Pharmacokinetics and renal effects of cidofovir with a reduced dose of probenecid in HIV-infected patients with cytomegalovirus retinitis.
To reduce possible nephrotoxicity, intravenous prehydration with normal saline and administration of probenecid must be used with each infusing of the antiviral cidofovir. The recommended standard-dose probenecid (SDP) regimen is 2 g at 3 hours before cidofovir, then 1 g at 2 and 8 hours after cidofovir (total 4 g). A new regimen of reduced-dose probenecid (RDP), 2 g at 1 hour before cidofovir without additional probenecid administrations after infusion (total 2 g), was compared with SDP using a randomized, open-label, parallel design. A single dose of cidofovir (5 mg/kg) was given as a 1-hour infusion after saline prehydration to 24 HIV-infected patients (11 males, 13 females) with cytomegalovirus retinitis and good renal function. Blood was sampled for 48 hours and urine for 24 hours after the start of the cidofovir infusion. Cidofovir pharmacokinetics did not differ significantly between groups. Average key pharmacokinetic parameters (Cmax, tmax, lambda z, AUC0-infinity, Vss, CL, CLR, fe, ER) for RDP differed by less than 17% from SDP and were consistent with previously reported SDP data. Renal function parameters, other safety endpoints, and adverse events were similar between the groups. Therefore, the reduced-dose regimen of probenecid provided renal protection after a single dose of cidofovir and did not alter the pharmacokinetics of cidofovir in patients with moderately good renal function. Although the overall pharmacokinetic results do not show a significant difference in cidofovir exposure with the new probenecid regimen, the main issue of safety of the new dose regimen, both relating to renal toxicity and probenecid-related adverse events, is not adequately addressed in a small study.
Wolf
Daniel L
DL
Pharmacia Corporation, Kalamazoo, MI 49007, USA.
Rodríguez
Carlos A
CA
Mucci
Massimiliano
M
Ingrosso
Antonella
A
Duncan
Barbara A
BA
Nickens
Dana J
DJ
D017088:AIDS-Related Opportunistic Infections / Q000188:drug therapy* / Q000378:metabolism; D000328:Adult; D000998:Antiviral Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000077404:Cidofovir; D017726:Cytomegalovirus Retinitis / Q000188:drug therapy* / Q000378:metabolism; D003596:Cytosine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011339:Probenecid / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use
D000998:Antiviral Agents; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D003596:Cytosine; D000077404:Cidofovir; D011339:Probenecid