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Open Access Research article

Dose selection method for pharmacokinetic study in hemodialysis patients using a subpharmacological dose: oseltamivir as a model drug

Dong Ki Kim1, Jay Wook Lee2, Kwang-Hee Shin3, Sejoong Kim4, Kook-Hwan Oh1, Myounghee Kim5, Kyung-Sang Yu6, Jung Pyo Lee7, Chun-Soo Lim7, Yon Su Kim1 and Kwon Wook Joo18*

Author Affiliations

1 Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea

2 Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea

3 College of Pharmacy, Kyungpook National University, Daegu, Korea

4 Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea

5 Department of Dental Hygiene, College of Health Science, Eulji University, Seongnam, Korea

6 Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine, Seoul, Korea

7 Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Korea

8 Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongro-gu, Seoul 110-744, Korea

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BMC Nephrology 2014, 15:46  doi:10.1186/1471-2369-15-46

Published: 17 March 2014

Abstract

Background

Dose selection is an important step in pharmacokinetic (PK) studies of hemodialysis patients. We propose a simulation-based dose-selection method for PK studies of hemodialysis patients using a subpharmacological dose of oseltamivir as a model drug.

Methods

The concentrations of oseltamivir and its active metabolite, oseltamivir carboxylate (OC), were measured by liquid chromatography-tandem mass spectrometry. To determine a low oseltamivir dose exhibiting PK linearity, a pilot low dose determination investigation (n = 4) was performed using a single administration dose-escalation study. After the dose was determined, a low dose study (n = 10) was performed, and the optimal dose required to reach the hypothetical target OC exposure (area under the concentration-time curve [AUC] of 60,000 ng · hr/mL) was simulated using a nonparametric superposition method. Finally, observed PKs at the optimal dose were compared to the simulated PKs to verify PK predictability.

Results

In the pilot low dose determination study, 2.5 mg of oseltamivir was determined to be the low dose. Subsequently, we performed a single-dose PK study with the low oseltamivir dose in an additional group of 10 hemodialysis patients. The predicted AUClast of OC following continuous oseltamivir doses was simulated, and 35 mg of oseltamivir corresponded to the hypothetical target AUClast of OC. The observed PK profiles of OC at a 35-mg oseltamivir dose and the simulated data based on the low dose study were in close alignment.

Conclusion

The results indicate that the proposed method provides a rational approach to determine the proper PK dose in hemodialysis patients.

Keywords:
Hemodialysis; Pharmacokinetics; Drug; Dosage