Pharmacokinetics of Polymyxin B in Hospitalized Adults with Cystic Fibrosis

Abstract

The optimal polymyxin B dosage needed to achieve an efficacy target of 50 to 100 mg · h/liter when treating multidrug-resistant bacterial infections in adult cystic fibrosis (CF) patients is unclear. The pharmacokinetics of intravenous polymyxin B were evaluated to better inform dosing. This was a prospective, observational pharmacokinetic (PK) study of nine CF adults receiving intravenous polymyxin B as part of usual clinical care. Doses preceding PK sampling ranged from 50 to 100 mg every 12 h. Five PK samples were collected following the fourth or fifth dose and concentrations of polymyxin subcomponents B1 and B2 were quantified using liquid chromatography mass spectrometry (LC-MS). Population PK (NONMEM software) analysis was performed using pooled polymyxin B1+B2 concentrations. Participants were Caucasian, predominantly male, with mean age and weight of 31 years (range 21 to 57 years) and 58.0 kg (range 38.3 to 70.4 kg), respectively. A 1-compartment zero-order infusion and linear elimination model adequately described the data with estimated clearance and volume of distribution being 2.09 liters/h and 12.7 liters, respectively, corresponding to a 4.1 h mean half-life (t1/2). Although body weight was observed to influence the volume of distribution, a fixed dose of 75 mg every 12 h was predicted to achieve the target steady-state exposure. Neurotoxicities were reported in all patients, with acute kidney injury events in two patients. These events resolved within 2 to 4 days after discontinuing polymyxin B. Fixed maintenance dosing of polymyxin B without loading is predicted to achieve the targeted therapeutic exposure in CF adults. Treatment-limiting neurotoxicities are very common in this population.

Keywords: body weight; neurotoxocity; population pharmacokinetics.

Figures

FIG 1

Observed polymyxin B1, B2, and B1+B2 concentration-time profiles.

FIG 2

Forest plot of the impact of body weight on predicted steady-state exposure. Cmax, peak (maximum) concentration; AUC0–24, area under the concentration-time curve (AUC) over 24 h. Note: circles show the ratio of the median exposure metric under the test conditions compared to the reference. The line segments represent the corresponding 90% CI. The reference condition was a cystic fibrosis patient receiving polymyxin B at 75 mg every 12 h with a body weight of 60 kg. Test conditions were body weights of 40 to 80 kg in 5 kg increments. Vertical dashed lines indicate the reference interval of 0.8 to 1.25.