Abstract
BackgroundDose 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.MethodsThe 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.ResultsIn 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.ConclusionThe results indicate that the proposed method provides a rational approach to determine the proper PK dose in hemodialysis patients.
Highlights
Dose selection is an important step in pharmacokinetic (PK) studies of hemodialysis patients
Two of the 10 participants who received a dose of 35 mg of oseltamivir experienced nausea, which was mild in intensity
Oseltamivir could not be detected after 6 hr, the shapes of the oseltamivir and oseltamivir carboxylate (OC) dose response curves were similar, and the curves were predominantly superimposable at the various doses
Summary
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. In addition to impaired renal function, hemodialysis patients may possess altered pharmacokinetics (PKs) caused by hemodialysis itself. Clinical concerns have arisen regarding oseltamivir use in patients with ESRD because of their high mortality from influenza, generally severe courses of influenza infection, and reduced response to vaccinations [9]. These PK and clinical characteristics of oseltamivir correspond to a drug category where the U.S FDA recommends mandatory PK studies in patients with impaired renal function [10]. We selected oseltamivir, even though this drug is already approved for mass marketing and its therapeutic dose PKs in ESRD patients are well known [5]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
