Pharmacokinetics Of Atorvastatin Research Articles

Abstract O.46: A Phase I/IIa Dose Escalating, Open-label Study of Atorvastatin in Children with Acute Kawasaki Disease and Coronary Artery Abnormalities

Background: Although high-dose intravenous immunoglobulin plus aspirin reduces the risk of coronary artery damage, 5-10% of children with Kawasaki disease (KD) will go on to develop coronary artery aneurysms that may result in myocardial ischemia, infarction, or death. Arterial damage in KD results from immune activation and vessel wall infiltration by myofibroblasts, neutrophils, and T-cells with secretion of pro-inflammatory cytokines, elastases, and matrix metalloproteinases. Resolution of inflammation and recovery from the acute illness occurs through T-cell regulation. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, also known as statins, have extensive anti-inflammatory effects that target all of these pathways. These effects are independent of their cholesterol-lowering effect. Given these anti-inflammatory effects, statins would be a reasonable therapy to block coronary artery abnormality (CAA) progression in KD Methods: We designed a Phase I/IIa, two-center, dose-escalating, 6-week open-label study of atorvastatin. Acute KD patients within the first 20 days after fever onset are eligible if they are between the ages of 2 and 17 years old, have had fever for ≥ 3 days, and have ≥ 2 clinical criteria with LAD/RCA z-score ≥ 2.5 or a coronary artery aneurysm (≥ 1.5 x the adjacent segment). Dose escalation (0.125-0.75 mg/kg/day) follows a 3+3 design with evaluations for dose limiting toxicities at 2 and 6 weeks after enrollment. The primary outcome measure is safety with secondary outcome measures including the pharmacokinetics (PK) of atorvastatin, changes in measures of oxidative stress and inflammation, enumeration and characterization of regulatory T-cells, and echocardiographic changes in the internal diameter of the coronary arteries. Results: To date we have enrolled 9 subjects, 7 at Rady Children’s Hospital San Diego and 2 at Children’s Hospital Colorado. The median age at enrollment was 4 years with 5/9 (55%) males and a median illness day at enrollment of 6 days. The median baseline Z worst score was 3.5. The study is currently enrolling at the second dose level. Conclusions: The safety, tolerability, and PK of atorvastatin for acute KD patients will be established by this clinical trial.

Impact of ABCG2 and SLCO1B1 polymorphisms on pharmacokinetics of rosuvastatin, atorvastatin and simvastatin acid in Caucasian and Asian subjects: a class effect?

Systemic exposure to rosuvastatin is approximately double that of Caucasians in Asian subjects. We investigated whether this pattern of increased exposure exists for other statins. Plasma exposure following single-dose rosuvastatin 20 mg, atorvastatin 40 mg or simvastatin 40 mg was studied in Chinese, Japanese and Caucasian subjects. Plasma concentrations were determined using LC-MS methods. Impact of polymorphisms in SLCO1B1 (T521>C and A388>G) and in ABCG2 (C421>A) on exposure to rosuvastatin, atorvastatin, simvastatin and simvastatin acid was assessed. Relative to Caucasians, geometric mean area under the curve from time zero to time of last quantifiable concentration was 86 % (90 % confidence interval (CI), 51-130 %) and 55 % (26-91 %) higher for rosuvastatin in Chinese and Japanese subjects, respectively, 53 % (25-88 %) and 69 % (37-108 %) higher for atorvastatin, 23 % (0-52 %) and 12 % (-0.9-39 %) higher for simvastatin and 28 % (5-56 %) and 34 % (10-64 %) higher for simvastatin acid. Geometric mean maximum drug concentration was also proportionally higher for each statin. Polymorphisms in SLCO1B1 T521>C or ABCG2 C421>A were associated with higher exposure to rosuvastatin, atorvastatin and simvastatin acid (but not simvastatin) within a population, but only the ABCG2 C421>A polymorphism contributed towards between-population exposure differences. In individuals carrying wild-type alleles for both SLCO1B1 and ABCG2, area under the plasma concentration-time curve (AUC) still appeared to be higher for rosuvastatin, atorvastatin and simvastatin acid in Chinese and Japanese subjects compared with Caucasians, respectively. Increased exposure to statins in Asian subjects versus Caucasians may represent a more general class phenomenon than previously recognized.

Use of Atorvastatin in Lipid Disorders and Cardiovascular Disease in Chinese Patients

Objective:Statins are still underused for the prevention of cardiovascular disease (CVD) in China. Hence, we conducted a systemic review on the pharmacology, clinical efficacy, and adverse events of atorvastatin, as well as on patient adherence.Data Sources:We conducted a systemic search in PubMed with the following keywords: “atorvastatin” (Supplementary concept) or “atorvastatin” (All field) and (“China” [AD] or “China” [all field] or “Chinese” [All field]).Study Selection:Clinical or basic research articles on atorvastatin were included.Results:Atorvastatin is a reversible and competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, decreasing the de novo cholesterol synthesis. The pharmacokinetics of atorvastatin among Chinese is similar to those in Caucasians, and several gene polymorphisms have proved to be associated with the metabolism of atorvastatin in the Chinese population. Several international multiple-center randomized control trials have demonstrated the benefit of atorvastatin for primary and secondary prevention of CVD. None of them, however, included the Chinese, and current evidence in the population is still inadequate, due to the small sample size, low study quality, short study duration, and the use of surrogate endpoints instead of clinical endpoints. The overall incidence of adverse events observed with atorvastatin did not increase in the 10–80 mg dose range, and was similar to that observed with placebo and in patients treated with other statins, which makes atorvastatin well-tolerated in the Chinese population. Moreover, high patient adherence was observed in clinical studies.Conclusions:Based on the current available evidence, there is no significant difference between Chinese and non-Chinese population in term of pharmacology and clinical efficacy/safety. High-quality evidence is still needed to support the use of atorvastatin in high-risk Chinese population.

Effect of concomitant icosapent ethyl (eicosapentaenoic acid ethyl ester) on the pharmacokinetics of atorvastatin.

Background and ObjectiveIcosapent ethyl is a high-purity prescription form of eicosapentaenoic acid ethyl ester approved as an adjunct to diet to reduce triglyceride levels in adult patients with triglyceride levels ≥500 mg/dL (≥5.65 mmol/L). The objective of this open-label, drug–drug interaction study was to examine the effects of icosapent ethyl on the steady-state pharmacokinetics of atorvastatin, a commonly prescribed medication in patients with dyslipidaemia.MethodsThirty healthy subjects received atorvastatin 80 mg/day on days 1–7, icosapent ethyl 4 g/day on days 8–28, and co-administration on days 29–35. Primary end-points were natural log-transformed maximum plasma concentration (C max) and area under the concentration-versus-time curve from 0 to 24 h (AUC0–24) for atorvastatin, 2-hydroxyatorvastatin, and 4-hydroxyatorvastatin with and without icosapent ethyl.ResultsOf the 30 subjects enrolled, 26 completed the study. The 90 % confidence intervals for C max and AUC0–24 least-squares geometric mean ratios were within the 0.80–1.25 bounds. Concomitant administration of icosapent ethyl and atorvastatin was safe and well tolerated and icosapent ethyl did not significantly change the steady state C max and AUC0–24 of atorvastatin, 2-hydroxyatorvastatin, or 4-hydroxyatorvastatin.ConclusionsAt steady-state concentrations, icosapent ethyl did not have an effect on the pharmacokinetics of atorvastatin. Co-administration of icosapent ethyl and atorvastatin was safe and well tolerated in healthy adult subjects.

Effects of silymarin on the pharmacokinetics of atorvastatin in diabetic rats

The effect of silymarin (SMN) on the pharmacokinetics of atorvastatin in diabetic rats was evaluated. Male Wistar rats were assigned into two major groups and then sub-grouped according to the purposes of the study. The first major group was subdivided into three groups (n=6) including control, non-treated diabetic and SMN-treated diabetic animals. In the first major group, metabolism of testosterone by the hepatic microsomes was studied. The second major group also was divided to three groups including atorvastatin-treated non-diabetic, atorvastatin-treated diabetic and diabetic animals which received both atorvastatin and SMN. To study the pharmacokinetics of atorvastatin, serum samples were collected at 0, 3, 6, 12 and 24h after the atorvastatin administration. Pharmacokinetic parameters were calculated using non-compartmental model. Streptozotocin-induced diabetes resulted in a remarkable induction of testosterone hydroxylation as the V max for 6β-hydroxytestosterone production in the diabetic rats (77.3±8.6pM/min/mg) was significantly higher than that in the control animals (45.9±5.9pM/min/mg). Moreover, SMN-treated animals showed a significant (P<0.05) reduction of V max (59.4±6.1pM/min/mg). Diabetes resulted in a significant reduction of AUC (control 6.98±0.58 vs diabetic rats 4.35±0.24hmg/ml) and C max values (control 0.52±0.03 vs diabetic group 0.33±0.01μg/ml), while the SMN-received group showed remarkable recovery of diabetes-reduced values of AUC and C max. These findings indicated that diabetes resulted in a significant up-regulation of microsomal enzyme activities. Moreover, as SMN could significantly regulate the enzyme activities and consequently the atorvastatin pharmacokinetics in diabetic rats, its regulative effect in a combination therapy is concluded.

The effect of CYP3A4*1G allele on the pharmacokinetics of atorvastatin in Chinese han patients with coronary heart disease

The present study aimed to evaluate the impact of CYP3A4*1G allele on the pharmacokinetics of atorvastatin in the Chinese Han patients with coronary heart disease (CHD). Twenty male patients of CHD with different CYP3A4*1G genotypes were orally administered a single 20 mg dose of atorvastatin. Plasma concentrations of atorvastatin and 2-hydroxyatorvastatin were measured by high-performance liquid chromatography tandem mass spectrometry. The mean area under the plasma concentration-time curve from 0 to infinity (AUC0-∞ ) of atorvastatin in subjects with the CYP3A4*1G/*1G genotype were 36% or 25% lower than in those with the wild-type or the *1/*1G genotype, respectively. The time to peak plasma concentration (Tmax ) and oral clearance of atorvastatin (CL/F) were significantly different between subjects with the CYP3A4*1G/*1G genotype and the wild-type. The AUC0-∞ for 2-hydroxyatorvastatin in subjects with the CYP3A4*1G/*1G genotype was 44% or 31% lower than in those with the wild-type or the *1/*1G genotype, respectively. The peak plasma concentration, Tmax and apparent clearance of 2-hydroxyatorvastatin (CL/Fm) were significantly different between subjects with the CYP3A4*1G/*1G genotype and the wild-type. This study indicates that the CYP3A4*1G allele is associated with the pharmacokinetics of atorvastatin and its metabolites in those Chinese Han patients with CHD after a single oral dose.

SLCO1B1 polymorphisms affect atorvastatin pharmacokinetics and cholesterol-lowering effects in patients with hypercholesterolemia in a microdosing approach

Background: Atorvastatin is taken up into hepatocytes via organic anion transporting polypeptide (OATP). SLCO1B1 (encoding OATP1B1) 521T>C polymorphism has been reported to increase significantly its plasma AUC of in healthy volunteers. However, effects of SLCO1B1*15 (388A>G and 521T>C) on its pharmacokinetics and cholesterol-lowering effects in patients with hypercholesterolemia remain to be investigated. A microdosing approach can avoid the unexpected high concentrations of drugs in certain populations during pharmacogenetic or drug interaction studies. Therefore, we examined feasibility of clinical microdosing pharmacogenetic study in real clinical settings. Methods: Statin-naive patients (n=47, M/F=37/10, mean age 69yr) clinically indicated to LDL cholesterol-lowering therapy with atorvastatin were enrolled in a two-period crossover study. In the first period, microdose (100 ug) of atorvastatin was orally administered and blood was collected up to following 24 hrs. After washout for 1-2 days, therapeutic dose (10 mg) of atorvastatin was orally administered and its pharmacokinetics was monitored in the similar manner, with all concomitant medications. Results: The AUC/Dose of atorvastatin at microdose was smallerthan that at therapeutic dose (204±139 vs. 445±210 pg·hr/ml/100 ug), suggesting the saturation of efflux transporters. The plasma concentration of atorvastatin in subjects with SLCO1B1*15 was significantly greater both at microdose and therapeutic dose (+73% and +80%, p<0.05), which was associated with smaller %LDL-cholesterol lowering after 6 months (-33% and -25%, p<0.1). Conclusions: In real clinical settings, microdosing pharmacogenetic study appears to be feasible and could predict plasma AUC of atorvastatin at a therapeutic dose and the magnitude of LDL-cholesterol lowering in hypercholesterolemic subjects with SLCO1B1*15.

Phase 1 Study of the Effect of Icosapent Ethyl on Atorvastatin Pharmacokinetics in Healthy Subjects

Phase 1 Study of the Effect of Icosapent Ethyl on Atorvastatin Pharmacokinetics in Healthy Subjects

Elucidation of the biochemical basis for a clinical drug–drug interaction between atorvastatin and 5-(N-(4-((4-ethylbenzyl)thio)phenyl)sulfamoyl)-2-methyl benzoic acid (CP-778 875), a subtype selective agonist of the peroxisome proliferator-activated receptor alpha

1. 5-(N-(4-((4-ethylbenzyl)thio)phenyl)sulfamoyl)-2-methyl benzoic acid (CP-778 875), an agonist of the peroxisome proliferator-activated receptor alpha, has been evaluated in the clinic to treat dyslipidemia and type 2 diabetes mellitus. Herein, we investigate the effect of CP-778 875 on the pharmacokinetics of atorvastatin acid and its metabolites in humans.2. The study incorporated a fixed-sequence design conducted in two groups. Group A was designed to estimate the effects of multiple doses of CP-778 875 on the single dose pharmacokinetics of atorvastatin. Subjects in group A (n = 26) received atorvastatin (40 mg) on days 1 and 9 and CP-778 875 (1.0 mg QD) on days 5–12. Group B was designed to examine the effects of multiple doses of atorvastatin on the single dose pharmacokinetics of CP-778 875. Subjects in group B (n = 29) received CP-778 875 (0.3 mg) on days 1 and 9 and atorvastatin (40 mg QD) on days 5–12.3. Mean maximum serum concentration (Cmax) and area under the curve of atorvastatin were increased by 45% and 20%, respectively, upon co-administration with CP-778 875. Statistically significant increases in the systemic exposure of ortho- and para-hydroxyatorvastatin were also observed upon concomitant dosing with CP-778 875. CP-778 875 pharmacokinetics, however, were not impacted upon concomitant dosing with atorvastatin.4. Inhibition of organic anion transporting polypeptide 1B1 by CP-778 875 (IC50 = 2.14 ±0.40 μM) could be the dominant cause of the pharmacokinetic interaction as CP-778 875 did not exhibit significant inhibition of cytochrome P450 3A4/3A5, multidrug resistant protein 1 or breast cancer resistant protein, which are also involved in the hepatobiliary disposition of atorvastatin.

Population Pharmacokinetics of Atorvastatin and Its Active Metabolites in Children and Adolescents With Heterozygous Familial Hypercholesterolemia: Selective Use of Informative Prior Distributions from Adults

The population pharmacokinetics (PPK) of atorvastatin and its principal active metabolite, o-hydroxyatorvastatin, were described in 6-17 years old pediatric hypercholesterolemia patients with a 2-compartment model for both parent and metabolite. Informative prior distributions on selected parameters, based on adult data, were required to stabilize the model and were implemented using a Bayesian penalty term on the likelihood function in the nonlinear mixed effects model (NONMEM VI with PRIOR). Concentrations below the limit of quantitation were treated as censored data using a conditional likelihood function. Atorvastatin apparent oral clearance (CL/F) was described as a function of body weight using an allometric equation. Based on the final model, the typical CL/F estimates for a Tanner Stage 1 patient (35 kg weight) and Tanner Stage ≥2 (50 kg weight), would be 553 and 543 L/hour, respectively. When scaled allometrically, CL/F was similar to values reported for adults. Variability in atorvastatin PK was primarily affected by weight.

Genetics is a major determinant of expression of the human hepatic uptake transporter OATP1B1, but not of OATP1B3 and OATP2B1.

BackgroundOrganic anion transporting polypeptide (OATP) 1B1, OATP1B3, and OATP2B1 (encoded by SLCO1B1, SLCO1B3, SLCO2B1) mediate the hepatic uptake of endogenous compounds like bile acids and of drugs, for example, the lipid-lowering atorvastatin, thereby influencing hepatobiliary elimination. Here we systematically elucidated the contribution of SLCO variants on expression of the three hepatic OATPs under consideration of additional important covariates.MethodsExpression was quantified by RT-PCR and immunoblotting in 143 Caucasian liver samples. A total of 109 rare and common variants in the SLCO1B3-SLCO1B1 genomic region and the SLCO2B1 gene were genotyped by MALDI-TOF mass spectrometry and genome-wide SNP microarray technology. SLCO1B1 haplotypes affecting hepatic OATP1B1 expression were associated with pharmacokinetic data of the OATP1B1 substrate atorvastatin (n = 82).ResultsExpression of OATP1B1, OATP1B3, and OATP2B1 at the mRNA and protein levels showed marked interindividual variability. All three OATPs were expressed in a coordinated fashion. By a multivariate regression analysis adjusted for non-genetic and transcription covariates, increased OATP1B1 expression was associated with the coding SLCO1B1 variant c.388A > G (rs2306283) even after correction for multiple testing (P = 0.00034). This held true for haplotypes harboring c.388A > G but not the functional variant c.521T > C (rs4149056) associated with statin-related myopathy. c.388A > G also significantly affected atorvastatin pharmacokinetics. SLCO variants and non-genetic and regulatory covariates together accounted for 59% of variability of OATP1B1 expression.ConclusionsOur results show that expression of OATP1B1, but not of OATP1B3 and OATP2B1, is significantly affected by genetic variants. The SLCO1B1 variant c.388A > G is the major determinant with additional consequences on atorvastatin plasma levels.

Impact of OATP1B1, MDR1, and CYP3A4 Expression in Liver and Intestine on Interpatient Pharmacokinetic Variability of Atorvastatin in Obese Subjects

Individual variability in expression and function of organic anion-transporting polypeptide 1B1 (OATP1B1), multidrug resistance protein 1 (MDR1), and/or cytochrome P450 3A4 (CYP3A4) may impact the clinical response of many drugs. We investigated the correlation between expression of these proteins and pharmacokinetics of atorvastatin, a substrate of all three, in 21 obese patients with paired biopsies from liver and intestinal segments. The patients were also screened for the SLCO1B1 c.521T→C variant alleles. Approximately 30% (r(2) = 0.28) of the variation in oral clearance (CL/F) of atorvastatin was explained by hepatic OATP1B1 protein expression (P = 0.041). Patients carrying the SLCO1B1 c.521C variant allele (homozygous, n = 4; heterozygous, n = 2) exhibited 45% lower CL/F of atorvastatin than the c.521TT carriers (P = 0.067). No association between hepatic and intestinal expression of MDR1 or CYP3A4 and atorvastatin pharmacokinetics was found (P > 0.149). In conclusion, this study suggests that OATP1B1 phenotype is more important than CYP3A4 and MDR1 phenotypes for the individual pharmacokinetic variability of atorvastatin.

Pharmacokinetic interaction studies of co-administration of ticagrelor and atorvastatin or simvastatin in healthy volunteers

Interactions between ticagrelor and atorvastatin or simvastatin were investigated in two-way crossover studies. Both studies were open-label for statin; the atorvastatin study was placebo-controlled for ticagrelor. For atorvastatin, volunteers (n = 24) received ticagrelor (loading dose 270 mg; 90 mg twice daily, 7 days) or placebo, plus atorvastatin calcium (80 mg; day 5). For simvastatin, volunteers (n = 24) received simvastatin 80 mg, or ticagrelor (loading dose 270 mg; 180 mg twice daily, 7 days) plus simvastatin (80 mg; day 5). In each study, volunteers received the alternate treatment after washout (≥ 7 days). Ticagrelor increased mean atorvastatin maximum plasma concentration (C(max)) and area under the plasma concentration-time curve from zero to infinity (AUC) by 23 % and 36 %, respectively. Simvastatin C(max) and AUC were increased by 81 % and 56 % with ticagrelor. Ticagrelor also increased C(max) and AUC of analysed atorvastatin metabolites by 13-55 % and 32-67 %, respectively, and simvastatin acid by 64 % and 52 %, respectively. Co-administration of ticagrelor with each statin was well tolerated. Exposure to ticagrelor and its active metabolite, AR-C124910XX, was generally unchanged by a single dose of either statin, except for a minor increase in ticagrelor C(max) in the presence of simvastatin. Effects of ticagrelor on atorvastatin pharmacokinetics were modest and unlikely clinically relevant, while with simvastatin, changes were slightly larger, and simvastatin doses >40 mg with ticagrelor should be avoided.

Comparative pharmacokinetic study of Normostatin tablets

Comparative pharmaceutical research of Normostatin and Atorvastatin tablets has been reported. A comparative estimation of pharmacokinetic indicators has been performed, the influence of the joint introduction of Mexicor and Atorvastatin as part of the Normostatin preparation on the pharmacokinetics of Atorvastatin is established, and the relative bioavailability of the preparation is defined.

Simultaneous Determination of Atorvastatin and Glimepiride by LC-MS/MS in Human Plasma and Its Application to a Pharmacokinetic Study

The aim of the proposed research work was to develop and validate a simple, selective high sensitive and high-throughput assay for the simultaneous estimation of Atorvastatin and Glimepiride in human plasma using liquid chromatography tandem mass spectrometry (LC-MS/MS). Atorvastatin–Glimepiride combines a competitive inhibitor of HMG-CoA reductase and a sulfonylurea anti-diabetic drug. The purpose of this study was to develop single method for Atorvastatin and Glimepiride in plasma by liquid chromatography-tandem mass spectrometry (LC-MS/MS) that would result into a simultaneous estimation of Atorvastatin and Glimepiride avoiding acid –lactone inter conversions right from sample collections to analysis on the LC-MS/MS. Sample collection procedure optimized for Atorvastatin holds good for Glimepiride, hence resulting into a simultaneous estimation of Atorvastatin and Glimepiride. Liquid-liquid extraction and liquid chromatography coupled to positive ion mode tandem mass spectrometry was used to develop the method and was validated according to US FDA guidelines. The calibration curves for two analytes were linear (R2 ≥ 0.9950, n = 4) over the concentration range of 0.2 - 30 ng/mL for Atorvastatin and 1 - 250 ng/mL for Glimepiride. Mean extraction recoveries 80.34 ± 9.43 for Atorvastatin and 88.19 ± 7.13 for Glimepiride. Intra- and inter-run mean percent accuracy was between 85% - 115% and percent imprecision was ≤15%. Stability studies revealed that Atorvastatin and Glimepiride were stable in plasma during bench top (10.5 h at room temperature), in Injector (47.5 h), at the end of three successive freeze and thaw cycles and long term at -65℃ ± 15℃ for 114 days. The method was successfully applied to the study of pharmacokinetics of Atorvastatin and Glimepiride in healthy volunteers. Simultaneous estimation of Atorvastatin and Glimepiride is cost effective, reduces analysis cycle time, enables effective utilization of resources and reduces bleeding burden on human volunteers.

The effect of bexarotene on atorvastatin pharmacokinetics: results from a phase I trial of bexarotene plus chemotherapy in patients with advanced non-small cell lung cancer

Bexarotene (Targretin(®) capsules) is a retinoid-X-receptor agonist and an inducer of CYP3A4-mediated metabolism. This phase I trial evaluated the pharmacokinetic (PK) and drug-drug interactions of bexarotene with chemotherapy and a lipid-lowering agent (atorvastatin or fenofibrate). This trial was run in parallel with phase III trials of the combinations to determine whether repeated doses of bexarotene capsules affect the pharmacokinetics (PK) of the chemotherapeutic or the lipid-lowering agents. Patients (n=48) with advanced non-small cell lung cancer were treated with repetitive cycles of either paclitaxel/carboplatin or cisplatin/vinorelbine chemotherapy, bexarotene (400mg/m(2)/day) administered continuously starting on day 4 of chemotherapy, and a lipid-lowering drug, either atorvastatin or fenofibrate, starting at least 5days before chemotherapy due to hypertriglyceridemia induced by bexarotene. Extensive plasma sampling to characterize the PK profiles of the lipid-lowering drugs, relevant chemotherapy agents was performed on day 1 (without bexarotene) and during chemotherapy cycles 2 or 3 (with bexarotene). Here, we report the drug-drug interactions between the lipid-lowering agents and bexarotene. Mean atorvastatin clearance and dose-corrected AUC values were reduced by nearly 50% with the addition of concomitant bexarotene. As fenofibrate was less effective at controlling hypertriglyceridemia, too few patients received this agent to make any meaningful conclusions about drug-drug interactions. A drug-drug interaction was seen in this trial with bexarotene co-administration leading to a significant reduction in the AUC of atorvastatin. The likely mechanism for this interaction is through induction of CYP3A4 by bexarotene given the role of this enzyme in the metabolism of atorvastatin. Knowledge of this interaction is important for optimizing lipid management with atorvastatin for patients receiving bexarotene.

The Effect of the Newly Developed Angiotensin Receptor II Antagonist Fimasartan on the Pharmacokinetics of Atorvastatin in Relation to OATP1B1 in Healthy Male Volunteers

Interactions between coadministered drugs may unfavorably affect pharmacokinetics. This study evaluated whether fimasartan, an angiotensin receptor II antagonist, affected the pharmacokinetics of atorvastatin. A randomized, open-label, 2-period, 2-sequence, crossover, multiple-dosing study was conducted with 24 healthy male volunteers. Twelve subjects received 80-mg atorvastatin once daily for 7 days; later, they received 80-mg atorvastatin with 240-mg fimasartan for 7 days. Twelve other subjects received the same drugs in the opposite sequence. Blood samples were collected scheduled intervals for 24 hours after the last dosing to determine plasma concentrations of atorvastatin acid, atorvastatin lactone, 2-hydroxy atorvastatin acid, and 2-hydroxy atorvastatin lactone. Compared with atorvastatin alone, coadministration of fimasartan and atorvastatin increased the atorvastatin acid mean (95% confidence interval) maximum concentration (Cmax,ss) by 1.89-fold (1.49-2.39) and the area under the concentration curve (AUCτ,ss) by 1.19-fold (0.96-1.48). Fimasartan also increased the mean 2-hydroxy atorvastatin acid Cmax,ss and AUCτ,ss by 2.45-fold (1.80-3.35) and 1.42-fold (1.09-1.85), respectively. The Cmax,ss and AUCτ,ss of the lactone forms of atorvastatin showed smaller changes than those observed for the acidic forms. We showed that fimasartan raised plasma atorvastatin concentrations. In vitro tests suggested that this effect may have been mediated by fimasartan inhibition of organic anion-transporting polypeptide 1B1.

Effect of Cytochrome P450 3A5 Genotype on Atorvastatin Pharmacokinetics and Its Interaction with Clarithromycin

Abstract Study Objective. To assess the effects of the cytochrome P450 (CYP) 3A genotype, CYP3A5, on atorvastatin pharmacokinetics and its interaction with clarithromycin. Design. Prospective, two-phase, randomized-sequence, open-label pharmacokinetic study. Setting. Clinical research center at a teaching hospital. Subjects. Twenty-three healthy volunteers who were screened for genotype: 10 subjects carried the CYP3A5*1 allele (expressors) and 13 subjects did not (nonexpressors). Intervention. In one phase, subjects received a single oral dose of atorvastatin 20 mg. In the other phase, subjects received clarithromycin 500 mg twice/day for 5 days; on day 4 after the morning dose, subjects also received a single oral dose of atorvastatin 20 mg. All subjects participated in both phases of the study, which were separated by at least 14 days. Measurements and Main Results. Pharmacokinetic parameters of both forms of atorvastatin-atorvastatin acid and atorvastatin lactone-were compared between CYP3A5 expressors and nonexpressors, both in the absence and presence of clarithromycin, a strong CYP3A inhibitor. The acid form is pharmacologically active, and the lactone form has been associated with the atorvastatin's muscle-related adverse effects. Atorvastatin acid exposure did not differ significantly between CYP3A5 genotype groups. When subjects had not received clarithromycin pretreatment, the area under the concentration-time curve from time zero extrapolated to infinity (AUC(0-∞)) of atorvastatin lactone was 36% higher in nonexpressors than in expressors (median 47.6 ng•hr/ml [interquartile range (IQR) 37.8-64.3 ng•hr/ml] vs 34.9 ng•hr/ml [IQR 21.6-42.2 ng•hr/ml], p=0.038). After clarithromycin pretreatment, changes in the pharmacokinetic parameters of atorvastatin acid and lactone were not significantly different between the nonexpressors versus the expressors; however, the increase in the AUC(0-∞) of atorvastatin lactone was 37% greater in expressors than in nonexpressors (geometric mean ± SD 3.59 ± 0.57 vs 2.62 ± 0.35, p=0.049). Conclusion. Our data suggest that the CYP3A5 genotype has minimal effects on the pharmacokinetic parameters of atorvastatin and its interaction with clarithromycin; these effects are unlikely to be clinically significant.

Effects of lamotrigine and phenytoin on the pharmacokinetics of atorvastatin in healthy volunteers

Statins and antiepileptic drugs (AEDs) are frequently coprescribed to individuals with hypercholesterolemia and new-onset seizures. Statins are metabolized by the cytochrome P450 (CYP) enzyme system. Interactions between statins and agents that undergo CYP metabolism are common. In this study, the effects of two commonly prescribed AEDs, lamotrigine and phenytoin, with different routes of metabolism (CYP3A4 versus glucuronic acid conjugation) on atorvastatin pharmacokinetics were evaluated. Healthy volunteers (n=119) received atorvastatin 40 mg/day for 7 days followed by addition of lamotrigine (target 300 mg/day) or phenytoin (target ~4 mg/kg per day) in this open-label, single-sequence, two-cohort study. Serial pharmacokinetic sampling of atorvastatin was conducted on day 7 of atorvastatin dosing and day 70 of lamotrigine + atorvastatin dosing or day 28 of phenytoin + atorvastatin dosing. Main outcome measures were steady-state area under the curve over the 24-h dosing interval (AUC((0-τ)) ) and maximum concentration (C(max) ) of atorvastatin and its metabolites, 2OH-atorvastatin and 4OH-atorvastatin, in the presence of lamotrigine or phenytoin. When atorvastatin was administered with lamotrigine compared with when atorvastatin was administered alone, atorvastatin AUC((0-τ)) was within bounds indicating no interaction, whereas C(max) was slightly higher(14%); AUC((0-τ)) and C(max) were 3% and 20% higher, respectively, for 2OH-atorvastatin and 25% and 21% higher, respectively, for 4OH-atorvastatin.When atorvastatin was administered with phenytoin compared with when atorvastatin was administered alone, reductions in AUC((0-τ)) and C(max) were observed for atorvastatin (54% and 24%, respectively), 2OH-atorvastatin (53% and 22%, respectively), and 4OH-atorvastatin (44% and 52%, respectively). Pharmacokinetics of atorvastatin were not significantly affected by coadministration with lamotrigine. Phenytoin significantly reduced atorvastatin bioavailability. Consistent with the published literature, these data are consonant with the possibility that atorvastatin does not require dose adjustment when coadministered with lamotrigine at doses to 300 mg/day, whereas atorvastatin coadministered with phenytoin may require atorvastatin dose adjustment to maintain atorvastatin exposure.

Effect of Gemfibrozil and Fenofibrate on the Pharmacokinetics of Atorvastatin

Coadministration of statins and fibrates is beneficial in some patients by allowing simultaneous reduction of triglycerides and low-density lipoprotein cholesterol alongside elevation of high-density lipoprotein cholesterol. However, the potential for drug interactions must be taken into consideration. Gemfibrozil increases systemic exposure to various different statins, whereas similar effects are not observed with fenofibrate, suggesting it may be a more appropriate choice for coadministration with statins. Gemfibrozil is reported to cause a moderate increase in the area under the curve (AUC) of atorvastatin, but the effect of fenofibrate on atorvastatin pharmacokinetics has not been described. This study compared the effects of multiple-dose administration of gemfibrozil and fenofibrate on the single-dose pharmacokinetics of atorvastatin. Gemfibrozil coadministration led to significant increases in the AUC of atorvastatin, 2-hydroxyatorvastatin, 2-hydroxyatorvastatin lactone, and 4-hydroxyatorvastatin lactone. In contrast, fenofibrate administration did not lead to clinically meaningful changes in the AUC for atorvastatin, atorvastatin lactone, 2-hydroxyatorvastatin, or 2-hydroxyatorvastatin lactone. The absence of a significant pharmacokinetic interaction between fenofibrate and atorvastatin is consistent with recent results showing no difference in safety profile between atorvastatin as monotherapy or in combination with fenofibric acid. Together, these data suggest that atorvastatin-fenofibrate combination therapy is unlikely to pose a risk to patients.