Pharmacokinetics and Renal Effects of Cidofovir with a Reduced Dose of Probenecid in HIV‐Infected Patients with Cytomegalovirus Retinitis

Abstract

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.

Low-dose cidofovir treatment of BK virus-associated hemorrhagic cystitis in recipients of hematopoietic stem cell transplant

“…[21][22][23][24][25] After 1 h infusions of 1, 3, 5, 7.5 and 10 mg/kg, the drug demonstrated doseindependent pharmacokinetics both with and without probenecid. Without probenecid, in patients with normal renal function, approximately 80-100% of the cidofovir dose was recovered unchanged in urine within 24 h, whereas approximately 70-85% of cidofovir was excreted within 24 h in patients who were also given probenicid.…”

The History and Future of Probenecid

“…It was found that as little as 2 g of probenecid administered orally daily was able to increase two-to fivefold the serum concentrations of penicillin [12]. This finding led to a number of subsequent studies of concomitant administration with antibiotics and antivirals to treat a range of infections from the rather mundane-like gonorrhea [36,37] and the influenza virus [35] to some of the most devastating infectious diseases of our time including typhoid fever [56], mycobacterial diseases [13], and even HIV [80]. The clinical relevance of this effect has mostly waned as the production of the antibiotics, and other agents have become easier, cheaper, and safer [5]; however, some researchers still continue to investigate the use of probenecid as adjunct therapy with antibiotics for the treatment of persistent infections [50,76].…”

Combination of probenecid-sulphadoxine-pyrimethamine for intermittent preventive treatment in pregnancy

“…Since its introduction, it has been found to inhibit the tubular secretion of other weak organic acids, such as p-aminohippuric acid, salicylic acid and uric acid, as well as other antibiotics (including cephalosporins), and anti-retrovirals (including oseltamavir and zidovudine). This characteristic of probenecid allows for decreased doses of medications to be used, thus limiting toxicity, especially with nephrotoxic agents [27-30]. Probenecid has been widely used as an uricosuric agent in the treatment of gout [26], and has a long history of use without serious toxicity [31].…”