Absolute Bioavailability and Pharmacokinetics of Linezolid in Hospitalized Patients Given Enteral Feedings

Abstract

Linezolid is a new antimicrobial agent effective against drug-resistant gram-positive pathogens which are common causes of infections in hospitalized patients. Many such patients rely on the intravenous or enteral route for nutrition and drug administration. Therefore, the bioavailability of linezolid administered enterally in the presence of enteral feedings in hospitalized patients was examined. Eighteen subjects were assessed in a randomized single-dose crossover study; 12 received continuous enteral feedings, while 6 did not (controls). Both groups received linezolid 600 mg intravenously and orally (control) or enterally, with the alternate route of administration separated by a 24-h washout period. Pharmacokinetic parameters derived from noncompartmental and compartmental analysis incorporating linear and nonlinear elimination pathways were compared between groups: F, K a , V s , K 23 , K 32 , V max , K m , and K 20 (bioavailability, absorption rate constant, volume of central compartment normalized to body weight, intercompartmental rate constants, maximum velocity, Michaelis-Menten constant, and elimination rate constant, respectively). Pharmacokinetic (PK) data were available from 17 patients. The linezolid oral suspension was rapidly and completely absorbed by either the oral or enteral route of administration. Bioavailability was unaltered in the presence of enteral feedings. PK estimates remain similar regardless of the model applied. At the therapeutic dose used, only slight nonlinearity in elimination was observed. A linezolid oral suspension may be administered via the enteral route to hospitalized patients without compromise in its excellent bioavailability and rapid rate of absorption. Compartmental pharmacokinetic analysis offers a more flexible study application, since bioavailability (F) can be estimated directly with intermixed intravenous/oral doses without a need for a washout period.

Pharmacokinetics of Intravenous Linezolid in Moderately to Morbidly Obese Adults

“…When one considers that the reported clearance in this model is the maximum initial clearance and then is reduced by the fraction of RCLF, the mean population clearance reported by Plock and colleagues is reduced to 8.48 liters/h over time and that of our obese population is reduced to 6.5 liters/h. Both values are among those reported in other linezolid pharmacokinetic studies (13,19,20,26,27). Thus, it can at least be determined based on these data that the obese bariatric patients in our study do not have higher clearance and reduced AUC exposure compared to other studies.…”

“…As in other studies, linezolid concentrations in this obese population of bariatric patients fit a 2-compartment model with nonlinear clearance (13,14,26,27). Based on the log likelihood and Akaike information criterion, the model originally described by Plock and colleagues (14) resulted in the best fit of the data.…”

Pharmacokinetics of Intravenous and Oral Linezolid in Adults with Cystic Fibrosis

“…Our final model estimates for clearance and volume of distribution were very similar to those reported for septic shock patients and Additionally, oral bioavailability in our CF population was found to be approximately 85.1% and was quite variable (range, 47% to 137%). This observation is substantially different from those in studies in non-CF subjects, which have reported linezolid bioavailability of nearly 100% (2,29). Linezolid is a moderately lipophilic molecule (4), and pancreatic enzyme deficiency, which is common in CF patients, can impact the absorption of lipophilic medications (14).…”

“…Most notably, CF patients tend to have a more rapid clearance and a greater volume of distribution for antibiotics eliminated via glomerular filtration, tubular secretion, as well as nonrenal metabolism pathways (6,7,16,27). In non-CF populations, linezolid concentration data are best described by nonlinear elimination models (2,19,28). The previously well-described population pharmacokinetic model applied in this study best predicted parameter estimates and minimized model misspecifications (20).…”

“…Previous studies have proposed that CF patients with inadequate clinical responses may require more frequent dosing due to variability in their pharmacokinetic parameters (3,22). Neither of these studies, however, considered the potential for nonlinear elimination of linezolid, which has been demonstrated in other populations after multiple doses (2,19,20). Additionally, no study has assessed the bioavailability of linezolid in CF patients, a population that often exhibits malabsorption.…”