Prediction of total and renal clearance of renally secreted drugs in neonates and infants (≤3 months of age)
Background: Renal excretion is a major route of elimination for many drugs. Renal clearance is the sum of three processes: glomerular filtration, tubular secretion, and tubular re-absorption. Tubular secretion is an active transport process and is immature at birth. In the neonates, renal tubular secretion can be important for the elimination of those drugs which are renally secreted, such as penicillins and cephalosporins.
Aim: The objective of this study was to evaluate the predictive performances of three models to predict total and renal clearance of renally secreted drugs in neonates (≤3 months of age).
Methods: From the literature, clearance values for 12 renally secreted drugs for neonates and adults were obtained. Three models were used to predict the clearances of these drugs. The predictive performances of these models were evaluated by comparing the predicted values of total and renal clearance with the observed clearance values in the neonates. Results: There were 12 drugs with 22 observations (preterm and term neonates, ≤3 months of age) for total clearance and 6 drugs with 8 observations for renal clearance. For both total and renal clearance, a prediction error of <50% was observed by all three models evaluated in this study.
Conclusions: The proposed models can predict mean total and renal clearances of renally secreted drugs in preterm and term neonates (≤3 months of age) with reasonable accuracy (50% prediction error) and are of practical value during neonatal drug development.
Relevance for patients: The work may help in dose selection for neonates for medicines that are renally secreted.
[1] Alcorn J, McNamara PJ. Ontogeny “Ontogeny” of Hepatic and Renal Systemic Clearance Pathways in Infants: Part I. Clin Pharmacokinet 2002;41:959-98.
[2] Alcorn J, McNamara PJ. Ontogeny “Ontogeny” of Hepatic and Renal Systemic Clearance Pathways in Infants: Part II. Clin Pharmacokinet 2002;41:1077-94.
[3] Shargel L, Yu AB. Drug Clearance “Clearance”. In: Introduction to Pharmacokinetics: Applied Biopharmaceutics and Pharmacokinetics. 3rd ed. Norwalk: Appleton and Lange; 1993. p. 265-92.
[4] Arant BS Jr. Developmental Patterns of Renal Functional Maturation Compared in the Human Neonate. J Pediatr 1978;92:705-12.
[5] Brown RD, Campoli-Richards DM. Antimicrobial Therapy in Neonates, Infants “infants” and children. Clin Pharmacokinet 1989;17:105-15.
[6] Mahmood I. Prediction of Drug Clearance in Premature and Mature Neonates, Infants, and Children ≤2 Years of Age: A Comparison of the Predictive Performance of 4 Allometric Models. J Clin Pharmacol 2016;56:733-9.
[7] Bjorkman S. Prediction of Drug Disposition in Infants and Children by Means of Physiologically Based Pharmacokinetic (PBPK) Modelling: Theophylline and Midazolam as Model Drugs. Br J Clin Pharmacol 2004;6:691-704.
[8] Mahmood I. Prediction of Renally Excreted Drugs in Children (<12 years): A Comparison of Three Methods. In: Pharmacokinetic Allometric Scaling in Pediatric Drug Development. Rockville, MD: Pine House Publishers; 2013. p. 78-88.
[9] Rubin MI, Bruck E, Rapoport M, Snively M, McKay H, Baumler A. Maturation of Renal Function in Childhood; Clearance Studies. J Clin Invest 1949;28:1144-62.
[10] Mahmood I. Interspecies Scaling of Drugs Cleared by the Kidneys and the Bile. In: Interspecies Pharmacokinetic Scaling: Principles and Application of Allometric Scaling. Rockville, MD: Pine House Publishers; 2005. p. 105-43.
[11] Mahmood I. Interspecies Scaling of Renally Secreted Drugs. Life Sci 1998;63:2365-71.
[12] Mahmood I, Staschen CM. Prediction of Human Glomerular Filtration Rate from Preterm Neonates to Adults: Evaluation of Predictive Performance of Several Empirical Models. AAPS J 2016;18:445-54.
[13] Ritschel WA, Banerjee PS. Physiological Pharmacokinetic Models: Principles, Applications, Limitations and Outlook. Methods Find Exp Clin Pharmacol 1986;8:603-14.
[14] Loebstein R, Koren G. Clinical Pharmacology and Therapeutic Drug Monitoring in Neonates and Children. Ped Rev 1998;19:423-28.
[15] Mahmood I. Prediction of Drug Clearance in Preterm and Term Neonates: Different Exponents for Different Age Groups? In: Pharmacokinetic Allometric Scaling in Pediatric Drug Development. Rockville, MD: Pine House Publishers; 2013. p. 88-100.
[16] Mahmood I. Prediction of Drug Clearance in Children 3 Months and Younger: An Allometric Approach. Drug Metabol Drug Interact 2010;25:25-34.
[17] Edginton AN, Shah B, Sevestre M. The integration of allometry and virtual populations to predict clearance and clearance variability in pediatric populations over the age of 6 years. Clin Pharmacokinet 2013;52:693-703.
[18] Momper JD, Mulugeta Y, Green DJ, Karesh A, Krudys KM, Sachs HC, et al. Adolescent Dosing and Labeling Since the Food and Drug Administration Amendments Act of 2007. JAMA Pediatr 2013;167:926-32.
[19] Wang C, Allegaert K, Peeters MY, Tibboel D, Danhof M, Knibbe CA. The Allometric Exponent for Scaling Clearance Varies with Age: A Study on Seven Propofol Datasets Ranging from Preterm Neonates to Adults. Br J Clin Pharmacol 2014;77:149-59.
[20] Rhodin MM, Anderson BJ, Peters AM, Coulthard MG, Wilkins B, Cole M, et al. Human Renal Function Maturation: AQuantitative Description Using Weight and Postmenstrual Age. Pediatr Nephrol 2009;24:67-76.
[21] Rowland M, Peck C, Tucker G. Physiologically-based Pharmacokinetics in Drug Development and Regulatory Science. Annu Rev Pharmacol Toxicol 2011;51:45-73.
[22] Edginton AN, Theil FP, Schmitt W, Willmann S. Whole Body Physiologically-based Pharmacokinetic Models: Their Use in Clinical Drug Development. Expert Opin Drug Metab Toxicol 2008;4:1143-52.
[23] Sager JE, Yu J, Ragueneau-Majlessi I, Isoherranen N. Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulation Approaches: A Systematic Review of Published Models, Applications, and Model Verification. Drug Metab Dispos 2015;43:1823-37.
[24] Cao Y, Jusko WJ. Applications of Minimal Physiologically Based Pharmacokinetic Models. J Pharmacokinet Pharmacodyn 2012;39:711-23.
[25] Björkman S. Reduction and Lumping of Physiologically Based Pharmacokinetic Models: Prediction of the Disposition of Fentanyl and Pethidine in Humans by Successively Simplified Models. J Pharmacokinet Pharmacodyn 2003;30:285-307.
[26] Mahmood I, Ahmad T, Mansoor N, Sharib SM. Prediction of Clearance in Neonates and Infants (≤ 3 Months of Age) for Drugs that are Glucuronidated: A Comparative Study between Allometric Scaling and Physiologically Based Pharmacokinetic Modeling. J Clin Pharmacol 2017;57:476-83.
[27] Mahmood I, Tegenge MA. Spreadsheet-based Minimal Physiological Models for the Prediction of Clearance of Therapeutic Proteins in Pediatric Patients. J Clin Pharmacol 2021;61:S108-16.
[28] Mahmood I. A GFR-Based Method to Predict the Effect of Renal Impairment on the Exposure or Clearance of Renally Excreted Drugs: A Comparative Study between a Simple GFR Method and a Physiologically Based Pharmacokinetic Model. Drugs R D 2020;20:377-87.
[29] Mahmood I, Tegenge MA. A Comparative Study between Allometric Scaling and Physiologically Based Pharmacokinetic Modeling for the Prediction of Drug Clearance from Neonates to Adolescents. J Clin Pharmacol 2019;59:189-97.
References (children)
[S1] Hintz M, Connor JD, Spector SA, Blum MR, Keeney RE, Yeager AS. Neonatal Acyclovir Pharmacokinetics in Patients with Herpes Virus Infections. Am J Med 1982;73:210-4.
[S2] Huisman-de Boer JJ, van den Anker JN, Vogel M, Goessens WH, Schoemaker RC, de Groot R. Amoxicillin Pharmacokinetics in Preterm Infants with Gestational Ages of Less Than 32 Weeks. Antimicrob Agents Chemother 1995;39:431-4.
[S3] Tremoulet A, Le J, Poindexter B, Sullivan JE, Laughon M, Delmore P, et al. Characterization of the population pharmacokinetics of ampicillin in neonates using an opportunistic study design. Antimicrob Agents Chemother 2014;58:3013-20.
[S4] Yoshioka H, Takimoto M, Shimizu T, Haga H. Pharmacokinetics of Intramuscular Carbenicillin. Infection 1979;7:27-9.
[S5] McCracken GH Jr., Threlkeld NE, Thomas ML. Pharmacokinetics of Cefotaxime in Newborn Infants. Antimicrob Agents Chemother 1982;21:683-4.
[S6] Gouyon JB, Pechinot A, Safran C, Chretien P, Sandre D, Kazmierczak A. Pharmacokinetics of Cefotaxime in Preterm Infants. Dev Pharmacol Ther 1990;14:29-34.
[S7] Gruber WC, Rench MA, Garcia-Prats JA, Edwards MS, Baker CJ. Single-dose Pharmacokinetics of Imipenem-cilastatin in Neonates. Antimicrob Agents Chemother 1985;27:511-4.
[S8] Reed MD, Kliegman RM, Yamashita TS, Myers CM, Blumer JL. Clinical Pharmacology of Imipenem and Cilastatin in Premature Infants During the First Week of Life. Antimicrob Agents Chemother 1990;34:1172-7.
[S9] Ziemniak JA, Wynn RJ, Aranda JV, Zarowitz BJ, Schentag JJ. The Pharmacokinetics and Metabolism of Cimetidine in Neonates. Dev Pharmacol Ther 1984;7:30-8.
[S10] Wenning LA, Murphy MG, James LP, Blumer JL, MarshallJD, Baier J, et al. Pharmacokinetics of Famotidine in Infants. Clin Pharmacokinet 2005;44:395-406.
[S11] James LP, Marotti T, Stowe CD, Farrar HC, Taylor BJ, Kearns GL. Pharmacokinetics and Pharmacodynamics of Famotidine in Infants. J Clin Pharmacol 1998;38:1089-95.
[S12] Rubio T, Wirth F, Karotkin E. Pharmacokinetic Studies of Mezlocillin in Newborn Infants. J Antimicrob Chemother 1982;9:241-4.
[S13] Metsvaht T, Oselin K, Ilmoja ML, Anier K, Lutsar I. Pharmacokinetics of Penicillin g in Very-low-birth-weight Neonates. Antimicrob Agents Chemother 2007;51:1995- 2000.
[S14] Kacet N, Roussel-Delvallez M, Gremillet C, Dubos JP, Storme L, Lequien P. Pharmacokinetic Study of Piperacillin in Newborns Relating to Gestational and Postnatal Age. Pediatr Infect Dis J 1992;11:365-9.
[S15] Wells TG, Heulitt MJ, Taylor BJ, Fasules JW, Kearns GL. Pharmacokinetics and Pharmacodynamics of Ranitidine in Neonates Treated with Extracorporeal Membrane Oxygenation. J Clin Pharmacol 1998;38:402-7.
References (adults)
[S16] Laskin OL, Longstreth JA, Saral R, de Miranda P, Keeney R, Lietman PS. Pharmacokinetics and Tolerance of Acyclovir, a New Anti-herpesvirus Agent, in Humans. Antimicrob Agents Chemother 1982;21:393-8.
[S17] Spyker DA, Rugloski RJ, Vann RL, O’Brien WM. Pharmacokinetics of Amoxicillin: Dose Dependence after Intravenous, Oral, and Intramuscular Administration. Antimicrob Agents Chemother 1977;11:132-41.
[S18] Clarke JT, Libke RD, Ralph ED, Luthy RP, Kirby WM. Human Pharmacokinetics of BL-P1654 Compared with Ampicillin. Antimicrob Agents Chemother 1974;6:729-33.
[S19] Meyers BR, Hirschman SZ, Strougo L, Srulevitch E. Comparative study of Piperacillin, Ticarcillin, and Carbenicillin Pharmacokinetics. Antimicrob Agents Chemother 1980;17:608-11.
[S20] Kemmerich B, Lode H, Belmega G, Jendroschek T, Borner K, Koeppe P. Comparative Pharmacokinetics of Cefoperazone, Cefotaxime, and Moxalactam. Antimicrob Agents Chemother 1983;23:429-34.
[S21] Drusano GL, Standiford HC, Bustamante C, Forrest A, Rivera G, Leslie J, et al. Multiple-dose Pharmacokinetics of Imipenem-cilastatin. Antimicrob Agents Chemother 1984;26:715-21.
[S22] Larsson R, Erlanson P, Bodemar G, Walan A, Bertler A, Fransson L, et al. The Pharmacokinetics of Cimetidine and its Sulphoxide Metabolite in Patients with Normal and Impaired Renal Function. Br J Clin Pharmacol 1982;13:163-70.
[S23] Yeh KC, Chremos AN, Lin JH, Constanzer ML, Kanovsky SM, Hucker HB, et al. Single-dose Pharmacokinetics and Bioavailability of Famotidine in Man. Results of Multicenter Collaborative Studies. Biopharm Drug Dispos 1987;8:549-60.
[S24] Bergan T. Pharmacokinetics of Mezlocillin in Healthy Volunteers. Antimicrob Agents Chemother 1978;14:801-6.
[S25] Benzylpenicillin. Canada: DrugBank. Available from: https://www.drugbank.ca/drugs/DB01053
[S26] Chau NP, Zech PY, Pozet N, Hadj-Aissa A. Ranitidine kinetics in normal subjects. Clin Pharmacol Ther 1982;31:770-4.
[S27] Tjandramaga TB, Mullie A, Verbesselt R, De Schepper PJ, Verbist L. Piperacillin: Human Pharmacokinetics After Intravenous and Intramuscular Administration. Antimicrob Agents Chemother 1978;14:829-37.