Summary:
Objectives: To study various dose regimens of the antibiotic tigecycline in a
group of hospitalized patients and assess the potential applicability of TDM
for this drug.
Methods: Blood samples from 14 hospitalized patients were collected during
treatment with tigecycline, between the first and the second hour after the end
of the intravenous infusion, and the concentrations of the drug were quantified
using a recently developed sensitive HPLC method. Patients were treated for
about 10 days and were administered either 50 mg bid or 50 mg tid with or
without a loading dose of 100 mg. Using literature population priors for the
two-compartment pharmacokinetic parameters, Empirical Bayes Estimates (EBE)
were derived for each of the patients’ PK parameters with NONMEM and the
corresponding AUC24/MIC were calculated. Further, using the population estimate
and the intersubject variability of clearance and clinical targets from
literature, Monte Carlo simulations were performed and the distributions of
AUC24/MIC were computed to assess the applicability of the different dosing
schemes.
Results: The MC simulations showed that the high dose of 50 mg tid is
theoretically efficacious for almost all patients while the low dose of 50 mg
bid leaves a significant percentage of more than 20% of the population in
undertherapeutic levels. The clinical picture for the efficacy of the drug in
the group of real patients partially confirms the result that the low dose may
be undetherapeutic for some patients, while the high dose was very often not
tolerated by the patients causing GI adverse effects. This mixed picture
suggests that dose adjustment with TDM may be applicable for this drug.
Conclusion: Monte Carlo simulations show that the low dose of tigecycline may
produce undertherapeutic levels of the drug in a significant portion of the
population while in a group of patients the high dose was often not tolerated,
suggesting that potential dose adjustment could be useful.
Keywords:
Tigecycline, Dose adjustment, Population pharmacokinetics, Infections
