Scaling renal function in neonates and infants to describe the pharmacodynamics of antibiotic nephrotoxicity
Nick Holford (1) Catherine Sherwin (2)
(1) University of Auckland (2) University of Utah
Objectives: 1. To use pharmacokinetic analysis methods to inform systems biology 2. To apply systems pharmacology to describe renal function (RF) in neonates and infants 3. To describe the pharmacodynamics of gentamicin (G), amikacin (A) and vancomycin (V) on RF
Methods: "Systems pharmacology is the application of systems biology principles to the field of pharmacology."[1]. The pharmacokinetics of the antibiotics G, A and V have been widely described. Target concentration intervention is recommended to reduce the risk of nephrotoxicity. The time course of RF in relation to antibiotic exposure has not been well defined. A systems pharmacology approach using pharmacokinetic parameters such as clearance (CL) in combination with biological data (GFR) and clinical data (weight, height, post-menstrual age (PMA), serum creatinine) has been applied to scale RF in neonates and infants. A joint model of GFR in neonates and young adults [2] and creatinine production rate (CPR) and G, A, and V pharmacokinetics was developed using NONMEM 7.4 alpha. A standard model [3] was used to describe size and maturation of all processes. RF was defined by the ratio of apparent creatinine clearance to normal GFR expected based on weight and PMA (2). We are grateful to our colleagues who shared data and/or helped with the analysis of G, A and V (Karel Allegaert, Nicolas Simon, Amicar Falcao), GFR (Malin Rhodin, Brian Anderson) and FFM (Anita Sumpter, Heshem Al-Sallami).
Results: The time course of size standardized CPR production in 108 subjects (neonates to young adults (age 20 y)) was described by a linear function of PMA. Individual GFR, CPR and PK of all 3 drugs in 2,248 neonates and young infants was described. The best size metric for all parameters was fat free mass (FFM). CL of each drug had a predominant renal component predicted by RF and GFR. There was also a substantial non-renal component of CL. Renal function in neonates and young infants (post-natal age 0-90 d, PMA 23-48 w) increased within 7 d of birth and stabilized with respect to PNA. V and A had a greater effect than G on the subsequent progression of RF.
Conclusions: Systems pharmacology can be used to inform the development of biological systems (CPR and RF) in human neonates. A common model for G, A and V precisely describes neonatal concentrations in relation to time after dose, post-natal age and weight. The nephrotoxicity of antibiotic use in early life can be described using this model.
References:
[1] Wikipedia. Systems Pharmacology available at: http://en.wikipedia.org/wiki/Systems_pharmacology. 2014 Accessed 26 Feb 2017.
[2] Rhodin MM, Anderson BJ, Peters AM, Coulthard MG, Wilkins B, Cole M, et al. Human renal function maturation: a quantitative description using weight and postmenstrual age. Pediatr Nephrol. 2009;24(1):67-76.
[3] Holford N, Heo YA, Anderson B. A pharmacokinetic standard for babies and adults. J Pharm Sci. 2013;102(9):2941-52
