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Pharmacokinetic and Pharmacodynamic Profile of Rosuvastatin in Patients with End-Stage Renal Disease on Chronic Haemodialysis

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Abstract

Background

Rosuvastatin has been shown to provide effective treatment of dyslipidaemia in patients with end-stage renal disease (ESRD) undergoing haemodialysis, but data from controlled trials are very limited on the pharmacokinetics and pharmacodynamics of rosuvastatin in this population.

Objective

The aim of the present study was to better define the pharmacokinetic and pharmacodynamic profiles of repeated doses of rosuvastatin at a starting dose of 10 mg/day in a group of patients with ESRD.

Study Design

This was a single-centre, open-label study of rosuvastatin 10 mg daily, given over a 16-day treatment period in patients with ESRD undergoing chronic haemodialysis.

Setting

The study was carried out at a single site in the USA.

Patients

Patients aged 18–65 years with ESRD who had been on dialysis for ≥3 months were eligible for inclusion. Of 12 patients enrolled, 11 were included in the pharmacokinetic and pharmacodynamic analysis and all were included in the safety evaluation. The mean age of patients was 43.9 years (range 24–60 years). Five patients were Caucasian, six were black and one was Hispanic.

Intervention

Patients received an oral dose of rosuvastatin 10 mg once daily in the morning for 16 consecutive days.

Main Outcome Measure

The primary objective was to estimate the degree of rosuvastatin accumulation in plasma by measuring the area under the plasma concentration time curve (AUC) from time zero to 24 h following a single dose of rosuvastatin 10 mg on day 1, and the AUC at steady state on day 15.

Results

Following administration of single and multiple doses, plasma concentrations of rosuvastatin declined in an apparent bi-exponential manner and remained above the limit of assay detection throughout the entire sampling periods on both day 1 and day 15. Steady-state plasma concentrations of rosuvastatin were achieved by day 11. Little accumulation of rosuvastatin after repeated, once-daily dosing was observed; the geometric mean accumulation ratio for rosuvastatin was 1.37 (coefficient of variation = 36.4 %). Clearance of rosuvastatin and its metabolites via dialysis was minimal. Following rosuvastatin 10 mg daily for 16 days, total cholesterol, low-density lipoprotein cholesterol and apolipoprotein B were reduced from baseline by 30.6 %, 38.9 % and 30.6 %, respectively. Rosuvastatin was well tolerated.

Conclusion

The degree of rosuvastatin accumulation observed in patients receiving dialysis is similar to that in healthy individuals. The results of the current study suggest that rosuvastatin 10 mg may be administered to patients with ESRD on chronic haemodialysis without need for dose reduction.

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Acknowledgments

This study was sponsored by AstraZeneca. The sponsor was involved in the design of the study and the collection, analysis and interpretation of the data, as well as the writing of the report, and was involved in the decision to submit the paper for publication. PM and CA are employees of AstraZeneca. BB, YW, TP and JZ are former employees of AstraZeneca. BB is currently employed by Yoh, a Service Provider to AstraZeneca Pharmaceuticals (Philadelphia, PA, USA), YW is currently employed by Purdue Pharma (Stamford, CT, USA), TP is currently employed by Janssen Pharmaceutical (Springhouse, PA, USA), JZ is currently employed by Amgen, PKDM-Seattle (Seattle, WA, USA). SS is a former employee of DaVita Clinical Research & Hennepin County Medical Center, and is currently employed by PAREXEL (Billerica, MA, USA). BB, PM, CA, JZ and YW all hold stock in AstraZeneca. Dennis Schneck, a former employee of AstraZeneca, acted as a medical advisor and was involved in the study design. Medical writing support was provided by Neil Venn and Kerry Knight of Prime Medica Ltd (Knutsford, Cheshire, UK) and editorial support by Maren White of White Quill Ltd, supported by AstraZeneca. Responsibility for opinions, conclusions, and interpretation of data lies with the authors.

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Authors and Affiliations

  1. AstraZeneca, Wilmington, DE, USA

    Bruce K. Birmingham, Tom Puchalski, Pat Mitchell, Connie Azumaya, Julie Zalikowski & Yi Wang

  2. DaVita Clinical Research & Hennepin County Medical Center, Minneapolis, MN, USA

    Suzanne K. Swan

  3. Purdue Pharma, One Stamford Forum, Stamford, CT, 06901, USA

    Yi Wang

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  1. Bruce K. Birmingham
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Correspondence to Yi Wang.

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Birmingham, B.K., Swan, S.K., Puchalski, T. et al. Pharmacokinetic and Pharmacodynamic Profile of Rosuvastatin in Patients with End-Stage Renal Disease on Chronic Haemodialysis. Clin Drug Investig 33, 233–241 (2013). https://doi.org/10.1007/s40261-013-0071-3

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