Zidovudine disposition in patients with severe renal impairment: influence of hemodialysis.

ABSTRACT

Pharmacokinetics of zidovudine (azidothymidine, AZT) was investigated after oral administration (200 mg) in 25 HIV seronegative subjects: 14 patients with severe renal impairment (creatinine clearance 6 to 31 ml/min), five hemodialyzed anuric patients, and six healthy subjects. Plasma and urine concentrations of zidovudine and its glucuronidated metabolite (GAZT) were measured simultaneously by HPLC assay. In healthy subjects, GAZT concentrations were higher than those of AZT; AUC values were 23.7 +/- 1.9 and 5.2 +/- 0.6 mumol.hr/L, respectively. Formation of GAZT rate-limits its elimination GAZT half-life (t 1/2) parallels that of AZT, which is around 1 hour. In uremic patients, AZT concentrations were moderately increased (AUC = 11.7 +/- 1.1 mumol.hr/L), whereas t 1/2 and mean residence time (MRT) remain unchanged despite the decreased renal clearance (16 +/- 2 versus 220 +/- 58 ml/min) and decreased urinary excretion (1.6 +/- 0.3 versus 8.1 +/- 1.0% of the dose). In contrast, GAZT concentrations are markedly increased (AUC = 402.9 +/- 88.6 mumol.hr/L). As a consequence of the decreased renal clearance (27 +/- 3 versus 331 +/- 42 ml/min), elimination is the rate-limiting step and t 1/2 is increased (8 +/- 2 versus 0.9 +/- 0.1 hr). Contribution of a 4-hour hemodialysis session to AZT elimination appears to be negligible, whereas elimination of GAZT is enhanced. On the sole basis of AZT pharmacokinetic data, no particular dose adjustment appears to be necessary in patients who have severe renal impairment (creatinine clearance between 10 and 30 ml/min). However, high levels of GAZT should be anticipated with the usual dosage regimen.