Assessment of dosage regimens of tigecycline in hospitalised patients
O. Karani (1), G. Charkoftaki (1), E. Vryonis (2), A. Skoutelis (2), S. Markantonis (1), H. Archontaki (3), A. Dokoumetzidis (1), G. Valsami (1)
(1) School of Pharmacy, University of Athens, Greece; (2) Fifth Department of Internal Medicine, Evangelismos General Hospital, Athens, Greece; (3) Department of Chemistry, University of Athens, Greece
Objectives: To study various dose regimens of the antibiotic tigecycline in a group of hospitalised patients and assess the potential applicability of TDM for this drug.
Methods: Blood samples from 11 hospitalised patients were collected, during treatment with tigecycline and the concentrations of the drug were quantified using an HPLC method [1]. Patients were treated for about 2 weeks and were administered either a 100 mg or a 150 mg daily dose, with or without a loading dose of 100 mg. Using literature population priors for the two-compartment pharmacokinetic parameters [2], 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 from [2] and clinical targets from literature, Monte Carlo (MC) simulations were performed and the distributions of AUC/MIC were computed to assess the applicability of the different dosing schemes.
Results: The MC simulations showed that the high dose of 150 mg is theoretically efficacious for almost all patients while the low dose of 100 mg 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.
References:
[1] Zorpas K, Valsami G, Vryonis E, Skoutelis A, Archontaki H. Robust and Sensitive Liquid Chromatographic/UV detection technique for the determination of tigecycline in rabbit plasma, J AOAC Int. 2011, accepted for publication.
[2] Rubino CM, Forrest A, Bhavnani SM, Dukart G, Cooper A, Korth-Bradley J, Ambrose PG. Tigecycline population pharmacokinetics in patients with community- or hospital-acquired pneumonia. Antimicrob Agents Chemother. 2010, 54:5180-6.
