Pharmacokinetics and safety of intravesicular cidofovir in allogeneic HSCT recipients

• Published in: Journal of antimicrobial chemotherapy Vol. 71; no. 3; pp. 727 - 730
• Main Authors: Aitken, Samuel L., Zhou, Jian, Ghantoji, Shashank S., Kontoyiannis, Dimitrios P., Jones, Roy B., Tam, Vincent H., Chemaly, Roy F.
• Format: Journal Article
• Language: English
• Published: England Oxford Publishing Limited (England) 01.03.2016
• Subjects: Adenoviridae Infections - drug therapy; Adenovirus; Administration, Intravesical; Adolescent; Aged; Antiviral Agents - administration & dosage; Antiviral Agents - adverse effects; Antiviral Agents - pharmacokinetics; Chemotherapy; Cystitis - drug therapy; Cytosine - administration & dosage; Cytosine - adverse effects; Cytosine - analogs & derivatives; Cytosine - pharmacokinetics; Drug dosages; Female; Hematopoietic Stem Cell Transplantation - adverse effects; Humans; Kinetics; Male; Middle Aged; Organophosphonates - administration & dosage; Organophosphonates - adverse effects; Organophosphonates - pharmacokinetics; Pharmacology; Plasma - chemistry; Prospective Studies; Transplantation, Homologous - adverse effects; Young Adult
• ISSN: 0305-7453; 1460-2091; 1460-2091
• DOI: 10.1093/jac/dkv393

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). 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. 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. Intravesicular administration of cidofovir resulted in highly variable systemic exposures. The safety and efficacy of intravesicular cidofovir should be further evaluated before routine use.