Population Pharmacokinetics and Dosing Optimization of Norvancomycin for Chinese Patients with Community-Acquired Pneumonia

Yaqian Li,1 Xiaodan Jiao,2 Guozhu Sun,3 Fuxu Wang,4 Xikun Wu,1 Weichong Dong,1 Wenpeng Lu,3 Zhiyong Zhang,1 Yadong Yuan,2 Zhiqing Zhang1 1Department of Pharmacy, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, People’s Republic of China; 3Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, People’s Republic of China; 4Department of Hematology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, People’s Republic of ChinaCorrespondence: Zhiqing Zhang, Department of Pharmacy, The Second Hospital of Hebei Medical University, 215 hepingxi Road, Shijiazhuang, Hebei Province, 050000, People’s Republic of China, Email [email protected] Yadong Yuan, Department of Respiratory and Critical Care Medicine, The Second Hospital of Hebei Medical University, 215 hepingxi Road, Shijiazhuang, Hebei Province, 050000, People’s Republic of China, Email [email protected]: Determining the optimal dosage of norvancomycin (NVCM) for Chinese patients with community-acquired pneumonia (CAP) caused by gram-positive cocci remains uncertain. This research aimed to identify influential factors affecting NVCM pharmacokinetics and explore optimal dosage regimens via population pharmacokinetic (PPK) analysis.Patients and Methods: A prospective analysis was conducted at the Second Hospital of Hebei Medical University (Shijiazhuang, China). CAP patients aged ≥ 18 years and receiving intravenous NVCM were enrolled. Each patient underwent the collection of 3– 8 blood samples for analysis during the treatment. Nonlinear mixed effect model (NONMEM) software was used to develop PPK models, while Monte Carlo simulations were employed to optimize dose regimens. Pharmacokinetic-pharmacodynamic (PK/PD) breakpoint was defined as daily area under the concentration on the second day of therapy to minimum inhibitory concentration ratio (AUC24-48h/MIC) ≥ 361, and a steady-state AUC to MIC radio (AUCss,24h/MIC) ≥ 361.Results: A prospective PPK analysis of 231 NVCM concentrations was performed in 34 patients. A two-compartment model with first-order elimination adequately described the pharmacokinetics. The population typical clearance (CL) of NVCM was 3.15 L/h, and the central volume of distribution was 12.3 L. Notably, CL exhibited significant correlations with age and serum creatinine (Scr) levels. For mild or moderate CAP patients, the recommended doses were 400– 800 mg every 12 h to achieve the target exposure with AUCss,24h/MIC ≥ 361. For community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) pneumonia, the suggested dosage regimen was 600– 800 mg every 8 h, which could achieve the target exposure preferably within the initial 24 to 48 h.Conclusion: Age and Scr levels significantly influenced the pharmacokinetic parameters of NVCM in CAP patients. Our model-informed precision dosing approach may help for early optimization of NVCM exposure. Further prospective studies with larger samples will be needed.Keywords: norvancomycin, population pharmacokinetics, community-acquired pneumonia, dosing optimization