Rosuvastatin Pharmacokinetics in Asian and White Subjects Wild Type for Both OATP1B1 and BCRP Under Control and Inhibited Conditions

Wu, Hsin-Fang; Hristeva, Nadya; Chang, Jae Hoon; Liang, Xiaorong; Li, Ruina; Frassetto, Lynda; Benet, Leslie Z.

doi:10.1016/j.xphs.2017.03.027

Cited by 64 publications

(63 citation statements)

References 32 publications

(57 reference statements)

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“…We also recently demonstrated for 20 mg oral rosuvastatin doses in White subjects wild type for both OATP1B1 and BCRP that the ratio of CL/F in control versus a 600 mg IV single dose of rifampin was 3.6, while the ratio of Vss/F in the control versus rifampin phase was 12.2 and the half-life ratio was 1.6 (31). In contrast, as noted above, Mück et al (28) when analyzing the cyclosporine-cerivastatin interaction found no change in half-life, which as we noted above is consistent with V 1 / F changing in a parallel manner with CL/F .…”

Section: Resultsmentioning

confidence: 87%

The Extended Clearance Concept Following Oral and Intravenous Dosing: Theory and Critical Analyses

et al. 2018

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Purpose: To derive the theoretical basis for the extended clearance model of organ elimination following both oral and IV dosing, and critically analyze the approaches previously taken. Methods: We derived from first principles the theoretical basis for the extended clearance concept of organ elimination following both oral and IV dosing and critically analyzed previous approaches. Results: We point out a number of critical characteristics that have either been misinterpreted or not clearly presented in previously published treatments. First, the extended clearance concept is derived based on the well-stirred model. It is not appropriate to use alternative models of hepatic clearance. In analyzing equations, clearance terms are all intrinsic clearances, not total drug clearances. Flow and protein binding parameters should reflect blood measurements, not plasma values. In calculating the AUCR-factor following oral dosing, the AUC terms do not include flow parameters. We propose that calculations of AUCR may be a more useful approach to evaluate drug-drug and pharmacogenomic interactions than evaluating rate-determining steps. Through analyses of cerivastatin and fluvastatin interactions with cyclosporine we emphasize the need to characterize volume of distribution changes resulting from transporter inhibition/induction that can affect rate constants in PBPK models. Finally, we note that for oral doses, prediction of systemic and intrahepatic drug-drug interactions do not require knowledge of fu,H or Kp,uu for substrates/victims. Conclusions: The extended clearance concept is a powerful tool to evaluate drug-drug interactions, pharmacogenomic and disease state variance but evaluating the AUCR-factor may provide a more valuable approach than characterizing rate-determining steps.

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Section: Resultsmentioning

confidence: 87%

The Extended Clearance Concept Following Oral and Intravenous Dosing: Theory and Critical Analyses

et al. 2018

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“…In order to reduce the formulation interference from different manufacturers' products, pharmacokinetic data of the reference product (Crestor) were evaluated. 26 These findings may be helpful to further understand the statin pharmacokinetic profiles across ethnic groups. Meanwhile, the mean systemic exposure was observed to be 35.1%, 22.5%, 52.6%, and 50.6% decreased (ß41.5% reduction, average of AUC 0-t ), respectively, under fed conditions.…”

Section: Discussionmentioning

confidence: 96%

Effects of Food and Gender on Pharmacokinetics of Rosuvastatin in a Chinese Population Based on 4 Bioequivalence Studies

Chen

Lou

Jiang

et al. 2019

Clinical Pharm in Drug Dev

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The effects of food and gender on the pharmacokinetics of rosuvastatin in healthy Chinese subjects were investigated from 4 bioequivalence studies. These studies were designed as randomized, open-label, and 2-period crossover in both fasting and fed states. A total of 204 subjects were enrolled, 134 men and 70 women. These subjects received a single oral 10-mg dose of rosuvastatin with a 7-day washout between 2 periods. The plasma concentrations were determined using a validated liquid chromatography tandem mass spectrometry method, and pharmacokinetic parameters were calculated by noncompartmental methods. Compared with the fasting condition, administration after a high-fat and high-calorie meal resulted in an approximately 40% reduction of rosuvastatin exposure and a near 50% decrease in absorption rate. Moreover, the apparent clearance was significantly greater in the fed state than that in the fasting state. It was noted that the adverse events incidence is increased by approximately 30% in the fasting state; however, no serious adverse events were observed. Additionally, small differences in pharmacokinetic characteristics were found between male and female subjects. Food effect might be considered for optimal effectiveness and safety of rosuvastatin therapy.

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“…Recently we addressed the pharmacogenomic issues related to rosuvastatin dosing. 38,39 Asian patients receiving the HMG-CoA reductase inhibitor rosuvastatin for lowering cholesterol levels exhibit on average 2-times higher rosuvastatin blood concentrations than those observed in white patients. The US FDA recommends that Asian patients should receive one-half the dose of rosuvastatin given to white patients because of rhabdomyolysis and myalgia concerns.…”

Section: Pharmacogenomicsmentioning

confidence: 93%

“…Recently we addressed the pharmacogenomic issues related to rosuvastatin dosing . Asian patients receiving the HMG‐CoA reductase inhibitor rosuvastatin for lowering cholesterol levels exhibit on average 2‐times higher rosuvastatin blood concentrations than those observed in white patients.…”

Section: The Concept Of Dettlimentioning

confidence: 99%

“…Based on the rosuvastatin label, pharmacogenomic variance in OATP1B1 alone could not explain this difference. Therefore, we investigated rosuvastatin PK in Asian and white subjects wild type for both OATP1B1 and BCRP under control and when the transporters are inhibited by dosing rifampin . Table depicts the measures for C max and AUC 0→48 and CL/F for white and Asian subjects under control conditions and when they are given a single 600‐mg IV dose of rifampin.…”

Section: The Concept Of Dettlimentioning

confidence: 99%

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Predicting Pharmacokinetics/Pharmacodynamics in the Individual Patient: Separating Reality From Hype

Benet

2018

The Journal of Clinical Pharma

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Individualization of patient drug dosing to maximize efficacy and minimize toxicity is the goal of clinical pharmacology. Here we review the history of drug dosing individualization from early predictions for renally eliminated drugs based on kidney function through the introduction of clearance concepts for metabolic processes, the differentiation of volume of distribution between pharmacokinetics and chemistry, the role of transporters, the unique pharmacokinetic aspects of oral dosing, and the relevance of protein binding to the emergence of pharmacogenomics. The Food and Drug Administration listing of pharmacogenomic markers in approved drug labeling is analyzed with respect to the promise of genomics in terms of picking the right drug for the patient based on genetic information vs selecting or adjusting the dosage regimen based on genetic information: the former resulting in a great advance, whereas the latter has shown less convincing evidence of clinical relevance. Finally, new information on individualized predictive methodologies based on marker drugs for enzymes and transporters is reviewed. We conclude that although individualization of drug dosing will work for most drugs primarily excreted unchanged in the urine, individualization of dosing regimens is not critical for wide-therapeutic-index drugs, whereas for narrow-therapeutic-index drugs predictions are most often more hype than reality, with therapeutic drug monitoring required. However, continuing advances in discovering and validating biomarkers will lead to predictions of pharmacokinetics/pharmacodynamics in the individualized patient that should result in shifting the hype to reality with time.

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Rosuvastatin Pharmacokinetics in Asian and White Subjects Wild Type for Both OATP1B1 and BCRP Under Control and Inhibited Conditions

Cited by 64 publications

References 32 publications

The Extended Clearance Concept Following Oral and Intravenous Dosing: Theory and Critical Analyses

The Extended Clearance Concept Following Oral and Intravenous Dosing: Theory and Critical Analyses

Effects of Food and Gender on Pharmacokinetics of Rosuvastatin in a Chinese Population Based on 4 Bioequivalence Studies

Predicting Pharmacokinetics/Pharmacodynamics in the Individual Patient: Separating Reality From Hype

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