Background: Tedizolid (200mg qd for 6 days) is approved in the US, Canada, and the EU for treatment of acute bacterial skin and skin structure infections. Population pharmacokinetics (PK) analyses showed tedizolid PK to be similar across a wide range of patient factors, with IBW (an anthropometric measurement based on height) being the covariate accounting for the greatest variability (not clinically significant). Tedizolid dose adjustments are assumed as not required in any patient population, including elderly patients and in severe renal or hepatic impairment. However, Phase 1 data suggested a minor difference in tedizolid exposure (~25% reduction) in subjects with ESRD on dialysis relative to non-dialyzed subjects with severe renal impairment and matched controls. The reasons for these differences are unknown.
Methods: In this post-hoc analysis of a Phase 1 study conducted in subjects with varying degrees of renal impairment, we compared individual subjects' tedizolid exposure expressed as area under the concentration-time curve (AUC) as a function of IBW between 3 groups (N=8 each): (1) subjects with ESRD requiring chronic dialysis, as well as (2) severe renally impaired subjects not requiring dialysis and (3) their matched (by sex, age, and BMI) healthy control subjects. Our objective was to determine if between-group differences in IBW may explain the previously reported differences in AUC.
Results: Differences in tedizolid AUC between the 3 groups were readily explained by differences in IBW (Figure). Whereas most of the control and non-dialyzed severe renal impairment subjects IBW were in the lower half of the range, all but one of the dialyzed subjects were in the top half of the range. Since tedizolid AUC varies inversely with IBW, it is not surprising that in this particular study tedizolid exposure in dialyzed subjects was found to be somewhat lower than in severe renal impairment and controls.
Conclusion: Small differences observed in tedizolid exposure among dialyzed subjects were likely due to differences in IBW, and not underlying renal clearance. These results further support the assumption that no tedizolid dose adjustments are required in patients with any degree of renal impairment, including those with ESRD.