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

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Abstract

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.

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Abbreviations

AE:

Adverse events

AKI:

Acute kidney injury

AUC0–12 :

Area under the concentration–time curve from time 0 to 12 h after drug administration

AUC0–24 :

Area under the concentration–time curve from time 0 to 24 h after drug administration

AUC0-inf :

Area under the concentration–time curve from time zero to infinity after drug administration

AUCss,24 :

Steady-state 24-h area under the concentration-time curve

BMI:

Body mass index

CBA:

Colistin base activity

CLr :

Renal clearance

CLt :

Total clearance

Cmax :

Peak concentration

CMS:

Colistin methanesulfonate

CMSA:

Colistin A methanesulfonate

CMSB:

Colistin B methanesulfonate

Css,avg :

Average steady-state concentration

CysC:

Cysteine dehydrogenase inhibitor C

fAUC/MIC:

Ratio of area under curve of free colistin over minimum inhibitory concentration

f m :

Fraction of CMS converted into colistin in blood

MIC:

Minimum inhibitory concentration

NGAL:

Neutrophil gelatinase-associated lipocalin

PK:

Pharmacokinetics

PK/PD:

Pharmacokinetic/pharmacodynamic

SAE:

Serious adverse events

T1/2 :

Half time

TDM:

Therapeutic drug monitoring

Tmax :

Time to peak concentration

Vd :

Distribution volume

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ACKNOWLEDGEMENT AND DISCLOSURES

The authors declare no conflict of interest. The authors would like to thank CHIA TAI TIAN-QING Pharmaceutical Group Co., Ltd. (Jiangsu, China) for kindly providing the CMS formula. This study was supported by Major Research and Development Project of Innovative Drugs, Ministry of Science and Technology (2017ZX09304005). The authors would also like to thank Professor Jian Li, Facility for Anti-Infective Drug Development and Innovation, Victorian College of Pharmacy, Monash University for his advice on PK analysis.

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Author notes

  1. Ya-Xin Fan and Yuan-Cheng Chen contributed equally to this work.

Authors and Affiliations

  1. Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, 200040, China

    Ya-Xin Fan, Yi Li, Xing-Chen Bian, Xin Li, Wan-Zhen Li, Bei-Ning Guo, Hai-Lan Wu, Xiao-Fen Liu, Yu Wang, Xiao-Yong Xu, Jia-Li Hu, Ying-Yuan Zhang & Jing Zhang

  2. Key Laboratory of Clinical Pharmacology of Antibiotics, National Population and Family Planning Commission, Shanghai, 200040, China

    Ya-Xin Fan, Yuan-Cheng Chen, Yi Li, Ji-Cheng Yu, Xing-Chen Bian, Xin Li, Wan-Zhen Li, Bei-Ning Guo, Hai-Lan Wu, Xiao-Fen Liu, Yu Wang, Xiao-Yong Xu, Jia-Li Hu, Jing-Jing Wang, Xiao-Jie Wu, Guo-Ying Cao, Ju-Fang Wu, Ying-Yuan Zhang & Jing Zhang

  3. National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, China

    Ya-Xin Fan, Yuan-Cheng Chen, Yi Li, Ji-Cheng Yu, Xing-Chen Bian, Xin Li, Wan-Zhen Li, Bei-Ning Guo, Hai-Lan Wu, Xiao-Fen Liu, Yu Wang, Xiao-Yong Xu, Jia-Li Hu, Jing-Jing Wang, Xiao-Jie Wu, Guo-Ying Cao, Ju-Fang Wu, Ying-Yuan Zhang & Jing Zhang

  4. Phase I Unit, Huashan Hospital, Fudan University, Shanghai, 200040, China

    Yuan-Cheng Chen, Ji-Cheng Yu, Jing-Jing Wang, Xiao-Jie Wu, Guo-Ying Cao & Ju-Fang Wu

  5. Shanghai Institute of Pharmaceutical Industry, Shanghai, 201203, China

    Chun-Jia Xue & Jun Feng

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  1. Ya-Xin Fan
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Correspondence to Jing Zhang.

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Fan, YX., Chen, YC., Li, Y. et al. Effects of Different Component Contents of Colistin Methanesulfonate on the Pharmacokinetics of Prodrug and Formed Colistin in Human. Pharm Res 38, 79–87 (2021). https://doi.org/10.1007/s11095-021-02991-4

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