LAUSR

Hellfritzsch et al. discuss an apparent lack of consistency in reporting of renal elimination data among novel oral anticoagulant drugs: with a focus on apixaban.1 We would like to provide the totality of data that contribute to our understanding of the renal elimination profile of apixaban. As discussed previously,2 intravenous (IV) administration is required to accurately estimate the extent of renal elimination, and the estimate of 27% for apixaban was obtained from two IV studies.3,4 In the first study, 30 subjects were treated with a single IV dose of apixaban (0.5 to 5 mg; six subjects per dose level).3 In the second study, 20 subjects received a single 5-mg IV dose.4 In these studies, total clearance and renal clearance were calculated as previously described.2 Apixaban renal clearance was 17%–30% and 34% of total clearance, from the first and second studies, respectively,3,4 averaging approximately 27% across both studies, as reported in the package inserts.5,6 As Hellfritzsch et al. point out, results of these studies were previously only available as published abstracts, but results of one of these studies have since been published as a manuscript.4 It should be noted that the mass balance study of orally administered apixaban has been incorrectly cited to support an estimate of the extent of apixaban renal elimination, as it is impossible to determine the renal contribution to total clearance from these data without knowing the absolute bioavailability of apixaban in these subjects.7 Hellfritzsch et al. also appear to question the validity of the assessment of the impact of renal impairment on the exposure of apixaban and its relevance to the patient populations treated with apixaban. The pharmacokinetics of apixaban in subjects with renal impairment or on hemodialysis was evaluated in two studies,8,9 consistent with current regulatory guidance.10,11 The first study examined the impact of mild-to-severe renal impairment on apixaban exposure (24 subjects with mild-to-severe renal impairment and eight subjects with normal renal function) after administration of a single 10-mg oral dose.8 The second study compared the pharmacokinetics of apixaban in eight subjects with end-stage renal disease (ESRD) on hemodialysis to eight subjects with normal renal function after administration of a single 5-mg dose.9 The results of the two studies were consistent, with an estimated 44% higher area under the plasma concentration-time curve (AUC) in subjects with severe renal impairment8 and a 36% higher AUC in subjects with ESRD,9 compared with subjects with normal renal function. These results are also consistent with the 27% renal elimination for apixaban determined from the IV studies. If renal clearance were as high as ~48% of total clearance, as suggested by Hellfritzsch et al., and renal impairment is assumed not to affect other elimination processes, then an approximately two-fold (100%) increase in AUC would have been expected in subjects with severe renal impairment or ESRD, as renal clearance is expected to be close to zero in these subjects. Thus, based on the results of the IV and renal impairment studies, we have concluded that the effect of renal impairment on apixaban pharmacokinetics has been well characterized and has been shown to be modest. Hellfritzsch et al. question whether the results of these single-dose studies are applicable to patients who receive multiple doses over a prolonged period, citing a “38% higher AUC” in subjects with nonvalvular atrial fibrillation (NVAF) and moderate renal impairment in the ARISTOTLE trial.12 However, this citation appears to be incorrect, as the population pharmacokinetic analysis for subjects with