Novel Population Pharmacokinetic Approach to Explain the Differences between Cystic Fibrosis Patients and Healthy Volunteers via Protein Binding

Abstract

The pharmacokinetics in patients with cystic fibrosis (CF) has long been thought to differ considerably from that in healthy volunteers. For highly protein bound β-lactams, profound pharmacokinetic differences were observed between comparatively morbid patients with CF and healthy volunteers. These differences could be explained by body weight and body composition for β-lactams with low protein binding. This study aimed to develop a novel population modeling approach to describe the pharmacokinetic differences between both subject groups by estimating protein binding. Eight patients with CF (lean body mass [LBM]: 39.8 ± 5.4kg) and six healthy volunteers (LBM: 53.1 ± 9.5kg) received 1027.5 mg cefotiam intravenously. Plasma concentrations and amounts in urine were simultaneously modelled. Unscaled total clearance and volume of distribution were 3% smaller in patients with CF compared to those in healthy volunteers. After allometric scaling by LBM to account for body size and composition, the remaining pharmacokinetic differences were explained by estimating the unbound fraction of cefotiam in plasma. The latter was fixed to 50% in male and estimated as 54.5% in female healthy volunteers as well as 56.3% in male and 74.4% in female patients with CF. This novel approach holds promise for characterizing the pharmacokinetics in special patient populations with altered protein binding.

The pharmacokinetics of antibiotics in cystic fibrosis

“…More recent studies used body size and body composition (with body surface area or lean body mass) to compare CF patients and healthy volunteers. They found that in CF patients who were not underweight V d for ß-lactam antibiotics was similar to that of non-CF patients [47,48]. Thus, in normal nourished CF patients, the dose per kg of bodyweight may be similar to healthy controls, whereas underweight CF patients may require a larger dose per kg of bodyweight.…”

“…Antibiotics bind reversibly to plasma proteins (serum albumin, alpha-1 acid glycoprotein, and lipoproteins). Decreased plasma protein binding for some antibiotics, especially multiple ß-lactam antibiotics [47], is observed in people with CF (mostly adults combined with a few adolescents), of which the precise mechanism is not completely understood [47,48]. Increased inflammatory processes that occur during acute pulmonary exacerbations may result in decreased production of albumin and, in addition, may alter albumin and protein binding of drugs [49].…”

“…They found that V d was similar between subject groups after scaling by body size and composition. However, Shah studied the PK differences of cefotiam between patients with CF and healthy volunteers [48]. After accounting for differences in body size and body composition, CF patients still had a 38% larger V d than healthy volunteers.…”

“…As an alternative, shorter dosing intervals or prolonged infusion (for example, 3 hours instead of 3 min) or continuous infusion may be used to achieve similar times of unbound ß-lactam concentrations above the minimal inhibitory concentration. A CF-population PK model for cefotiam developed by Shah, showed that besides having a higher V d , CF patients also have an 11% higher clearance rate [48]. The model explained these PK differences by a higher unbound fraction of cefotiam in patients with CF than in healthy volunteers, with higher unbound fractions of 74.4% in female and 56.3% in male patients with CF compared to 54.5% in female healthy volunteers and 50% in male healthy volunteers.…”

An Algorithm for Nonparametric Estimation of a Multivariate Mixing Distribution with Applications to Population Pharmacokinetics

“…Otherwise, the population analysis problem is the same. Bulitta et al [ 38 ] and Shah et al [ 39 ] use the method S-ADAPT. S-ADAPT is based on the ADAPT package developed by D’Argenio, Wang and Schumitzky.…”