Effect of Renal Impairment on the Pharmacokinetics and Safety of Doxecitine and Doxribtimine: A Single‐Dose Phase 1 Study

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.