title: Single dose, dose-escalating trial with fozivudine tidoxil (BM 21.1290).
abstract: OBJECTIVE
  In vitro and in vivo experimental data for fozivudine tidoxil [BM21.1290 (FZD) an ether-lipid conjugate of zidovudine] have shown better efficacy, no myelotoxicity and better tolerability compared with zidovudine. Therefore, the objectives of our study were to evaluate the safety of FZD in patients with human immunodeficiency virus (HIV) infection and to establish basic pharmacokinetic data.
  
  
  METHODS
  In a Phase I dose-escalating trial, seven different single dose applications were studied in 39 patients: 50, 100, 300, 600, 900, 1200 and 1800 mg in capsule and tablet formulations. Inclusion criteria were HIV infection, CD4 count > 100 cells/mm3 and informed consent. Exclusion criteria were active opportunistic manifestations, concomitant zidovudine therapy and neutropenia (< 750 neutrophils/mm3). Safety parameters, 24 h plasma levels and urinary excretion were determined.
  
  
  RESULTS
  The tolerance of FZD was excellent up to single doses of 1800 mg. In only one case, a single episode of loose stool was reproducible in a second treatment period and was therefore considered to be a probable drug-related event. In an amendment to the trial, a tablet formulation of FZD did not induce diarrhoea in this patient. FZD was available in measurable concentrations after 2 to 4 h. Maximum concentrations were reached after 4 to 8 h. After normalization for a dose of 100 mg/patient, the mean AUC was 8.6 mg x h/l and the mean Cmax was 1.13 mg/l; t1/2 was 3.78 h. Interestingly, plasma concentrations of zidovudine and zidovudine glucuronide were much lower than with equimolar zidovudine doses.
  
  
  CONCLUSIONS
  The zidovudine conjugate FZD is safe and well tolerated at the seven doses tested. Phase II trials are warranted.
authors.affiliation: Medizinische Poliklinik, Klinikum Innenstadt, University of Munich, Germany. jobogner@pk-i.med.uni-muenchen.de
authors.forename: J R
authors.initials: JR
authors.lastname: Bogner
authors.forename: D
authors.initials: D
authors.lastname: Boerner
authors.forename: A
authors.initials: A
authors.lastname: Mühlhöfer
authors.forename: E
authors.initials: E
authors.lastname: Thoma-Greber
authors.forename: D B
authors.initials: DB
authors.lastname: Herrmann
authors.forename: L
authors.initials: L
authors.lastname: Hoegl
authors.forename: M
authors.initials: M
authors.lastname: Roecken
authors.forename: V
authors.initials: V
authors.lastname: Jost
authors.forename: F D
authors.initials: FD
authors.lastname: Goebel
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects*; D005502:Food; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D008055:Lipids / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D015215:Zidovudine / Q000008:administration & dosage / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D019380:Anti-HIV Agents; D008055:Lipids; D015215:Zidovudine; C408972:fozivudine tidoxil