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 (Css,avg) following multiple dosing, once every 12 h for 7 days, were simulated with the non-compartment model.
Results: The systemic exposure (AUC0-inf) of CMS were 59.49 ± 5.90 h·μg/mL and 51.09 ± 4.70 h·μg/mL, and the AUC0-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 AUC0-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 Css,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.
Keywords: colistin; colistin methanesulfonate; component content; pharmacokinetics.