Pharmacokinetics of low‐dose cidofovir in kidney transplant recipients with BK virus infection

Abstract

Background BK virus (BKV) infection in kidney transplant recipients is associated with progressive graft dysfunction and graft loss. Cidofovir, an antiviral agent with known nephrotoxicity, has been used in low doses to treat BKV infections. However, the systemic exposure and disposition of the low-dose cidofovir regimen is unknown in kidney transplant recipients. Methods We investigated the pharmacokinetics of low-dose cidofovir both without and with oral probenecid in 9 transplant patients with persistent BK viremia without nephropathy in a crossover design. Results The mean estimated glomerular filtration rate (eGFR) of the study participants was 46.2 mL/min/1.73 m2 (range: 17 – 75 mL/min/1.73 m2). The contribution of active renal secretion to cidofovir total body clearance was assessed by evaluating the effect of probenecid on cidofovir pharmacokinetics. Maximum cidofovir plasma concentrations, which averaged approximately 1 μg/mL, were significantly below the 36 μg/mL 50% effective concentration in vitro for cidofovir against BKV. The plasma concentration of cidofovir declined with an overall disposition half-life of 5.1 ± 3.5 and 5.3 ± 2.9 h in the absence and in the presence of probenecid, respectively (P> 0.05). Conclusions Cidofovir clearance and eGFR were linearly related irrespective of probenecid administration (r2=0.8 without probenecid; r2=0.7 with probenecid). This relationship allows for the prediction of systemic cidofovir exposure in individual patients and may be utilized to evaluate exposure-response relationships in order to optimize the cidofovir dosing regimen for BKV infection.

Cidofovir in the Treatment of BK Virus–Associated Hemorrhagic Cystitis after Allogeneic Hematopoietic Stem Cell Transplantation

“…The limitation of this approach is that the pharmacokinetic criterion (area under the concentrationtime curve) is probably not the best predictor of cidofovir efficacy: Concentration in the kidney may be much higher than in plasma [20]. Moreover, the high affinity of cidofovir for the kidney may partially explain the virological response observed in some patients despite low systemic exposure [37]. Although the renal toxicity of cidofovir is now well documented, the impact of other drugs should be taken into account; almost all patients also received cyclosporine as part of transplantation care but also other nephrotoxic drugs (antibiotics, antivirals, antifungals).…”

Insights into the mechanism of action of cidofovir and other acyclic nucleoside phosphonates against polyoma- and papillomaviruses and non-viral induced neoplasia

“…The use of adjuvant low-dose CDV therapy was shown to result in prolonged graft survival and stabilized graft function in renal transplant recipients suffering from BKPyV interstitial nephritis (Kuypers et al, 2005). A recent study has demonstrated that CDV clearance and the mean estimated glomerular filtration rate in renal transplant recipients with persistent BKPyV viremia without nephropathy were linearly related irrespective of probenecid administration (Momper et al, 2013). Based on this relationship, the systemic exposure to CDV in individual patients can be predicted and may be used to evaluate exposure-response relationships to optimize CDV dosing regimen for BKPyV infection.…”

The Oncogenic Small Tumor Antigen of Merkel Cell Polyomavirus Is an Iron-Sulfur Cluster Protein That Enhances Viral DNA Replication

“…Although cidofovir has long been known to inhibit the replication of polyomaviruses in culture, its mechanism of action has remained uncertain (38,39,57). Here, we show that cidofovir can inhibit MCPyV replication.…”

“…Cidofovir is a potent inhibitor of polyomavirus replication (38,39,57). Although its active metabolite, cidofovir diphosphate, is known to inhibit viral DNA replication by selectively inhibiting virally encoded DNA polymerases, polyomaviruses do not encode any polymerases.…”