telavancin and Body-Weight

A population pharmacokinetic model of telavancin, a lipoglycopeptide antibiotic, was developed and used to identify sources of interindividual variability. Data were obtained from healthy subjects (seven phase 1 studies), patients with complicated skin and skin structure infections (cSSSI; two phase 2 and two phase 3 studies), and patients with hospital-acquired pneumonia (HAP; two phase 3 studies). A two-compartment open model with zero-order input best fit the telavancin data from healthy individuals and patients with cSSSI or HAP. Telavancin clearance was highly correlated with renal function and, to a lesser extent, with body weight. Other covariates were related to at least one parameter in cSSSI (gender, bacterial eradication, and surgery) or HAP (age of ≥ 75 years) but did not markedly affect exposure. These analyses support current dosing recommendations for telavancin based on patient weight and renal function.

Topics: Adult; Aged; Aged, 80 and over; Algorithms; Aminoglycosides; Anti-Bacterial Agents; Area Under Curve; Bacterial Infections; Bayes Theorem; Body Weight; Calibration; Cross Infection; Female; Humans; Lipoglycopeptides; Male; Middle Aged; Models, Statistical; Population; Sex Characteristics; Young Adult

U.S. Food and Drug Administration (FDA) recommended telavancin dosing is based on total body weight (TBW) but lacks adjusted regimens for obese subjects with varying renal function. Our aim was to develop a physiologically based pharmacokinetic (PBPK) model of telavancin to design optimized dosing regimens for obese patients with hospital-acquired pneumonia (HAP) and varying renal function.. The PBPK model was verified using clinical pharmacokinetic (PK) data of telavancin in healthy populations with varying renal function and obese populations with normal renal function. Then, the PBPK model was applied to predict the PK in obese HAP patients with renal impairment (RI).. The fold error values of PK parameters (AUC, C. The PBPK simulation proposed that using TBW-based regimen in obesity with RI should be avoided. Dose recommendations in obesity from the PBPK model are 750 mg daily for normal renal function and mild RI, 610 mg daily for moderate RI, 530 mg daily for severe RI, and 480 mg daily for ESRD.

Topics: Adult; Aminoglycosides; Anti-Bacterial Agents; Area Under Curve; Body Weight; Computer Simulation; Healthcare-Associated Pneumonia; Humans; Lipoglycopeptides; Male; Models, Biological; Monte Carlo Method; Obesity; Renal Insufficiency

This study characterized the pharmacokinetic/pharmacodynamic profiles of the Food and Drug Administration (FDA)-approved telavancin renal dose adjustment schemes. A previously published two-compartment open model with first-order elimination and a combined additive and proportional residual error model derived from 749 adult subjects in 11 clinical trials was used to simulate the individual concentration-time profiles for 10,260 subjects (NONMEM). The dosing regimens simulated were 10 mg/kg of body weight once daily for individuals with creatinine clearances (CL(CR)s) of >50 ml/min, 7.5 mg/kg once daily for individuals with CL(CR)s of 30 to 50 ml/min, and 10 mg/kg every 2 days for those with CL(CR)s of <30 ml/min. The area under the concentration-time curve (AUC) under one dosing interval (AUC(τ)) was computed as dose/CL. The probability of achieving an AUC(τ)/MIC ratio of ≥ 219 was evaluated separately for each renal dosing scheme. Evaluation of the dosing regimens demonstrated similar AUC values across the different renal function groups. For all renal dosing strata, >90% of the simulated subjects achieved an AUC(τ)/MIC ratio of ≥ 219 for MIC values as high as 2 mg/liter. For patients with CL(CR)s of <30 ml/min, the probability of target attainment (PTA) exceeded 90% for both the AUC₀₋₂₄ (AUC from 0 to 24 h) and AUC₂₄₋₄₈ intervals for MICs of ≤ 1 mg/liter. At a MIC of 2 mg/liter, the PTAs were 89.3% and 23.6% for the AUC₀₋₂₄ and AUC₂₄₋₄₈ intervals, respectively. The comparable PTA profiles for the three dosing regimens across their respective dosing intervals indicate that the dose adjustments employed in phase III trials for complicated skin and skin structure infections were appropriate.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aminoglycosides; Area Under Curve; Body Weight; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Creatinine; Female; Humans; Kidney; Kidney Function Tests; Lipoglycopeptides; Male; Microbial Sensitivity Tests; Middle Aged; Models, Statistical; Monte Carlo Method; Population; Probability; Skin Diseases, Infectious; Treatment Outcome; Young Adult