Measurement of soft tissue drug concentrations in morbidly obese and non-obese patients – A prospective, parallel group, open-labeled, controlled, phase IV, single center clinical trial

Abstract

Background Pharmacokinetic (PK) and pharmacodynamic (PD) data on perioperative antibiotic prophylaxis or antibiotic therapy are rare in patients suffering from morbid obesity. Furthermore, dosing regimens should be based on PK/PD models that ensure effective antibiotic exposure not in plasma, but primarily at the site of infection, mostly in the interstitial fluid (ISF). The aim of this trial is to investigate whether current dosing regimens of various antibiotics lead to effective concentrations in the ISF of morbidly obese patients. Methods We designed a prospective, parallel group, open-labeled, controlled single center trial to investigate the plasma and tissue pharmacokinetics of the antibiotics linezolid, meropenem, tigecycline, piperacillin/tazobactam, fosfomcyine, cefazolin, metronidazole and as secondary aim the analgesics metamizole and acetaminophen. Inclusion criteria comprise body mass index ≥35 kg/m 2 for obese or between 18.5 and 30 kg/m 2 for non-obese patients scheduled for elective abdominal surgery. For PK analysis, blood and microdialysate samples of subcutaneous tissue were collected 0–8 h after study drug administration. The primary endpoint is to investigate a possible dependency of the area-under-the-curve (AUC 0-8 ) in the interstitial fluid on body weight and obesity with population based pharmacokinetic analysis. Discussion Inadequate dosing regimes of antibiotics may be a relevant factor for morbidity and mortality of patients, as well as for the development of bacterial antibiotic resistance. The measurement of plasma and tissue concentrations will provide information necessary for PK/PD-modelling. These data about antibiotic PK/PDcharacteristics in soft tissue and their dependence on weight should help to develop weight-dependent models for calculation of patient's individual doses of different antibiotics. Trial registration EU clinical trials register (EudraCT-No. 2012-004383-22) and German Clinical trials Register (DRKS00004776);

Linezolid Concentrations in Plasma and Subcutaneous Tissue are Reduced in Obese Patients, Resulting in a Higher Risk of Underdosing in Critically Ill Patients: A Controlled Clinical Pharmacokinetic Study

“…The expectation for the correlation coefficient was taken from data presented in publications along with simulation studies [11,12]. Further details on the methods, design, and sample size calculations have previously been described in detail, including a CONSORT diagram for the whole study [24].…”

“…Inclusion criteria comprised age ≥ 18 years and body mass index (BMI) ≥ 35 kg/m 2 for obese patients or between 18.5 and 30 kg/m 2 for non-obese patients. The non-obese patients were matched based on age (within five years) and sex, depending on the availability of sequentially encountered patients [24]. The main exclusion criteria were pregnancy or breastfeeding, a known allergic reaction to one of the investigated medications, and severe liver or severe kidney disease.…”

“…After equilibration (30 min), microdialysate was collected for 1 h and a baseline blood sample was taken. Additional blood samples were taken at 0.5 (end of infusion), 1, 2, 3, 4, 5, 6, and 8 h. Microdialysate samples were collected from 0-0.5, 0.5-1, 1-1.5, 1.5-2, 2-3, 3-4, 4-5, 5-6, 6-7, and 7-8 h [24]. The choice to sample for 8 h was based on a compromise between minimizing the burden to the patient, practicability, and ensuring rich sampling for various substances with different half-lives from a more extensive protocol (linezolid, meropenem, tigecycline, cefazolin, metronidazole, and piperacillin).…”

“…Microdialysis was performed at a constant flow rate of 2 µL/min. To obtain the drug concentration in the ISF from microdialysate concentrations (C µD ), the retrodialysis method was used [24,25]. Retroperfusate (C RP ) and retrodialysate (C RD ) drug concentrations were utilized to determine the in vivo relative recovery as follows: Relative recovery = (1 -C RD /C RP ) × 100%.…”

“…Retroperfusate (C RP ) and retrodialysate (C RD ) drug concentrations were utilized to determine the in vivo relative recovery as follows: Relative recovery = (1 -C RD /C RP ) × 100%. The concentration of the drug in the ISF was then given by C ISF = C µD × 100/relative recovery [24]. Due to the constant perfusate flow through the catheter and hence incomplete equilibrium at the membrane, only a fraction of the actual ISF drug concentration will be 'recovered' in the microdialysate, which is referred to as 'relative recovery' [26].…”