Although the terminal half-life of cidofovir is approximately 2.6 hours, the active metabolite cidofovir diphosphate has a prolonged intracellular half-life of 17–65 hours, thus allowing infrequent dosing. A separate metabolite, cidofovir phosphocholine, has a half-life of at least 87 hours and may serve as an intracellular reservoir of active drug. Cerebrospinal fluid penetration is poor. Elimination is by active renal tubular secretion. High-flux hemodialysis reduces serum levels of cidofovir by approximately 75%.
Intravenous cidofovir is effective for the treatment of CMV retinitis and is used experimentally to treat adenovirus, human papillomavirus, BK polyomavirus, vaccinia, and poxvirus infections. Intravenous cidofovir must be administered with high-dose probenecid (2 g at 3 hours before the infusion and 1 g at 2 and 8 hours after), which blocks active tubular secretion and decreases nephrotoxicity. Before each infusion, cidofovir dosage must be adjusted for alterations in the calculated creatinine clearance or for the presence of urine protein, and aggressive adjunctive hydration is required. Initiation of cidofovir therapy is contraindicated in patients with existing renal insufficiency. Direct intravitreal administration of cidofovir is not recommended because of ocular toxicity.
The primary adverse effect of intravenous cidofovir is a dose-dependent proximal tubular nephrotoxicity, which may be reduced with prehydration using normal saline. Proteinuria, azotemia, metabolic acidosis, and Fanconi’s syndrome may occur. Concurrent administration of other potentially nephrotoxic agents (eg, amphotericin B, aminoglycosides, nonsteroidal anti-inflammatory drugs, pentamidine, foscarnet) should be avoided. Prior administration of foscarnet may increase the risk of nephrotoxicity. Other potential adverse effects include uveitis, ocular hypotony, and neutropenia (15–24%). Concurrent probenecid use may result in other toxicities or drug-drug interactions (see Chapter 36). Cidofovir is mutagenic, gonadotoxic, and embryotoxic, and causes hypospermia and mammary adenocarcinomas in animals.
Brincidofovir is a nucleoside agent with activity against HSV, CMV, adenovirus, BK virus, and poxvirus. It is currently under clinical investigation for CMV and adenovirus infections.
Substantial advances have been made in antiretroviral therapy since the introduction of the first agent, zidovudine, in 1987. Six classes of antiretroviral agents are currently available for use: nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), fusion inhibitors, CCR5 co-receptor antagonists, and integrase strand transfer inhibitors (INSTIs) (Table 49–3). These agents inhibit HIV replication at different parts of the cycle (Figure 49–3).