Population pharmacokinetics of clindamycin orally and intravenously administered in patients with osteomyelitis

Abstract

Aims: This study was performed to describe clindamycin, administered either orally or intravenously, concentration-time courses to patients with osteomyelitis, to study the effects of different covariates on clindamycin pharmacokinetics and to simulate an optimized administration scheme.

Methods: Clindamycin concentrations were measured in 50 patients. A total of 122 plasma concentrations were available (58 from oral administration and 64 from i.v. infusion). A population pharmacokinetic model was developed with MONOLIX 4 software.

Results: A one compartment model adequately described the data. Clindamycin clearance increased significantly with body weight (BW). The typical population estimates (interindividual variability) for clearance, volume of distribution and absorption rate constant were 16.2 l h(-1) (0.39), 70.2 l and 0.92 h(-1) , respectively. The bioavailability of the oral form was estimated to be 87.6%. According to BW, theoretical doses needed to reach a C(min) of 2 mg l(-1) were then calculated.

Conclusions: The current recommendation of 600 mg three times daily seems to be effective up to 75 kg but the dose should be raised to 900 mg three times daily thereafter. These assumptions should be prospectively confirmed.

© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

Figures

Figure 1

Observed plasma clindamycin concentrations (closed circles) and population pharmacokinetic based model-predicted clindamycin concentrations (curve) as a function of time for i.v. infusion (black) and oral dosing (blue)

Figure 2

PC-VPC (prediction-corrected visual predictive check) for clindamycin concentrations A) after i.v. administration and B) after oral dosing. The green lines show the 10th, 50th and 90th percentiles of observed data; the areas represent the 90% confidence interval around the simulated percentiles

Figure 3

Diagnostic plots: population weighted residuals (WRES) (A, C) and normalized prediction distribution error (NPDE) (B, D) as a function of time (A, B) and population prediction (C, D)

Figure 4

Dose (mg 8 h−1) needed to achieve a target minimum concentration of 2 mg l−1 for clindamycin as a function of body weight. Dashed lines correspond to 90% confidence interval. Horizontal green line correspond to the usual dose of 600 mg every 8 h