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

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.

Consistent methods for fat-free mass, creatinine clearance, and glomerular filtration rate to describe renal function from neonates to adults.

Quantifying the effect of kidney disease on glomerular filtration rate (GFR) is important when describing variability in the clearance of drugs eliminated by the kidney. We aimed to develop a continuous model for renal function (RF) from prematurity to adulthood based on consistent models for fat-free mass (FFM), creatinine production rate (CPR), and GFR. A model for fractional FFM in premature neonates to adults was developed using pooled data from 4462 subjects and 2847 FFM observations. It was found that girls have an FFM higher than that predicted from adult women based on height, total body mass, and sex, and boys have an FFM lower than adult men until around the onset of puberty, when it approaches adult male values. Data from 108 subjects with measurements of serum creatinine (Scr) and GFR were used to construct a model for CPR. Creatinine clearance was predicted using a model for CPR (based on FFM, postmenstrual age, and sex) and Scr that avoids discontinuous predictions between neonates, children, and adults. Individual CPR may then be used with individual Scr to predict the estimated GFR (eGFR; eGFR = CPR/Scr). A previously published model for human GFR based on 1153 GFR observations in 923 subjects without known kidney disease was updated using the model for fractional FFM to predict individual size and age-consistent values for the expected normal GFR (nGFR). Individual renal function was then calculated using RF = eGFR/nGFR.

Predicting weight using postmenstrual age--neonates to adults.

OBJECTIVES: To describe the pattern and variability of body weight with postmenstrual age (PMA) using nonlinear mixed effect modeling and to create a single mathematical function that can be used from prematurity to adulthood. BACKGROUND: PMA has been shown to predict functional properties of humans such as glomerular filtration rate and drug clearance. Widely used growth charts use postnatal age to predict weight in an idealized population and are not available as a mathematical function. METHODS: We modeled 7164 body weight and PMA observations from a pooled database of 5031 premature neonates, infants, children, and adults. All subjects were participants in pharmacokinetic or renal function studies. PMA ranged from 23 weeks to 82 years. A mixed effect model was used to describe fixed (PMA, sex) and random between-subject variability. RESULTS: A model based on the sum of three sigmoid hyperbolic and one exponential functions described the data. Females were typically 12% lighter in weight. Part of the between-subject variability in weight decreased exponentially with a half-life of 3.5 PMA years, while the remainder stayed a constant fraction of the weight asymptote for each of the four functions. CONCLUSIONS: The change of weight with PMA and sex can be described with a simple equation. This is suitable for simulation of typical weight-age distributions and may be useful for evaluation of appropriate weight for age in children requiring medical treatment.

Pediatric pharmacology in the first year of life.

PURPOSE OF REVIEW: Toxicity concerns and awareness during anesthesia issues continue to concern pediatric anesthesiologists. Most developmental pharmacokinetic, pharmacodynamic and pharmacogenomic changes occur within the first year of life. Understanding these early changes can improve drug use in this cohort. RECENT FINDINGS: Growth and development are two major aspects of children not readily apparent in adults. Clearance in the pediatric population should be investigated using models that describe size, maturation and organ function influences. Glucuronide conjugation (hepatic phase II process) mirrors glomerular filtration maturation over the first year of life. Phase 1 processes appear more rapid, and differences attributable to single nuclear polymorphisms may be obvious by the end of the 4-week neonatal period in term infants.Pharmacodynamic differences in infancy remain poorly defined, and neonatal pharmacokinetic-pharmacodynamic analyses that might elucidate such differences are few, partly because of a paucity of effective pharmacodynamic measures. SUMMARY: Mechanistic models create a framework for the study of pharmacokinetic changes in infancy. Understanding these changes allows a target concentration approach to therapy and potential for reduced toxicity. The target concentration may be undefined because of a paucity of effect measures.