Pharmacokinetics and safety of intravesicular cidofovir in allogeneic HSCT recipients. (26th November 2015)

• Record Type: Journal Article
• Authors: Aitken, Samuel L.; Zhou, Jian; Ghantoji, Shashank S.; Kontoyiannis, Dimitrios P.; Jones, Roy B.; Tam, Vincent H.; Chemaly, Roy F.
• Is Part Of: Journal of antimicrobial chemotherapy. Volume 71:Number 3(2016:Mar.)
• Page Start: 727
• Page End: 730
• Publication Date: 2015-11-26
• Subjects: Anti-infective agents -- Periodicals; Chemotherapy -- Periodicals; 615.58
• DOI: 10.1093/jac/dkv393
• Languages: English
• ISSNs: 0305-7453

Abstract

Abstract: Objectives: The objective of this study was to evaluate the pharmacokinetics and safety of cidofovir administered via the intravesicular route to patients with haemorrhagic cystitis following allogeneic HSCT (allo-HSCT). Methods: Patients with gross haematuria and confirmed BK or adenovirus viruria following allo-HSCT were prospectively enrolled in an open-label pharmacokinetic study (ClinicalTrials.gov registration: NCT01816646). Three hours after an oral probenecid dose (2 g), cidofovir (2.5–5 mg/kg in 50–100 mL of normal saline) was given via a transurethral catheter for up to 2 h of dwell time. Serial plasma samples were obtained over 24 h and assayed for cidofovir concentrations using LC-MS/MS. A custom pharmacokinetic model with a time-limited absorption compartment was fitted to the concentration–time profile of each patient. Systemic drug exposure was expressed as AUC0–24, by integrating the best-fit profile with respect to time. Results: Six subjects (mean ± SD age = 38 ± 21 years) with baseline serum creatinine <1.4 mg/dL were enrolled. Mean values for volume of distribution, clearance and elimination half-life were 19.5 L, 5.6 L/h and 2.8 h, respectively. Compared with the reported AUC0–24 for an equivalent intravenous dose, intravesicular instillation of cidofovir resulted in 1%–74% of the corresponding systemic exposure. Owing to primarily lower abdominal pain, only two patients were able to tolerate a 2 h dwell time. One patient developed a >50% increase in serum creatinine within 7 days of administration. Conclusions: Intravesicular administration of cidofovir resulted in highly variable systemic exposures. The safety and efficacy of intravesicular cidofovir should be further evaluated before routine use.