Effects of Different Component Contents of Colistin Methanesulfonate on the Pharmacokinetics of Prodrug and Formed Colistin in Human

Purposes To evaluate the effects of component contents in different colistin methanesulfonate (CMS) formulas on their clinical pharmacokinetics of the prodrug CMS and the formed colistin. Methods Two CMS formulas (CTTQ and Parkedale) were investigated in a single dose, randomized, open-label, crossover study conducted in 18 healthy Chinese subjects. Both CMS formulas met the requirements of European Pharmacopoeia 9.2 with 12.1% difference in the two major active components (CMS A and CMS B). The PK parameters after a single intravenous infusion of CMS at 2.5 mg/kg were calculated and the steady-state plasma colistin concentrations (C ss,avg ) following multiple dosing, once every 12 h for 7 days, were simulated with the non-compartment model. Results The systemic exposure (AUC 0-inf ) of CMS were 59.49 ± 5.90 h·μg/mL and 51.09 ± 4.70 h·μg/mL, and the AUC 0-inf of colistin were 15.39 ± 2.63 h·μg/mL and 12.36 ± 2.10 h·μg/mL for CTTQ and Parkedale, respectively. The ratios (90% CI) of geometric mean of AUC 0-inf of CTTQ to Parkedale were 116.38% (112.95%, 119.91%) and 124.49% (120.76%, 128.35%) for CMS and colistin, respectively. The predicted C ss,avg (95% CI) were 0.92 (0.85, 0.99) μg/mL and 0.74 (0.69, 0.79) μg/mL for CTTQ and Parkedale, respectively. Conclusion The difference in component content in the two CMS formulas had a significant ( P < 0.001) impact on the systemic exposure of colistin in human, thus, warranted essential considerations in clinical applications.