Population pharmacokinetics and exposure-response analysis of tigecycline in patients with hospital-acquired pneumonia

Yangang Zhou; Ping Xu; Huande Li; Feng Wang; Han Yan; Wu Liang; Daxiong Xiang; Bikui Zhang; Hoan Linh Banh

doi:10.1111/bcp.14692

Population pharmacokinetics and exposure-response analysis of tigecycline in patients with hospital-acquired pneumonia

Br J Clin Pharmacol. 2021 Jul;87(7):2838-2846. doi: 10.1111/bcp.14692. Epub 2021 May 26.

Authors

Yangang Zhou^{1

2}, Ping Xu^{1

2}, Huande Li^{1

2}, Feng Wang^{1

2}, Han Yan^{1

2}, Wu Liang³, Daxiong Xiang^{1

2}, Bikui Zhang^{1

2}, Hoan Linh Banh^{1

2

4}

Affiliations

¹ Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, China.
² Institute of Clinical Pharmacy, Central South University, Changsha, China.
³ Changsha VALS Technology Co., Ltd, Changsha, China.
⁴ Department of Family Medicine, University of Alberta, Edmonton, Canada.

PMID: 33283892
DOI: 10.1111/bcp.14692

Abstract

Background: Tigecycline has been widely used to treat hospital-acquired pneumonia (HAP) off-label since it is effective against a wide range of multidrug-resistant bacteria. However, no recommended dosage for this indication has been evaluated, resulting in possible inadequate treatment.

Aims: The aims of this study are to establish the population pharmacokinetic (PPK) model of tigecycline in Chinese patients with HAP, as well as to evaluate the exposure-response relationship for the treatment of HAP with multidrug-resistant gram-negative bacteria.

Methods: A PPK analysis of tigecycline was conducted on pooled data from 328 blood samples obtained from 89 patients with HAP. Tigecycline plasma concentrations were measured by a two-dimensional liquid chromatographic system and the data were analysed using Phoenix NLMETM software. Exposure-response analyses for efficacy were performed based on the data from 79 HAP patients with multidrug-resistant gram-negative infections. Classification and regression tree and logistic regression analyses were employed to identify which pharmacokinetic-pharmacodynamic (PK-PD) indices and magnitudes were the significant predictors of tigecycline efficacy.

Results: A two-compartment model with zero-order absorption and first-order elimination adequately described the data. A larger body weight was associated with increased central volume of distribution and clearance (P < .005), and increased age, baseline creatinine concentration and aspertate aminotransferase were associated with decreased clearance (P < .005). The AUC_0-12h × V/MIC ratio, APACHEII score and combined Pseudomonas aeruginosa infection are the strong predictors for tigecycline clinical response. Classification and regression tree analyses indicated that the combination of APACHEII score < 24 and AUC_0-12h × V/MIC ratio ≥ 100 was associated with clinical success.

Conclusions: The proposed PPK model may serve as the basis for estimating tigecycline exposure for PK-PD analyses, and the PK-PD index and magnitude found in this study could be used for designing proper dosage regimens of tigecycline.

Keywords: hospital-acquired pneumonia; multidrug-resistant; pharmacokinetic-pharmacodynamic; population pharmacokinetics; tigecycline.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Bacterial Agents / therapeutic use
Hospitals
Humans
Microbial Sensitivity Tests
Minocycline*
Pneumonia* / drug therapy
Tigecycline

Substances

Anti-Bacterial Agents
Tigecycline
Minocycline