ABSTRACT
The recommended treatment for post-exposure prophylaxis (PEP) following known/suspected exposure to Bacillus anthracis involves immunization with anthrax vaccine adsorbed (AVA, i.e., BioThrax® vaccine) and a course of antimicrobial therapy. A drug-vaccine interaction clinical trial was conducted to determine whether this combined treatment might modify antimicrobial exposure or vaccine immunogenicity. A Phase 2, randomized, open-label, multi-center trial involving 154 healthy adult participants was completed to evaluate the effect of AVA immunization (three doses administered subcutaneously (SC) at weeks 0, 2 and 4) on the pharmacokinetics (PK) of ciprofloxacin, as well as the effect of ciprofloxacin administration (500 mg po bid) on the immunogenicity of AVA. PK parameters were derived using noncompartmental analysis of ciprofloxacin serum concentrations. Immunogenicity was assessed using a toxin neutralizing antibody (TNA) assay resulting in 50 % neutralization factor (NF50) values. Safety was assessed via reports of adverse events (AEs), clinically significant changes in laboratory parameters and vital signs, and collection of solicited local and systemic reactogenicity reactions. Statistical analyses of the steady state (SS) and single dose PK parameters Cmax and AUC0--12h indicated that the AVA PEP regimen did not significantly modify ciprofloxacin exposure. Comparison of the geometric mean TNA NF50 values between participants receiving AVA + ciprofloxacin and those receiving AVA alone showed that the combined treatment was non-inferior to AVA alone. The trial met all prospectively defined success criteria for the primary PK endpoint and for the secondary PK and immunogenicity endpoints. There were no deaths, SAEs or AEs leading to drug discontinuation or study withdrawal during the trial. Overall, concomitant administration of ciprofloxacin and AVA produced no significant changes in the PK profile of ciprofloxacin nor in the immunogenicity of AVA. Furthermore, this trial demonstrated that the co-administration of ciprofloxacin and AVA was well tolerated in healthy adult participants.
ABSTRACT
BACKGROUND: This study was conducted to support licensure of a post-exposure prophylaxis indication for BioThrax(®) (anthrax vaccine adsorbed) concurrent with antimicrobials for individuals exposed to aerosolized anthrax spores. METHODS: The immunogenicity and safety of a three-dose regimen (0, 2, and 4 weeks) of BioThrax administered subcutaneously (SC) were evaluated in 200 healthy adults 18-65 years of age. Toxin-neutralizing antibody (TNA) was expressed as 50% neutralization factor (NF50) at predetermined time points through Day 100. Safety was assessed by physical examinations, vital signs, solicited local and systemic reactions using web-enabled subject diaries, in-clinic solicited reactions, and unsolicited adverse events (AEs). RESULTS: The prospectively defined success criteria for the primary and secondary endpoints were met. This required the lower bound of the 95% confidence interval (CI) for the proportion of subjects with a TNA NF50 value to be greater than 40% at Day 63 (primary), Day 70 (secondary) and Days 63-100 (secondary). At Day 63, 71% of subjects achieved a TNA NF50 threshold value ≥ 0.56, with a lower bound of the 95% CI ≥ 40% (64%). The percentage of subjects achieving a TNA NF50 threshold value ≥ 0.56 at Day 70 was 58% (95% CI: 50%, 65%), and the mean value on Days 63-100 (inclusive) was 53% (95% CI: 41%, 55%). The threshold TNA NF50 value of 0.56 was developed from previous rabbit challenge and human immunogenicity studies. No related serious AEs occurred during the study, and no subjects withdrew from the study because of an AE. Tenderness and pain at the injection site were recorded most often in subject diaries following vaccination. CONCLUSIONS: BioThrax, administered as three SC doses at 0, 2, and 4 weeks, was well tolerated. The prospectively defined success criteria for TNA levels on Days 63, 70, and 63-100 were achieved.
