Background: “Systems pharmacology is the application of systems biology principles to the field of pharmacology.”(1). The pharmacokinetics of gentamicin (G), amikacin (A) and vancomycin (V) have been widely described including models with common features for each drug (2, 3) and a proposal to predict glomerular filtration rate (GFR) from drug clearance (CL). A reverse systems pharmacology approach using pharmacokinetic parameters such as CL in combination with biological data (GFR) and clinical data (serum creatinine, SCR) has been applied to inform systems biology.
Objectives:
1. To use pharmacokinetic analysis methods to inform systems biology
2. To apply systems pharmacology to understand and describe the pharmacokinetics of G, A and V (GAVamycin).
Methods: A joint model of GFR in neonates and young adults (4) and creatinine production rate (CPR) and GAVamycin pharmacokinetics in neonates (this work) was developed using NONMEM 7.4 alpha. A standard model was used to describe size and maturation (5) of all processes. Renal function (RF) was defined by the ratio of apparent creatinine clearance to normal GFR expected based on weight and post-menstrual age (PMA) (4).
Results: The time course of size standardized CPR production from neonates to young adults (post natal age 20 y, PMA 1080 w) was described by a linear function of PMA. Renal function in neonates (post-natal age 0-90 d, PMA 23-48 w) increased within 7 d of birth and stabilized with respect to PNA but declined slowly with respect to PMA. GFR, CPR and the PK of all 3 drugs was described best using fat free mass (FFM) for size. CL of each drug was predominantly predicted by RF and GFR but also had a non-renal component.
Conclusion: Systems pharmacology can be used to inform the development of biological systems (CPR and RF) in human neonates. A common model for GAVamycin precisely describes neonatal concentrations in relation to time after dose (TAD), PNA and weight.
Acknowledgements: I am grateful to my colleagues who shared data and/or helped with analysis of GAVamycin (Karel Allegaert, Nicolas Simon, Amicar Falcao and Catherine Sherwin, Brian Anderson), GFR (Malin Rhodin, Brian Anderson) and FFM (Anita Sumpter, Heshem Al-salami).
References:
1. Wikipedia. Systems Pharmacology available at: http://en.wikipedia.org/wiki/Systems_pharmacology. Accessed 23 Jan 2017.
2. De Cock RF, Allegaert K, Brussee JM, Sherwin CM, Mulla H, de Hoog M, et al. Simultaneous pharmacokinetic modeling of gentamicin, tobramycin and vancomycin clearance from neonates to adults: towards a semi-physiological function for maturation in glomerular filtration. Pharm Res. 2014;31(10):2643-54.
3. De Cock RFW, Allegaert K, Sherwin CMT, Nielsen EI, de Hoog M, van den Anker JN, et al. A Neonatal Amikacin Covariate Model Can Be Used to Predict Ontogeny of Other Drugs Eliminated Through Glomerular Filtration in Neonates. Pharm Res. 2014;31(3):754-67.
4. 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.
5. Holford N, Heo YA, Anderson B. A pharmacokinetic standard for babies and adults. J Pharm Sci. 2013;102(9):2941-52.