MODELING AND SIMULATION OF TEMOCILLIN IN PATIENTS

WITH END STAGE RENAL DISEASE UNDERGOING

HAEMODIALYSIS

BY ZOHEB ANJUM * MOHD.SHAFEEQUR RAHMAN KHALID

WHAT IS END STAGE RENAL DISEASE?

• End stage renal disease is a last stage of chronic kidney disease, this means that the kidneys are working below 10% of their normal function and can no longer supports a person –day to day life.

PATHOPHYSIOLOGY OF ESRD

SIGNS AND SYMPTOMS OF ESRD:a decrease in how much you urinatean inability to urinatefatiguea general ill feelinga general ill feelingunexplained weight lossa loss of appetitenausea and vomitingdry skin and itchingchanges in skin colorbone painconfusion and difficulty concentrating

TREATMENT OF ESRD:- Treatment of end stage renal disease includes haemodialysis , peritonial dialysis and kidney transplant.HAEMODIALYSIS:-Blood is removed from the body through plastic tubing and passed through a filter that removes waste products and extra water that build up. The “cleaned” blood is returned to the body through plastic tubing. Hemodialysis can be done at a clinic (in-center) or at home. Types of hemodialysis treatments include: ∞ Standard hemodialysis— treatments are 4-5 hours long, three treatments per week, in– center or at home.

∞ Nocturnal hemodialysis—treatments are 8 to 9 hours long, three treatments per week, in-center or at home.

∞ Short, daily hemodialysis—treatments are 2 or 3 hours 5 to 7 nights per week, usually done at home.

TEMOCILLINTemocillin(TMO) is a narrow-spectrum anti-gram-negative β-lactam antibiotic .Its molecular formula is 6-α-methoxy-Ticarcillin. Temocillin is a renally cleared penicillin with long serum half-live and potent activity against most gram-negative bacteria, making it an ideal candidate for treatment given on dialysis days only of severe gram-negative infections in patients with ESRD treated with haemodialysis.

STRUCTURE OF TEMOCILLIN

METHOD OF STUDY:•It is open ,non-randomized, single-center study.•In this case 12 patients were adminstered a single dose of 1.2 or 3g of TMO followed by a inter-dialytic (off-dialysis) of 20 , 44, 68 hour, respectively and a dialysis period of4h (total of 39 doses)•In this 351 serum sample were collected according to the sampling scheme and analysed for unbound concentrations using a HPLC-MS/MS assay.

Dosing scheme

POPULATION PHARMACOKINETIC MODELA Population pharmacokinetic(pk) model was developed using a non-linear mixed effect model. An apparent dialysis clearance was implemented in parallel to body clearance to describe the accelerated drug clearance by haemodialysis . The relationship between blood flow rate and apparent TMO dialysis clearance was described using michaels equation.

•Models were selected based upon decrease in objective function value,improvement in goodness-of-fit,and diagnostic plots.

•TMO serum unbound concentrations were best described by a two compartment model.

•The final model estimated all parameters with good precision (relative standard errors ) between 11.4% and 25.7%

•TMO clearance during dialysis was 8 fold higher than off-dialysis , resulting in significant reduction of TMO serum concentration.

•PTA95 was obtained for a MIC < 8mg/L, for a 2g dose (44h inter-dialytic period)

•The final model succesfully predicted the serum TMO concentrations described in two haemodialysis patients unknown to model.

CONCLUSIONS:•A two compartment pk model for TMO in ESRD patients undergoing haemodialysis was developed and demostrated to be predictive , including during the dailysis period .This model might serve as a useful tool to provide guidance in the optimization of TMO dosing regimens in haemodialysis patients.

•Temocillin appears to exhibit non-linear pharmacokinetics ,probably due to saturable protein binding.

•ESRD patients have high systemic exposure to temocillin and haemodialysis efficiently eliminates from patients body making post dialysis replacement dose required to maintain desired therupetic level.

REFERENCES:[1] Livemore DM, Tulkens PM. Temocillin revived. J Antimicrob(2009) 63:243-5

[2] Michaels AS ,Operating parameters and performance criteria for haemodialyzers and other membrane-seperation devices. Trans Arn Soc artif intern organs (1996) 12:387-92.

[3]De Jongh et al.continuous versus intermittent infusion of temocillin,a directed spectrum pencillin for intensive care patients with nosocomial pneumonia :stability , compatibility ,population pharmacokinetic studies and break point selection ,J AC 61 (2008) 382-388

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