title: Pharmacokinetics and safety of intravesicular cidofovir in allogeneic HSCT recipients.
abstract: OBJECTIVE
  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.
authors.affiliation: Division of Pharmacy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 0090, Houston, TX 77030, USA Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, 1441 Moursund St., Houston, TX 77030, USA.
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Aitken
authors.affiliation: Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, 1441 Moursund St., Houston, TX 77030, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1460, Houston, TX 77030, USA.
authors.forename: Shashank S
authors.initials: SS
authors.lastname: Ghantoji
authors.affiliation: Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1460, Houston, TX 77030, USA.
authors.forename: Dimitrios P
authors.initials: DP
authors.lastname: Kontoyiannis
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 0423, Houston, TX 77030, USA.
authors.forename: Roy B
authors.initials: RB
authors.lastname: Jones
authors.affiliation: Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, 1441 Moursund St., Houston, TX 77030, USA vtam@uh.edu.
authors.forename: Vincent H
authors.initials: VH
authors.lastname: Tam
authors.affiliation: Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1460, Houston, TX 77030, USA.
authors.forename: Roy F
authors.initials: RF
authors.lastname: Chemaly
mesh_terms: D000257:Adenoviridae Infections / Q000188:drug therapy*; D000283:Administration, Intravesical; D000293:Adolescent; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D000077404:Cidofovir; D003556:Cystitis / Q000188:drug therapy*; D003596:Cytosine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D010949:Plasma / Q000737:chemistry; D011446:Prospective Studies; D014184:Transplantation, Homologous / Q000009:adverse effects; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D063065:Organophosphonates; D003596:Cytosine; D000077404:Cidofovir