Response to Letter to the Editor From Drs. Stöllberger and Finsterer

Abstract

Dear Editor,We appreciate Professors Stöllberger's and Finsterer's interest and the opportunity to address their questions, which mainly concerned potential sources of variability in our apixaban renal impairment study. 1 The apixaban pharmacokinetic profile observed in this study is consistent with previous reports, 2-5 including the extent of variability that is considered low to moderate. The conduct-related concerns the professors raised were not factors in the study. This was a wellcontrolled and carefully designed study conducted in accordance with international guidelines at highly qualified and trained sites. All subjects consumed the correct dose, as confirmed by mouth-check, after a 10-hour fast and consumed standardized meals at specified times following administration. Concomitant medications and foods known to modulate CYP3A or P-gp activity were prohibited prior to and during participation. When appropriate, other comedications were held 4 hours before and after apixaban administration. Smoking is not expected to impact apixaban pharmacokinetics; in any case, the use of tobacco-related products was prohibited for 2 hours prior to and 6 hours after apixaban administration.Renal impairment is a complex disorder with diversity in etiology, severity, and rate of progression as well as comorbidities. Our study was not designed to evaluate the effects of individual chronic kidney disease characteristics; rather, it evaluated the relationship between an overall measure of renal function and apixaban pharmacokinetics, as is common practice. 6 Our study included individuals with stable chronic renal impairment, and the majority, 20 of 24 subjects, had underlying hypertension and/or diabetes. Conditions including hypercholesterolemia, anemia, and reflux were present in some individuals. Subjects with a history of drug abuse were excluded from the study. There was no evidence of hepatic impairment in baseline examinations or laboratory results. Regardless of medical history or comorbidities, the renal function assessments in an individual subject were highly consistent across the 4 methods used to determine renal function in our study. We are encouraged by the consistency between these results and those in subjects with end-stage renal disease. 7 Therefore, we remain confident that the effect of chronic renal impairment on apixaban pharmacokinetics was well characterized.Apixaban pharmacokinetics are linear over the therapeutic dose range and do not exhibit any time dependencies. 3,4 Therefore, the effect of renal impairment on single-dose apixaban pharmacokinetics is predictive of what would be expected at steady-state and reflects the relative increase in apixaban exposure resulting from accumulation following multiple dosing in renally impaired patients.Our study was not designed to determine the safety and efficacy of apixaban in atrial fibrillation patients with renal impairment. We discussed available clinical data for atrial fibrillation in our manuscript, 8,9 which are included in the meta-analysis 10 ...