Population Pharmacokinetic Analyses for Tebipenem after Oral Administration of Pro-Drug Tebipenem Pivoxil Hydrobromide
Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is definitely an dental (PO) carbapenem pro-drug that’s transformed into the active moiety tebipenem within the enterocytes. Tebipenem has activity against multidrug-resistant Gram-negative pathogens, including extended-spectrum beta lactamase-producing Enterobacterales, and it is being developed to treat patients with complicated urinary system infections (cUTI) and acute pyelonephritis (AP). The objectives of those analyses would create a population pharmacokinetic (PK) model for tebipenem using data from three phase 1 studies and something phase 3 study and also to identify covariates that described the variability in tebipenem PK. Following construction from the base model, a covariate analysis was conducted.
The model ended up being qualified by conducting a conjecture-remedied visual predictive check and evaluated using a sampling-importance-resampling procedure. The ultimate population PK data set was made up of data from 746 subjects who provided 3,448 plasma concentrations, including 650 patients (1,985 concentrations) with cUTI/AP. The ultimate population PK model that best described tebipenem PK was discovered to be a 2-compartment model with straight line, first-order elimination and 2 transit compartments to explain the speed of drug absorption after PO administration of TBP-PI-HBr. The connection between kidney clearance (CLR) and creatinine Tebipenem Pivoxil clearance (CLcr), probably the most clinically significant covariate, was described utilizing a sigmoidal Hill-type function. No dose adjustments are warranted based on age, bodily proportions, or sex as none of those covariates were connected with substantial variations in tebipenem exposure in patients with cUTI/AP. The resultant population PK model is anticipated to become suitable for model-based simulations and assessment of pharmacokinetic-pharmacodynamic relationships for tebipenem.