Cytochrome P450 3A4 Metabolism Research Articles

Effect of Mild or Moderate Hepatic Impairment on the Pharmacokinetics of Avacopan, a Small-Molecule Complement C5a Receptor Antagonist, for the Treatment of Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis.

Avacopan is currently approved in several regions of the world as an oral treatment in combination with standard therapy, including glucocorticoids, for adult patients with severe active antineutrophil cytoplasmic autoantibody-associated vasculitis. In vitro and clinical studies have established that avacopan is primarily eliminated through cytochrome P450 3A4 metabolism. This Phase 1, open-label, single-dose study (ClinicalTrials.gov identifier: NCT06004934) was conducted to evaluate the effect of mild (n=8) or moderate (n=8) hepatic impairment compared with normal hepatic function (n=8) on the pharmacokinetics, safety, and tolerability of a single oral dose of 30mg of avacopan in patients without active antineutrophil cytoplasmic autoantibody-associated vasculitis. Relative to participants with normal hepatic function, in participants with mild or moderate hepatic impairment, the avacopan area under the plasma concentration-time curve from time 0 to infinity geometric mean ratios (90% confidence intervals) were 1.3 (0.9-2.0) and 1.1(0.6-2.0), respectively, and the avacopan maximum plasma concentration geometric mean ratios (90% CIs) were 1.0(0.8-1.3) and 0.8 (0.6-1.1), respectively. The geometric mean ratios of metabolite M1 also revealed no pharmacokinetically relevant increase in the peak exposure of M1 in participants with mild or moderate hepatic impairment. Thus, no avacopan dosage adjustment is necessary for patients with mild or moderate hepatic impairment.

Physiologically Based Pharmacokinetic Modeling of the Drug-Drug Interaction Between CYP3A4 Substrate Glasdegib and Moderate CYP3A4 Inducers in Lieu of a Clinical Study.

Glasdegib (DAURISMO) is a hedgehog pathway inhibitor approved for the treatment of acute myeloid leukemia (AML). Cytochrome P450 3A4 (CYP3A4) has been identified as a major metabolism and clearance pathway for glasdegib. The role of CYP3A4 in the clearance of glasdegib has been confirmed with clinical drug-drug interaction (DDI) studies following the coadministration of glasdegib with the strong CYP3A4 inhibitor ketoconazole and the strong inducer rifampin. To evaluate potential drug interactions with CYP3A4 modulators, the coadministration of glasdegib with a moderate CYP3A4 inducer, efavirenz, was evaluated using physiologically based pharmacokinetic (PBPK) modeling using the Simcyp simulator. The glasdegib compound file was developed using measured physicochemical properties, data from human intravenous and oral pharmacokinetics, absorption, distribution, metabolism, and excretion studies, and invitro reaction phenotyping results. The modeling assumptions, model parameters, and assignments of fractional CYP3A4 metabolism were verified using results from clinical pharmacokinetics (PK) and DDI studies with ketoconazole and rifampin. The verified glasdegib and efavirenz compound files, the latter of which was available in the Simcyp simulator, were used to estimate the potential impact of efavirenz on the PK of glasdegib. PBPK modeling predicted a glasdegib area under the concentration-time curve ratio of 0.45 and maximum plasma concentration ratio of 0.75 following coadministration with efavirenz. The PBPK results, in lieu of a formal clinical study, informed the drug label, with the recommendation to double the clinical dose of glasdegib when administered in conjunction with a moderate CYP3A4 inducer, followed by a resumption of the original dose 7days post-discontinuation.

A Promising Approach to Treat Psoriasis: Inhibiting Cytochrome P450 3A4 Metabolism to Enhance Desoximetasone Therapy.

(1) Background: Human keratinocytes and murine skin express various cytochrome P450 enzymes. These include cytochrome P450 3A4, which may participate in the metabolism of cytochrome P450 3A4 substrate drugs. Desoximetasone, a topical corticosteroid and cytochrome P450 3A4 substrate, is used to treat skin conditions such as skin allergies, atopic dermatitis, and psoriasis. In this study, we aimed to investigate the anti-psoriatic effect of a low dose of desoximetasone by inhibiting cytochrome P450 3A4 metabolism in the epidermis. (2) Methods: Psoriasis-like skin was induced in BALB/c mice via the topical administration of imiquimod. The mice were then topically treated with 0.01-0.05% desoximetasone loaded into a cytochrome P450 3A4 enzyme inhibitor excipient base emollient microemulsion, 0.25% commercial desoximetasone ointment, or 0.5 mg/gm clobetasol ointment. (3) Results: The topical application of 0.05% desoximetasone loaded into a cytochrome P450 3A4 enzyme inhibitor excipient base emollient formulation restored the imiquimod-induced skin barrier disruption and resulted in fewer severe clinical and pathological features compared with the treatments with 0.25% commercial desoximetasone ointment and 0.5 mg/gm clobetasol ointment. (4) Conclusions: The cytochrome P450 3A4 enzyme inhibitor excipient base emollient formulation improved and prolonged the therapeutic effect of cytochrome P450 3A4 substrate drugs and may be a promising approach for psoriasis treatment.

1076 Enhanced the therapeutic effects of desoximetasone by inhibiting cytochrome P450 3A4 metabolism in the imiquimod-induced psoriasis animal model

1076 Enhanced the therapeutic effects of desoximetasone by inhibiting cytochrome P450 3A4 metabolism in the imiquimod-induced psoriasis animal model

Physiologically-based pharmacokinetic modeling to predict CYP3A4-mediated drug-drug interactions of finerenone.

Finerenone is a nonsteroidal, selective mineralocorticoid receptor antagonist that recently demonstrated its efficacy to delay chronic kidney disease (CKD) progression and reduce cardiovascular events in patients with CKD and type 2 diabetes. Here, we report the development of a physiologically‐based pharmacokinetic (PBPK) model for finerenone and its application as a victim drug of cytochrome P450 3A4 (CYP3A4)‐mediated drug‐drug interactions (DDIs) using the open‐source PBPK platform PK‐Sim, which has recently been qualified for this application purpose. First, the PBPK model for finerenone was developed using physicochemical, in vitro, and clinical (including mass balance) data. Subsequently, the finerenone model was validated regarding the contribution of CYP3A4 metabolism to total clearance by comparing to observed data from dedicated clinical interaction studies with erythromycin (simulated geometric mean ratios of the area under the plasma concentration‐time curve [AUCR] of 3.46 and geometric mean peak plasma concentration ratios [CmaxRs] of 2.00 vs. observed of 3.48 and 1.88, respectively) and verapamil (simulated AUCR of 2.91 and CmaxR of 1.86 vs. observed of 2.70 and 2.22, respectively). Finally, the finerenone model was applied to predict clinically untested DDI studies with various CYP3A4 modulators. An AUCR of 6.31 and a CmaxR of 2.37 was predicted with itraconazole, of 5.28 and 2.25 with clarithromycin, 1.59 and 1.40 with cimetidine, 1.57 and 1.38 with fluvoxamine, 0.19 and 0.32 with efavirenz, and 0.07 and 0.14 with rifampicin. This PBPK analysis provides a quantitative basis to guide the label and clinical use of finerenone with concomitant CYP3A4 modulators.

Effect of Hepatic Impairment on the Pharmacokinetics of Itacitinib.

Itacitinib is a potent, selective JAK-1 inhibitor currently in development for the treatment of chronic graft-vs-host-disease in combination with corticosteroids. Itacitinib is primarily eliminated via cytochrome P450 3A metabolism with minimal renal elimination. The purpose of this open-label study was to investigate the effect of hepatic impairment, as determined by Child-Pugh grade, on itacitinib pharmacokinetics. All participants received a single 300-mg dose of itacitinib orally in the fasted state. Blood samples were collected serially through 96 hours after dosing; 4 hours after dosing, an additional sample was collected for protein binding determination. Participants with moderate hepatic impairment (N = 8) had an approximate 2.5-fold increase in total exposure (area under the plasma concentration-time curve from time 0 to infinity [AUC0-∞ ]) and an approximate 2-fold increase in maximal exposure (Cmax ) compared to those with normal hepatic function (N = 8) (geometric mean ratio, 2.51 [90% confidence interval (CI), 1.54-4.08] for AUC0-∞ and 1.95 [90%CI, 1.14-3.35] for Cmax ). Participants with severe hepatic impairment (N = 6) had an approximate 4-fold increase in total exposure (AUC0-∞ ) and an approximate 3.5-fold increase in maximal exposure compared to participants with normal hepatic function (geometric mean ratio, 4.08 [90%CI, 2.41-6.89] for AUC0-∞ and 3.48 [90%CI, 1.94-6.23] for Cmax ). Protein binding was similar between participants with moderate or severe hepatic impairment and participants with normal hepatic function, with average unbound fractions (percent free) of 25.7%, 31.5%, and 25.6%, respectively. There were no serious or fatal treatment-related adverse events. The results of this study combined with exposure, efficacy, and safety data from the pivotal study in the relevant patient population will inform final dosing recommendations.

Elucidating the Plasma and Liver Pharmacokinetics of Simeprevir in Special Populations Using Physiologically Based Pharmacokinetic Modelling.

The disposition of simeprevir (SMV) in humans is characterised by cytochrome P450 3A4 metabolism and hepatic uptake by organic anion transporting polypeptide 1B1/3 (OATP1B1/3). This study was designed to investigate SMV plasma and liver exposure upon oral administration in subjects infected with hepatitis C virus (HCV), in subjects of Japanese or Chinese origin, subjects with organ impairment and subjects with OATP genetic polymorphisms, using physiologically based pharmacokinetic modelling. Simulations showed that compared with healthy Caucasian subjects, SMV plasma exposure was 2.4-, 1.7-, 2.2- and 2.0-fold higher, respectively, in HCV-infected Caucasian subjects, in healthy Japanese, healthy Chinese and subjects with severe renal impairment. Further simulations showed that compared with HCV-infected Caucasian subjects, SMV plasma exposure was 1.6-fold higher in HCV-infected Japanese subjects. In subjects with OATP1B1 genetic polymorphisms, no noteworthy changes in SMV pharmacokinetics were observed. Simulations suggested that liver concentrations in Caucasians with HCV are 18 times higher than plasma concentrations.

Improved Ticagrelor Antiplatelet Effect on Discontinuation of Phenytoin

To report the influence of phenytoin on the antiplatelet effects of ticagrelor using a validated platelet aggregation study. A 71-year-old man with coronary artery disease underwent percutaneous coronary intervention to revascularize several major coronary arteries. The patient was previously on phenytoin and was initiated on ticagrelor for antiplatelet therapy following stent placement. While the patient was receiving both drugs, platelet aggregation studies revealed less platelet inhibition than would be expected in a patient not taking a concomitant inducer of ticagrelor metabolism. On discontinuation of phenytoin, platelet inhibition improved. Dual antiplatelet therapy with aspirin and a P2Y12 receptor antagonist following placement of coronary stents is critical to prevent stent thrombosis and subsequent myocardial infarction. Ticagrelor is a recently approved P2Y12 receptor antagonist that is subject to drug-drug interactions involving the hepatic cytochrome P450-3A4 enzyme system because of its metabolic elimination pathway. This case demonstrates ticagrelor's drug-drug interaction with phenytoin through a platelet aggregation study and supports the manufacturer recommendation to avoid the combination of ticagrelor with any known inducers of cytochrome P450-3A4 metabolism. The combination of ticagrelor and phenytoin may represent a potentially clinically significant drug-drug interaction because of phenytoin induction of ticagrelor metabolism and reduced P2Y12 receptor inhibition in patients who have recently undergone percutaneous coronary intervention and cardiac stent placement.

Prediction of Drug Disposition on the Basis of its Chemical Structure

The chemical structure of any drug determines its pharmacokinetics and pharmacodynamics. Detailed understanding of relationships between the drug chemical structure and individual disposition pathways (i.e., distribution and elimination) is required for efficient use of existing drugs and effective development of new drugs. Different approaches have been developed for this purpose, ranging from statistics-based quantitative structure-property (or structure-pharmacokinetic) relationships (QSPR) analysis to physiologically based pharmacokinetic (PBPK) models. This review critically analyzes currently available approaches for analysis and prediction of drug disposition on the basis of chemical structure. Models that can be used to predict different aspects of disposition are presented, including: (a) value of the individual pharmacokinetic parameter (e.g., clearance or volume of distribution), (b) efficiency of the specific disposition pathway (e.g., biliary drug excretion or cytochrome P450 3A4 metabolism), (c) accumulation in a specific organ or tissue (e.g., permeability of the placenta or accumulation in the brain), and (d) the whole-body disposition in the individual patients. Examples of presented pharmacological agents include "classical" low-molecular-weight compounds, biopharmaceuticals, and drugs encapsulated in specialized drug-delivery systems. The clinical efficiency of agents from all these groups can be suboptimal, because of inefficient permeability of the drug to the site of action and/or excessive accumulation in other organs and tissues. Therefore, robust and reliable approaches for chemical structure-based prediction of drug disposition are required to overcome these limitations. PBPK models are increasingly being used for prediction of drug disposition. These models can reflect the complex interplay of factors that determine drug disposition in a mechanistically correct fashion and can be combined with other approaches, for example QSPR-based prediction of drug permeability and metabolism, pharmacogenomic data and tools, pharmacokinetic-pharmacodynamic modeling approaches, etc. Moreover, the PBPK models enable detailed analysis of clinically relevant scenarios, for example the effect of the specific conditions on the time course of the analyzed drug in the individual organs and tissues, including the site of action. It is expected that further development of such combined approaches will increase their precision, enhance the effectiveness of drugs, and lead to individualized drug therapy for different patient populations (geriatric, pediatric, specific diseases, etc.).

Drug interactions between voriconazole, darunavir/ritonavir and etravirine in an HIV-infected patient with Aspergillus pneumonia

Drug interactions between voriconazole, darunavir/ritonavir and etravirine in an HIV-infected patient with Aspergillus pneumonia

Effect of voriconazole and other azole antifungal agents on CYP3A activity and metabolism of tacrolimus in human liver microsomes

Azole antifungal agents are known to inhibit cytochrome P450 3A (CYP3A) enzymes. Limited information is available regarding the effect of voriconazole on CYP3A activity. We examined the effect of voriconazole on CYP3A activity in human liver microsomes as measured by the formation of 6β-hydroxytestosterone from testosterone. We also evaluated the interaction between voriconazole and tacrolimus, an immunosuppressive drug, using human liver microsomes. The effect of voriconazole on CYP3A activity and tacrolimus metabolism was compared to that of other azole antifungal agents.CYP3A4 activity and the metabolism of tacrolimus were measured in the absence and in the presence of various concentrations of voriconazole (0–1.43 mM), fluconazole (0–1.63 mM), itraconazole (0–14 µM) and ketoconazole (0–0.19 µM). At a concentration of 21.2 ± 15.4 µM and 29.8 ± 12.3 µM, voriconazole inhibited the formation of 6β-hydroxytestosterone from testosterone and the metabolism of tacrolimus by 50%, respectively.The rank order of inhibition of 6β-hydroxytestosterone formation from testosterone and the metabolism of tacrolimus, is ketoconazole > itraconazole > voriconazole > fluconazole.Our observations suggest that voriconazole at clinically relevant concentrations will inhibit the hepatic metabolism of tacrolimus and increase the concentration of tacrolimus more than two-fold. Close monitoring of the blood concentrations and adjustment in the dose of tacrolimus are warranted when transplant patients receiving tacrolimus are treated with voriconazole.

Boceprevir

Boceprevir is a hepatitis C virus (HCV) serine protease NS3 inhibitor that has recently been approved by the U.S. Food and Drug Administration, the European Medicines Agency and Health Canada for the treatment of chronic genotype 1 HCV infection. It has potent in vitro antiviral activity against HCV genotypes 1a and 1b and is primarily metabolized via the aldoketoreductase pathway with minor cytochrome P450 3A4 metabolism. Boceprevir is well tolerated with few drug-drug interactions which are easy to manage; no dose adjustment is required in patients with hepatic or renal impairment. Phase I trials of boceprevir demonstrated favorable pharmacokinetic, metabolic and safety profiles. Phase II and III trials of boceprevir confirmed the antiviral activity of the drug and its use at a dose of 800 mg three times daily. Clinical trials in treatment-naive and previously treated HCV-infected patients demonstrated a 26% and 45% (respectively) improvement in sustained viral response when boceprevir was added to standard pegylated interferon and ribavirin anti-HCV therapy. Boceprevir is the first-in-class of an exciting new phase of HCV treatment.

Triamcinolone Acetonide Induced Secondary Adrenal Insufficiency Related to Impaired CYP3A4 Metabolism by Coadministration of Nefazodone: Table 1

This case report seeks to promote physician awareness of the potential drug interaction between corticosteroid medications and cytochrome P450 3A4 (CYP3A4) inhibitors. Tertiary care multispecialty referral center. Corticosteroid injections are commonly used as effective treatments for a variety of pain disorders. Recently, there has been a greater appreciation of the potential drug interactions between CYP3A4 inhibitors and corticosteroid medications including topical steroid preparations. We report a case of triamcinolone acetonide induced secondary adrenal insufficiency related to impaired CYP3A4 metabolism by coadministration of nefazodone. Physicians should recognize the potential effects of CYP3A4 inhibitors particularly when administering or prescribing systemic corticosteroid medications.

Inhibition of oral midazolam clearance by boosting doses of ritonavir, and by 4,4‐dimethyl‐benziso‐(2H)‐selenazine (ALT‐2074), an experimental catalytic mimic of glutathione oxidase

* The viral protease inhibitor ritonavir is known to inhibit clearance of intravenous midazolam. * ALT-2074, a catalytic mimic of glutathione oxidase, inhibits human cytochrome P450 3A (CYP3A) isoforms in vitro. * Short-term administration of low-dose ritonavir increases area under the plasma concentration curve following oral midazolam by a factor of 28. * Therefore ritonavir is an appropriate positive control inhibitor for clinical drug interaction studies involving CYP3A substrates. * Midazolam clearance is weakly inhibited by ALT-2074, consistent with its in vitro profile. We evaluated whether 'boosting' doses of ritonavir can serve as a positive control inhibitor for pharmacokinetic drug-drug interaction studies involving cytochrome P450 3A (CYP3A). The study also determined whether 4,4-dimethyl-benziso-(2H)-selenazine (ALT-2074), an investigational organoselenium compound that acts as a catalytic mimic of glutathione oxidase, inhibits CYP3A metabolism in vivo. Thirteen healthy volunteers received single 3-mg oral doses of midazolam on three occasions: in the control condition, during co-treatment with low-dose ritonavir (three oral doses of 100 mg over 24 h), and during co-treatment with ALT-2074 (three oral doses of 80 mg over 24 h). Ritonavir increased mean (+/-SE) total area under the curve (AUC) for midazolam by a factor of 28.4 +/- 4.2 (P < 0.001), and reduced oral clearance to 4.2 +/- 0.5% of control (P < 0.001). In contrast, ALT-2074 increased midazolam AUC by 1.25 +/- 0.11 (P < 0.05), and reduced oral clearance to 88 +/- 8% of control. Low-dose ritonavir produces extensive CYP3A inhibition exceeding that of ketoconazole (typically 10- to 15-fold midazolam AUC enhancement), and is a suitable positive control index inhibitor for drug-drug interaction studies. ALT-2074 inhibits CYP3A metabolism to a small degree that is of uncertain clinical importance.

Adrenal suppression due to an interaction between ritonavir and injected triamcinolone: a case report

Two HIV-1 infected patients developed signs and symptoms consistent with adrenal suppression after being exposed to intra-articular triamcinolone acetate while also receiving ritonavir as part of their highly active antiretroviral therapy. Laboratory evaluation confirmed secondary adrenal suppression in both cases. Both patients recovered without the need for chronic replacement steroids. Adrenal suppression has been described as an adverse outcome in patients treated with fluticasone and concomitant ritonavir. In the reported cases, the adrenal suppression likely developed as a result of increased systemic concentrations of triamcinolone due to an inhibition of cytochrome p450 3A4 metabolism. Practitioners of HIV medicine should be aware of the potential negative interaction of injected triamcinolone and ritonavir.

Management of Metabolic Cytochrome P450 3A4 Drug-Drug Interaction between Everolimus and Azole Antifungals in a Renal Transplant Patient

We report a case of a 54-year-old male renal transplant patient who received antifungal azole treatment in combination with the recently introduced immunosuppressant agent everolimus to prevent post-transplantation aspergillosis reactivation. Voriconazole was withdrawn after 1 month because of elevated concentrations (5 mg/L trough plasma determination) and hepatotoxicity, and substituted by several months of treatment with posaconazole (observed concentration range 1-2 mg/L). We observed pharmacokinetic drug interactions between both voriconazole and posaconazole, and everolimus cytochrome P450 3A4 metabolism, resulting in 7.5- and 3.8-fold increase, respectively, in everolimus blood trough concentrations. Combined therapeutic drug monitoring (TDM) of both everolimus and azole inhibitors allowed for safe and convenient modification of everolimus dosage, which was tapered to maintain a target range of 5-15 ng/mL during and after antifungal treatments. While significant in their effects, these drug interactions were able to be managed safely through a careful approach to management and use of individual TDM.

Effect of Different Durations of Ketoconazole Dosing on the Single‐Dose Pharmacokinetics of Midazolam: Shortening the Paradigm

Given the prominent role of cytochrome P450 3A (CYP3A) in the metabolism of drugs, it is critical to determine whether new chemical entities will be affected by the inhibition of this enzyme system and result in clinically relevant drug interactions. Ketoconazole interaction studies are frequently performed to determine a given compound's sensitivity to CYP3A metabolism. The present study evaluated whether probing a sensitive substrate (midazolam) with a potent inhibitor (ketoconazole) at earlier time points (days 1 or 2) might be used to reliably gauge the magnitude of a meaningful interaction. The geometric mean ratios (ketoconazole+midazolamday 5/ketoconazole+midazolamday 1 and ketoconazole+midazolamday 5/ketoconazole+midazolamday 2) for midazolam AUC0-infinity were 1.36 and 1.06 with corresponding 90% confidence intervals of (1.17, 1.57) and (0.83, 1.23), respectively. These findings suggest that short-term drug-drug interaction studies can predict the magnitude of change in AUC as reliably as studies using longer duration treatments.

How important is intestinal cytochrome P450 3A metabolism?

Cytochrome P450 3A (CYP3A) enzymes metabolize a wide variety of xenobiotics including many drugs. Because CYP3A is localized in both the liver and intestine, it can make a major contribution to the presystemic elimination of substrate drugs after oral administration ('first-pass metabolism'). However, assessments of the relative importance of intestinal versus hepatic CYP3A-mediated first-pass metabolism have been difficult to make and are subject to extensive discussion. To assess systematically the relative contributions of the intestine and liver to first-pass metabolism in vivo, Cyp3a knockout mice expressing human CYP3A4 in the liver or intestine have recently been generated. Analysis of these mice, together with previous observations in humans, substantiates that intestinal CYP3A4 can operate independently of the liver as a highly efficient metabolic barrier during the uptake of various drugs from the intestine. We expect that the insights obtained with these mouse models will contribute to the development of better oral drugs and treatment regimens.

In vitro inhibition of CYP3A4 by herbal remedies frequently used by cancer patients

The herbal remedies Natto K2, Agaricus, mistletoe, noni juice, green tea and garlic, frequently used by cancer patients, were investigated for their in vitro inhibition potential of cytochrome P-450 3A4 (CYP3A4) metabolism. To our knowledge, only garlic and green tea had available data on the possible inhibition of CYP3A4 metabolism. Metabolic studies were performed with human c-DNA baculovirus expressed CYP3A4. Testosterone was used as a substrate and ketoconazole as a positive quantitative inhibition control. The formation of 6-beta-OH-testosterone was quantified by a validated HPLC methodology. Green tea was the most potent inhibitor of CYP3A4 metabolism (IC(50): 73 microg/mL), followed by Agaricus, mistletoe and noni juice (1324, 3594, >10 000 microg/mL, respectively). All IC(50) values were high compared with those determined for crude extracts of other herbal remedies. The IC(50)/IC(25) ratios for the inhibiting herbal remedies ranged from 2.15 to 2.67, indicating similar inhibition profiles of the herbal inhibitors of CYP3A4. Garlic and Natto K2 were classified as non-inhibitors. Although Agaricus, noni juice, mistletoe and green tea inhibited CYP3A4 metabolism in vitro, clinically relevant systemic or intestinal interactions with CYP3A4 were considered unlikely, except for a probable inhibition of intestinal CYP3A4 by the green tea product.

Rosuvastatin: a highly potent statin for the prevention and management of coronary artery disease

Since the identification of a fungal metabolite that inhibits HMG-CoA reductase in 1976, statins have emerged rapidly as the global leader in pharmacotherapeutics designed to lower low-density lipoprotein cholesterol (LDL-C). In conjunction, practice guidelines have recommended increasingly aggressive measures to improve coronary heart disease (CHD) outcomes by lowering LDL-C. By virtue of unique chemical characteristics, enhanced binding thermodynamics and limited cytochrome P450 3A4 metabolism, rosuvastatin calcium has a safety profile in line with currently marketed statins, but a different efficacy profile. Mirroring this chemical profile, the GALAXY program represents a comprehensive evaluation of the efficacy, safety and cost–effectiveness of rosuvastatin in individuals representing various clinical diagnoses, pathophysiological states and ethnicities. Also results from the Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study could provide further evidence for the use of rosuvastatin in individuals with traditional and emerging CHD risk factors, such as an elevated high sensitivity C-reactive protein level. This review will provide a comprehensive evaluation of the chemistry, clinical efficacy, safety and tolerability of rosuvastatin, and discuss the future role in the management of CHD and atherosclerosis.