Clinical pharmacokinetics of adefovir in human immunodeficiency virus type 1-infected patients.
The pharmacokinetics and bioavailability of adefovir [9-[2-(phosphonomethoxy)ethyl]adenine] were examined at two dose levels in three phase I/II studies in 28 human immunodeficiency type 1-infected patients. The concentrations of adefovir in serum following the intravenous infusion of 1.0 or 3.0 mg/kg of body weight were dose proportional and declined biexponentially, with an overall mean +/- standard deviation terminal half-life of 1.6 +/- 0.5 h (n = 28). Approximately 90% of the intravenous dose was recovered unchanged in the urine in 12 h, and more than 98% was recovered by 24 h postdosing. The overall mean +/- standard deviation total serum clearance of the drug (223 +/- 53 ml/h/kg; n = 25) approximated the renal clearance (205 +/- 78 ml/h/kg; n = 20), which was significantly higher (P < 0.01) than the baseline creatinine clearance in the same patients (88 +/- 18 ml/h/kg; n = 25). Since adefovir is essentially completely unbound in plasma or serum, these data indicate that active tubular secretion accounted for approximately 60% of the clearance of adefovir. The steady-state volume of distribution of adefovir (418 +/- 76 ml/kg; n = 28) suggests that the drug was distributed in total body water. Repeated daily dosing with adefovir at 1.0 mg/kg/day (n = 8) and 3.0 mg/kg/day (n = 4) for 22 days did not significantly alter the pharmacokinetics of the drug; there was no evidence of accumulation. The oral bioavailability of adefovir at a 3.0-mg/kg dose was < 12% (n = 5) on the basis of the concentrations in serum or 16.4% +/- 16.0% on the basis of urinary recovery. The subcutaneous bioavailability of adefovir at a 3.0-mg/kg dose was 102% +/- 8.3% (n = 5) on the basis of concentrations in serum or 84.8% +/- 28.5% on the basis of urinary recovery. These data are consistent with preclinical observations in various species.
Cundy
K C
KC
Gilead Sciences, Inc., Foster City, California 94404, USA.
Barditch-Crovo
P
P
Walker
R E
RE
Collier
A C
AC
Ebeling
D
D
Toole
J
J
Jaffe
H S
HS
D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000284:Administration, Oral; D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism* / Q000821:virology; D015497:HIV-1; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates; D011485:Protein Binding
D000998:Antiviral Agents; D063065:Organophosphonates; C053001:adefovir; D000225:Adenine