Pharmacokinetics/Pharmacodynamics (PK/PD) of Ciprofloxacin in the Complicated Urinary Tract Infection (cUTI) Model in Diabetic Mice

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Author(s): Mahesh Kumar Reniguntla, Randhir Yedle, Ramesh Puttaswamy, Pradeep Puttarangappa, Somashekharayya Hiremath, Avinash Pawar, Mahesh Nanjundappa, Ramesh Jayaraman*.

Journal Name: Current Drug Metabolism

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Background: The translation of Pharmacokinetics (PK)/Pharmacodynamics (PD) from preclinical models to the clinic has not been studied in detail for drugs used to treat complicated urinary tract infections (cUTI). Objective: The PK/PD of Ciprofloxacin (CIP), a drug used to treat cUTI, was evaluated in a mouse model of cUTI infected with Escherichia coli, and compared with clinical PK/PD in cUTI patients.

Method: Streptozotocin induced diabetic female BALB/c mice were infected trans-urethrally with Escherichia coli. Four hours post infection, CIP oral doses of 3, 10, 30,100, and 300 mg/kg, were administered as single doses (for PK and dose response) and repeated doses (for PD and PK/PD). Bacterial burden in kidneys, bladder, urine, body temperature, clinical signs were assessed twenty four hours post treatment.

Results: CIP displayed linear PK with dose proportional increase in Cmax and AUCinf in plasma. In PD time course studies, CIP showed rapid onset, intensity and duration of anti-bacterial effect in target tissues. In intrinsic PD studies, CIP showed a maximum effect at plasma AUC/MIC =1705 (300 mg/kg, twice daily) for bacterial load in bladder (r2= 0.979), kidney (r2 = 0.951) and rectal temperature (r2 = 0.67). The magnitude of plasma AUC/MIC of 412 was associated with maximum PD effect Imax=3.7 Log10CFU/bladder and Imax =1.97 Log10CFU/kidney. In dose fractionation studies, plasma AUC/MIC showed highest correlation with efficacy in bladder (r2=0.77) and kidney (r2=0.80).

Conclusion: The PK/PD of CIP in the mouse of model of cUTI was comparable to clinical data.

Keywords: Pharmacokinetics, Pharmacodynamics, Pharmacokinetics/Pharmacodynamics, Ciprofloxacin, cUTI, Mouse, Diabetes

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(E-pub Ahead of Print)
DOI: 10.2174/1389200221666200310105227
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