Violeta Balbas-Martinez(1,2,4), Andrea N. Edginton(3), Robin Michelet(4), Kevin Meesters(5,6) , Iñaki F. Trocóniz(1,2) , An Vermeulen(4
(1) Pharmacometrics and Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy and Nutrition, University of Navarra; Pamplona, Spain (2) IdiSNA, Navarra Institute for Health Research; Pamplona, Spain. (3) School of Pharmacy, University of Waterloo; Waterloo, Ontario, Canada. (4) Ghent University, Faculty of Pharmaceutical Sciences, Laboratory of Medical Biochemistry and Clinical Analysis; Ghent, Belgium. (5) Ghent University Hospital, Department of Pediatric Nephrology; Ghent, Belgium. (6) KidZ Health Castle, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel; Brussels, Belgium.
Objectives:
Ciprofloxacin is a second generation fluoroquinolone with a broad antibacterial spectrum labelled for treatment of complicated urinary tract infection (cUTI) in children. In a recent population pharmacokinetic study of ciprofloxacin administered to children suffering from cUTI, it was demonstrated that in this patient population, the apparent volume of distribution (V) and total plasma clearance (CL) showed up to a 83.6 and 41.5% decrease compared to healthy children[1].
The goal of the present study was to (i) build and evaluate a ciprofloxacin PBPK model for the adult population, (ii) extrapolate the adult model to the healthy paediatric population, (iii) perform a sensitivity analysis to identify those factors most important for describing elimination and disposition, and (iv) adapt the PBPK model in healthy children to the paediatric population suffering from cUTI.
Methods:
PK-Sim® (Open-Systems-Pharmacology.com) was the PBPK software and the well-established workflow for PBPK model development in children [2] was followed.
First, a ciprofloxacin adult PBPK model was developed with data extracted from literature[3–8] after intravenous and oral administration. Ciprofloxacin exhibits (i) renal elimination mediated by glomerular filtration (GFR) and tubular secretion (TS_CLint), (ii) CYP1A2 mediated metabolism (CLCYP1A2), and (iii) biliary excretion (CLBil). A value of 1.25 ml/min/kg corresponding to 15% of the adult CL was used for CLBil. An apical efflux transporter was added to fully characterize renal elimination. Distribution was characterized using tissue-to-plasma partition coefficients predicted by the in silico tissue composition approach proposed by Rodgers et al.[9] and the standard PK-Sim® model for small molecules. With respect to absorption, dissolution profiles were described by the Weibull function. Afterwards, assuming linear pharmacokinetics, TS_CLint, CLCYP1A2 and transcellular intestinal permeability were optimized.
Second, age-dependent physiological and anatomical changes were implemented enabling paediatric predictions from the PBPK model established for adults. PBPK based predictions were challenged with plasma concentrations simulated from a population pharmacokinetic model developed with data from 150 children (3 month to 17 years) of whom 97% had normal renal function or mild renal impairment[10].
Third, a sensitivity analysis was performed to assess the impact of model parameters on the CL and V. An increase of 10% of every model parameter was evaluated. Parameters with sensitivity values < -0.25 or > 0.25 were reported for V and CL.
Finally, to account for the renal impairment in cUTI children, TS_CLint and CLCYP1A2 were corrected according to their Kidney Function (KF) computed based on individual cystatin C and creatinine values from a clinical study with 22 enrolled cUTI children[11].
Results:
A PBPK model for ciprofloxacin has been successfully developed for adult and healthy paediatric populations. The model was able to describe ciprofloxacin concentration-time profiles and fraction excreted unchanged in urine (fe) in close agreement with the observed data. The final estimates obtained for intestinal permeability, CLCYP1A2, and TS_CLint were 3 x 10-6 cm/min, 20.61 mL/min and 1.32 L/min/kg tissue, respectively.
The sensitivity analysis revealed that V was greatly affected by tissue internal pH, fraction unbound in plasma and kidney volume, whereas for CL, the contribution of the tubular secretion, together with kidney volume and fraction unbound in plasma were the most influential parameters.
A significant improvement in the prediction of plasma concentrations of ciprofloxacin and fe were obtained in cUTI patients once TS_CLint and CLCYP1A2 were corrected according to the individual values of KF.
Conclusions:
A ciprofloxacin PBPK model has been developed for adult and paediatric populations. Changes in TS_CLint and CLCYP1A2 according to KF explained in part the differences seen in the plasma drug concentrations vs time profiles and fe between healthy and cUTI children. Furthermore, a sensitivity analysis indicated that intracellular pH had a great impact on drug distribution. Interestingly, metabolic acidosis is a common complication of chronic kidney disease[12], which might play a relevant role in the pharmacokinetics of the cUTI population.
References:
[1] Kevin Meesters, Robin Michelet, Reiner Mauel, Ann Raes, Jan Van Bocxlaer, Johan Vande Walle, An Vermeulen. Pharmacokinetics of ciprofloxacin in children with complicated urinary tract infection: results of a multicenter population pharmacokinetic study. Manuscript under preparation.
[2] Maharaj AR, Barrett JS, Edginton AN. A workflow example of PBPK modeling to support pediatric research and development: case study with lorazepam. AAPS J. 2013;15: 455–464.
[3] Davis RL, Koup JR, Williams-Warren J, Weber A, Heggen L, Stempel D, et al. Pharmacokinetics of ciprofloxacin in cystic fibrosis. Antimicrob Agents Chemother. 1987;31: 915–919.
[4] Lettieri JT, Rogge MC, Kaiser L, Echols RM, Heller AH. Pharmacokinetic profiles of ciprofloxacin after single intravenous and oral doses. Antimicrob Agents Chemother. 1992;36: 993–996.
[5] Schuck EL, Dalhoff A, Stass H, Derendorf H. Pharmacokinetic/pharmacodynamic (PK/PD) evaluation of a once-daily treatment using ciprofloxacin in an extended-release dosage form. Infection. 2005;33 Suppl 2: 22–28.
[6] Meagher AK, Forrest A, Dalhoff A, Stass H, Schentag JJ. Novel pharmacokinetic-pharmacodynamic model for prediction of outcomes with an extended-release formulation of ciprofloxacin. Antimicrob Agents Chemother. 2004;48: 2061–2068.
[7] Begg EJ, Robson RA, Saunders DA, Graham GG, Buttimore RC, Neill AM, et al. The pharmacokinetics of oral fleroxacin and ciprofloxacin in plasma and sputum during acute and chronic dosing. Br J Clin Pharmacol. 2000;49: 32–38.
[8] Jaehde U, Sörgel F, Reiter A, Sigl G, Naber KG, Schunack W. Effect of probenecid on the distribution and elimination of ciprofloxacin in humans. Clin Pharmacol Ther. 1995;58: 532–541.
[9] Rodgers T, Rowland M. Physiologically based pharmacokinetic modelling 2: predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions. J Pharm Sci. 2006;95: 1238–1257.
[10] Rajagopalan P, Gastonguay MR. Population pharmacokinetics of ciprofloxacin in pediatric patients. J Clin Pharmacol. 2003;43: 698–710.
[11] University Hospital G, Brussel UZ. Pharmacokinetics of Ciprofloxacin in Pediatric Patients: NCT02598362 [Internet]. 5 Nov 2015. Available: https://www.clinicaltrials.gov/ct2/show/NCT02598362?term=NCT02598362&rank=1[12] Kraut JA, Madias NE. Metabolic Acidosis of CKD: An Update. Am J Kidney Dis. 2016;67: 307–317.
Reference: PAGE 27 (2018) Abstr 8676 [www.page-meeting.org/?abstract=8676]
Poster: Drug/Disease Modelling - Paediatrics