Pharmacokinetics and safety of colistin sulfate after single and multiple intravenous doses in healthy Chinese subjects

Objective

Increasing antimicrobial resistance has led to the revival of the polymyxins as a last-resort therapeutic option for multidrug-resistant Gram-negative bacterial infections. A parenteral formulation of colistin sulfate is available solely in China. While the onset of action of IV colistin may occur faster than with its prodrug CMS, its pharmacokinetic (PK) profile remains unclear.

Methods

This single-centre, open-label, single- and multi-dose, phase 1 trial examined the PKs and safety of colistin sulfate in healthy Chinese adults. Participants received a single 10,000 units/kg (equivalent to 0.452 mg/kg) dose of colistin sulfate (single-dose group, n = 12) or the same dose q12h for 7 days (multi-dose group, n = 12) via a 2-h IV infusion. Colistin concentrations in plasma and urine were determined using LC-MS/MS, and the PK parameters calculated using non-compartmental analysis.

Results

After a single dose the peak concentration (C_max), area under the curve from 0 to 12 h (AUC_0-12h), terminal half-life (T_1/2), volume of distribution (V_d), and total body clearance (CL) of colistin were 1.08 ± 0.18 mg/L, 4.73 ± 0.89 h·mg/L, 3.65 ± 0.55 h, 16.82 ± 2.70 L, and 3.24 ± 0.51 L/h, respectively. No accumulation of colistin was observed after multiple doses. The cumulative urinary recovery of colistin was 0.9 ± 0.7% within 24 h after multi-dose administration. No nephrotoxicity was reported.

Conclusions

This study is the first to report colistin PKs in healthy Chinese subjects after single and multiple doses of colistin sulfate. The PK and safety data are required for optimal dose selection in clinical practice.