Abstract
This Phase 1 study investigated the pharmacokinetics and safety of a single dose of the FDA-approved doxecitine and doxribtimine (266.6 mg/kg; 133.3 mg/kg of deoxycytidine [dC] and deoxythymidine [dT]) in participants with severe (n = 8) or moderate (n = 8) renal impairment (estimated glomerular filtration rate [eGFR] 15-29 mL/min/1.73 m(2) and 30-59 mL/min/1.73 m(2), respectively) versus healthy matched controls (eGFR ≥90 mL/min/1.73 m(2); n = 16 [two groups of eight]). Participants underwent serial sampling to determine total dC and dT plasma concentrations before (baseline) and after dosing (up to 96 h). Participants with renal impairment had higher baseline-corrected dC and dT concentrations than controls, which peaked 0.75-1.5 h post-dose and declined to near baseline levels in ≤18 h. Geometric mean baseline-corrected plasma maximum concentration and area under the concentration-time curve (respectively) for dC and dT were higher in participants with severe (dC: 7.8 ng/mL and 52.8 h × ng/mL; dT: 18.8 ng/mL and 31.5 h × ng/mL) or moderate (dC: 8.2 ng/mL and 56.4 h × ng/mL; dT: 12.2 ng/mL and 23.7 h × ng/mL) renal impairment than in controls (dC: 4.6-5.3 ng/mL and 25.4-31.8 h × ng/mL; dT: 4.0-7.6 ng/mL and 4.3-12.7 h × ng/mL), with substantial variability. Geometric mean apparent terminal-phase half-lives in severe renal impairment, moderate renal impairment, and controls, respectively, were 14.5, 15.3, and 5.2-5.8 h for dC and 3.7, 4.5, and 0.4-1.5 h for dT. One participant experienced treatment-emergent adverse events (severe renal impairment cohort). In conclusion, renal impairment was associated with increased dC and dT exposure following a single dose of doxecitine and doxribtimine. No safety issues were identified.