced this differential distribution in a dose-dependent manner. Intravenous, subcutaneous and oral dose-occupancy curves were generated for haloperidol at the dopamine D2 receptor as were oral curves for the antipsychotic drugs olanzapine and clozapine. In vivo dose-occupancy curves were also generated for orally administered clozapine, olanzapine and haloperidol at the cortical 5-HT2A binding site. In vivo occupancy at the striatal neurokinin NK-1 binding site by various doses of orally administered MK-869 was also measured. Our results demonstrate the utility of LC/MS to quantify tracer distribution in preclinical brain receptor occupancy studies.

Rodent pharmacokinetics and receptor occupancy of the GABAA receptor subtype selective benzodiazepine site ligand L-838417.

The pharmacokinetics of L-838417, a GABAA receptor subtype selective benzodiazepine site agonist, were studied in rats and mice after single oral (p.o.), intraperitoneal (i.p.) and intravenous (i.v.) doses. In both species L-838417 was well absorbed following i.p. administration and whilst in rats p.o. bioavailability was good (41%), in mice it was negligible (<1%), precluding this as a route of administration for mouse behavioural studies. Despite having a similar volume of distribution (ca 1.4 l/kg) in rats and mice, L-838417 was cleared at twice liver blood flow in mice (161 ml/min/kg) and moderately cleared in rats (24 ml/min/kg), potentially explaining the poor oral bioavailability in mice. Finally, as a pharmacodynamic readout the benzodiazepine binding site occupancy was determined in rats (0.3-3 mg/kg, p.o.) and mice (1-30 mg/kg, i.p.) using a [3H]Ro 15-1788 in vivo binding assay. Although the resulting dose-occupancy relationship for both species demonstrated a dose-dependent increase in receptor occupancy, appreciable variability was observed at low dose levels, potentially making interpretation of behavioural responses difficult. In contrast, a clear relationship between plasma and brain concentrations and receptor occupancy were determined suggesting the observed dose-occupancy variability is a consequence of the pharmacokinetic properties of L-838417. The plasma and brain concentrations required to occupy 50% of the benzodiazepine binding sites were similar in both rats (28 ng/ml and 33 ng/ml g, respectively) and mice (63 ng/ml and 53 ng/ml g, respectively), with a non-linear concentration response observed with increasing doses of L-838417. These studies demonstrate the importance of utilizing pharmacokinetic/receptor occupancy data when interpreting pharmacodynamic responses at a given dose.

[Pharmacologic characteristics of rosuvastatin, a new HMG-CoA reductase inhibitor]. / Caractéristiques pharmacologiques de la rosuvastatine, un nouvel antagoniste de l'HMG-CoA réductase.

Rosuvastatin is a new synthetic statin that produces a more potent and prolonged inhibition of HMG-CoA reductase than any of the other statins currently available. It is also characterised by a very low lipophilicity, which is close to that of pravastatin, and by a high hepatic selectivity. Rosuvastatin is not extensively metabolised, with little or no transformation by the different isoenzymes of cytochrome P450. It is mainly eliminated in the faeces, with an elimination half-life in humans of between 13 and 21 hours. In patients with hypercholesterolaemia, rosuvastatin was associated with large dose-dependent reductions in low density lipoprotein (LDL)-cholesterol, by 50.5% at a dose of 10 mg/day and up to 64.8% at a dose of 80 mg. Each doubling of the dose of rosuvastatin results in an additional 4.5% decrease in blood LDL-cholesterol. In phase III studies, rosuvastatin decreased LDL-cholesterol significantly more than atorvastatin, pravastatin and simvastatin. Compared with the other statins, the decrease in triglyceride levels was similar and the increase in high density lipoprotein-cholesterol was more marked, with a significant difference in most cases. To date, there has not been an excess of adverse reactions, especially liver or muscle problems, compared with the reference statins. The safety of rosuvastatin can only be definitively established in post-marketing surveys.