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

Author(s):

Mahesh Kumar Reniguntla, Randhir Yedle, Ramesh Puttaswamy, Pradeep Puttarangappa , Somashekharayya Hiremath, Avinash Pawar, Mahesh Nanjundappa and Ramesh Jayaraman *   Pages 1 - 8 ( 8 )

Abstract:


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

Affiliation:

TheraIndx Lifesciences Pvt Ltd, Department of Pharmacology, Sy.no.27, Deganahalli, Budihal Post, Nelamangala, TheraIndx Lifesciences Pvt Ltd, Department of Pharmacology, sy 27, budhihal post, deganahalli post, nelamangala, 07760976277 , TheraIndx Lifesciences Pvt Ltd, Department of Microbiology, sy 27, budhihal post, deganahalli post, nelamangala, TheraIndx Lifesciences Pvt Ltd, Department of Microbiology, sy 27, budhihal post, deganahalli post, nelamangala, TheraIndx Lifesciences Pvt Ltd, Department of Pharmacology, sy 27, budhihal post, deganahalli post, nelamangala, TheraIndx Lifesciences Pvt Ltd, Department of Pharmacology, sy 27, budhihal post, deganahalli post, nelamangala, TheraIndx Lifesciences Pvt Ltd, Department of Pharmacology, sy 27, budhihal post, deganahalli post, nelamangala, TheraIndx Lifesciences Pvt Ltd, 9, 10th cross, Nanjappa Layout, Vidyaranyapura post



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