Pharmacokinetic/Pharmacodynamic Model For The Tolerability Of Tigecycline In Healthy Volunteers

Authors: Passarell JA, Meagher AK, Liolios K, Grasela TH, Babinchak T, Ellis-Grosse EJ
Conference: ECCMID
Keywords: anti-infectives, antibiotic, exposure-response, infectious disease, intravenous, IV, Kaplan-Meier, logistic regression, nausea, safety, vomiting
Division: Clinical Pharmacology and Pharmacometrics (CPP)

Abstract

Objectives: Tigecycline, a first-in-class glycylcycline, is an antimicrobial agent with demonstrated in vitro activity against susceptible and multiple-drug resistant gram-positive and gram-negative bacteria. Similar to tetracyclines, nausea and vomiting are frequently reported adverse events. Exposure-response relationships and subject covariates predictive of the first occurrence of nausea and vomiting in healthy volunteers were evaluated.

Methods: Subjects with PK data from 3 single-dose (12.5, 25, 50, 75, 100, 200, and 300 mg) phase 1 studies were pooled for analysis. Nausea and vomiting (definitely, possibly, or probably related to tigecycline) reported from the start of infusion until 24hrs post dose were included. Subjects administered ondansetron or with severe or end-stage renal disease were excluded. Individual tigecycline exposure measures [AUC0-∞ (AUC) and Cmax] were obtained from previously conducted noncompartmental analyses. Covariates included age, weight, gender, and geographic location. Logistic regression and Kaplan-Meier methods were used to evaluate the first occurrence of nausea and vomiting.

Results: The dataset included 136 subjects. Mean (SD) age and weight were 38 (20) years and 74 (12) kg. Approximately 87% were Caucasian, 84% were male, 38% were enrolled in USA, and 62% in Europe. Single nausea occurrences were reported in 51 (38%) and vomiting in 25 (18%) subjects. Two nausea or vomiting events were reported in 4 subjects. Nausea (vomiting) was reported in 12% (4%) of placebo subjects, 17% (0%) on tigecycline 25 mg, and 33% (0%) on tigecycline 50 mg. Females had a higher occurrence of nausea and vomiting (45% and 19%) versus males (36% and 14%). France and USA had similar nausea rates (39% versus 35%); France had a much higher vomiting rate (24% versus 10%). Most nausea (vomiting) events occurred ≤ 4 hours (≤6 hours) after tigecycline infusion for all doses. For doses ≤ 100 mg, median duration of nausea and vomiting was < 1 hour and increased dramatically for 200 and 300 mg dose groups (≤ 3 hours). Most nausea (vomiting) occurrences were mild [49% (20%)] and 27% (44%) were moderate. 111 subjects had PK. Final statistical model concluded AUC and Cmax as significant predictors of nausea (p ≤ 0.0001, p = 0.0022) and vomiting (p ≤ 0.0001, p = 0.0006). Increased exposures resulted in increased events. At the median AUC (Cmax) of 2.6 g.hr/mL (0.39 g/mL) for the 50-mg dose group, nausea probability was 0.26 (0.29) and vomiting probability was 0.07 (0.11).

Conclusion: Tigecycline exposure (AUC > Cmax) was a significant predictor of the probability of nausea and vomiting events in phase 1 subjects. Model predicted rates of nausea and vomiting were comparable with those seen with the tetracycline class of antibiotics, with tolerable rates predicted at the targeted tigecycline dose of 50 mg every 12 hours.

European Congress of Clinical Microbiology and Infectious Disease (ECCMID), Copenhagen, Denmark, April 2005

By Julie A. Passarell, AK Meagher, K Liolios, Thaddeus H. Grasela, T Babinchak, EJ Ellis-Grosse