Pharmacokinetic/Pharmacodynamic Model for the Safety of Tigecycline in Patients with Complicated Skin and Skin-Structure Infections

Authors: Meagher AK, Passarell JA, Liolios K, Cirincione B, Van Wart S, Grasela TH, Babinchak T, Ellis-Grosse EJ
Conference: IDSA
Keywords: age, anti-infectives, antibiotic, cSSSI, dermatology, dose, hosmer-lemeshow, infectious disease, intravenous, IV, Kaplan-Meier, logistic regression, males, nausea, PK/PD, region, ROC, SAS, vomiting
Division: Clinical Pharmacology and Pharmacometrics (CPP)

Abstract

Purpose: Tigecycline is a first-in-class glycylcycline for the treatment of serious bacterial infections. Reported adverse events from clinical trials include nausea and vomiting. Exposure-response relationships and patient covariates predictive of the first occurrence of nausea and vomiting in patients with complicated skin and skin-structure infections (cSSSI) were evaluated.

Methods: Patients from three cSSSI studies (one Phase 2 and two Phase 3) were pooled for analysis. Patients received 100-mg loading dose and 50 mg q12h (100/50) or 50-mg loading dose and 25 mg q12h (50/25). Nausea and vomiting (classified as definitely, possibly, or probably related) reported from the start of infusion until 24 hours after the last dose were included. Bayesian estimates of steady state 12-hour AUC (AUC0-12) and Cmax were derived using a population PK model. Logistic regression was used to evaluate predictors of the first occurrence of nausea and vomiting. Covariates included exposure, age, weight, sex, pre-existing diabetes, and region of treatment.

Results: Final dataset included 726 patients (102 with PK): 64% of patients were male; mean (SD) age and weight were 49 (16) years and 83 (23) kg; 45%, 27%, and 11% were enrolled in North America, Europe, and Latin America, respectively. Overall, nausea (vomiting) occurred in 29% (16%) of patients and 73% of first events were mild in nature. Women had more nausea and vomiting (38% and 26%) than men (23% and 9%). Nausea and vomiting were lower in Europe (14% and 4%) than in other regions. AUC0-12 and Cmax were not predictive of these events. The final nausea model included age, sex, region of treatment, and dose as predictors of the first nausea occurrence (p = 0.03, < 0.0001, < 0.0001, and = 0.0001, respectively). The final vomiting model also included age, sex, region, and dose as predictors of the first vomiting occurrence (p = 0.011, < 0.0001, < 0.0001, and = 0.004, respectively).

Conclusions: Nausea and vomiting were less likely in older patients, men, Europeans, and in the 50/25 dose group. AUC0-12 and Cmax were not predictors of nausea and vomiting.

Infectious Diseases Society of America (IDSA), San Francisco, California, October 2005

By AK Meagher, Julie A. Passarell, K Liolios, BB Cirincione, SA Van Wart, Thaddeus H. Grasela, T Babinchak, and EJ Ellis-Grosse