Time-Varying Clearance in Milrinone Pharmacokinetics from Premature Neonates to Adolescents

Overview

Journal Clin Pharmacokinet

Specialty Pharmacology

Date 2024 Apr 13

PMID 38613610

Authors

Conor J OHanlon

Anita Sumpter

Brian J Anderson

Jacqueline A Hannam

Affiliations

Soon will be listed here.

Abstract

Background And Objectives: Milrinone is an inotrope and vasodilator used for prophylaxis or treatment of low cardiac output syndrome after weaning from cardiopulmonary bypass (CPB). It is renally eliminated and has an acceptable therapeutic range of 100-300 μg/L, but weight-based dosing alone is associated with poor target attainment. We aimed to develop a population pharmacokinetic model for milrinone from premature neonates to adolescents, and to evaluate how age, renal function and recovery from CPB may impact dose selection.

Methods: Fifty paediatric patients (aged 4 days to 16 years) were studied after undergoing cardiac surgery supported by CPB. Data from 29 premature neonates (23-28 weeks' postmenstrual age) treated for prophylaxis of low systemic blood flow were available for a pooled pharmacokinetic analysis. Population parameters were estimated using non-linear mixed effects modelling (NONMEM 7.5.1).

Results: There were 369 milrinone measurements available for analysis. A one-compartment model with zero-order input and first-order elimination was used to describe milrinone disposition. Population parameters were clearance 17.8 L/70 kg [95% CI 15.8-19.9] and volume 20.4 L/h/70 kg [95% CI 17.8-22.1]. Covariates included size, postmenstrual age and renal function for clearance, and size and postnatal age for volume. Milrinone clearance is reduced by 39.5% [95% CI 24.0-53.7] immediately after bypass, and recovers to baseline clearance with a half-time of 12.0 h [95% CI 9.7-15.2]. Milrinone volume was 2.07 [95% CI 1.87-2.27] times greater at birth than the population standard and decreased over the first days of life with a half-time of 0.977 days [95% CI 0.833-1.12].

Conclusion: Milrinone is predominately renally eliminated and so renal function is an important covariate describing variability in clearance. Increasing clearance over time likely reflects increasing cardiac output and renal perfusion due to milrinone and return to baseline following CPB.

Citing Articles

Interaction of milrinone with extracorporeal life support.

Whelan A, Mim S, Hunt J, McKnite A, Green D, Imburgia C J Extra Corpor Technol. 2024; 56(4):167-173.

PMID: 39705580 PMC: 11661780. DOI: 10.1051/ject/2024014.

References

WEST G, Brown J, Enquist B . A general model for the origin of allometric scaling laws in biology. Science. 1997; 276(5309):122-6. DOI: 10.1126/science.276.5309.122. View

Hoffman T, Wernovsky G, Atz A, Kulik T, Nelson D, Chang A . Efficacy and safety of milrinone in preventing low cardiac output syndrome in infants and children after corrective surgery for congenital heart disease. Circulation. 2003; 107(7):996-1002. DOI: 10.1161/01.cir.0000051365.81920.28. View

Hornik C, Yogev R, Mourani P, Watt K, Sullivan J, Atz A . Population Pharmacokinetics of Milrinone in Infants, Children, and Adolescents. J Clin Pharmacol. 2019; 59(12):1606-1619. PMC: 6813877. DOI: 10.1002/jcph.1499. View

Gist K, Mizuno T, Goldstein S, Vinks A . Retrospective Evaluation of Milrinone Pharmacokinetics in Children With Kidney Injury. Ther Drug Monit. 2015; 37(6):792-6. DOI: 10.1097/FTD.0000000000000214. View

Beal S . Ways to fit a PK model with some data below the quantification limit. J Pharmacokinet Pharmacodyn. 2002; 28(5):481-504. DOI: 10.1023/a:1012299115260. View

Stroshane R, KOSS R, Biddlecome C, Luczkowec C, Edelson J . Oral and intravenous pharmacokinetics of milrinone in human volunteers. J Pharm Sci. 1984; 73(10):1438-41. DOI: 10.1002/jps.2600731029. View

Evans R, Lankadeva Y, Cochrane A, Marino B, Iguchi N, Zhu M . Renal haemodynamics and oxygenation during and after cardiac surgery and cardiopulmonary bypass. Acta Physiol (Oxf). 2017; 222(3). DOI: 10.1111/apha.12995. View

Grose R, Strain J, Greenberg M, Lejemtel T . Systemic and coronary effects of intravenous milrinone and dobutamine in congestive heart failure. J Am Coll Cardiol. 1986; 7(5):1107-13. DOI: 10.1016/s0735-1097(86)80231-5. View

Gist K, Korst A, Nakano S, Stauffer B, Karimpour-Fard A, Zhou W . Circulating cyclic adenosine monophosphate concentrations in milrinone treated paediatric patients after congenital heart surgery. Cardiol Young. 2021; 31(9):1393-1400. PMC: 9257900. DOI: 10.1017/S1047951121000251. View

10.

Giaccone A, Zuppa A, Sood B, Cohen M, OByrne M, Moorthy G . Milrinone Pharmacokinetics and Pharmacodynamics in Neonates with Persistent Pulmonary Hypertension of the Newborn. Am J Perinatol. 2017; 34(8):749-758. PMC: 6342009. DOI: 10.1055/s-0036-1597996. View

11.

Mizuno T, Gist K, Gao Z, Wempe M, Alten J, Cooper D . Developmental Pharmacokinetics and Age-Appropriate Dosing Design of Milrinone in Neonates and Infants with Acute Kidney Injury Following Cardiac Surgery. Clin Pharmacokinet. 2019; 58(6):793-803. DOI: 10.1007/s40262-018-0729-3. View

12.

Pierce C, Munoz A, Ng D, Warady B, Furth S, Schwartz G . Age- and sex-dependent clinical equations to estimate glomerular filtration rates in children and young adults with chronic kidney disease. Kidney Int. 2020; 99(4):948-956. PMC: 9083470. DOI: 10.1016/j.kint.2020.10.047. View

13.

Gist K, Goldstein S, Joy M, Vinks A . Milrinone Dosing Issues in Critically Ill Children With Kidney Injury: A Review. J Cardiovasc Pharmacol. 2015; 67(2):175-81. DOI: 10.1097/FJC.0000000000000327. View

14.

Algarni K, Maganti M, Yau T . Predictors of low cardiac output syndrome after isolated coronary artery bypass surgery: trends over 20 years. Ann Thorac Surg. 2011; 92(5):1678-84. DOI: 10.1016/j.athoracsur.2011.06.017. View

15.

Anderson B, van Lingen R, Hansen T, Lin Y, Holford N . Acetaminophen developmental pharmacokinetics in premature neonates and infants: a pooled population analysis. Anesthesiology. 2002; 96(6):1336-45. DOI: 10.1097/00000542-200206000-00012. View

16.

Holford N, Anderson B . Allometric size: The scientific theory and extension to normal fat mass. Eur J Pharm Sci. 2017; 109S:S59-S64. DOI: 10.1016/j.ejps.2017.05.056. View

17.

Anderson B, Holford N . Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol. 2007; 48:303-32. DOI: 10.1146/annurev.pharmtox.48.113006.094708. View

18.

Bergstrand M, Karlsson M . Handling data below the limit of quantification in mixed effect models. AAPS J. 2009; 11(2):371-80. PMC: 2691472. DOI: 10.1208/s12248-009-9112-5. View

19.

Paradisis M, Jiang X, McLachlan A, Evans N, Kluckow M, Osborn D . Population pharmacokinetics and dosing regimen design of milrinone in preterm infants. Arch Dis Child Fetal Neonatal Ed. 2006; 92(3):F204-9. PMC: 2675339. DOI: 10.1136/adc.2005.092817. View

20.

Parke J, Holford N, Charles B . A procedure for generating bootstrap samples for the validation of nonlinear mixed-effects population models. Comput Methods Programs Biomed. 1999; 59(1):19-29. DOI: 10.1016/s0169-2607(98)00098-4. View