Negligible impact of birth on renal function and drug metabolism.

BACKGROUND: Transition from the intrauterine to the extrauterine environment in neonates is associated with major changes in blood flow and oxygenation with consequent increases in metabolic functions. The additional impact of birth on renal function and drug metabolism above that predicted by postmenstrual age and allometry is uncertain. Increased clearance at birth could reduce analgesic effect attributable to a lowering of plasma concentration. These elimination processes can be described using the clearance concept. METHODS: Data from four publications that investigated the time course of glomerular filtration rate and clearance of paracetamol, morphine and tramadol were reanalyzed. The effect of birth, based on postnatal age, was used in conjunction with a theory-based allometric size scaling and maturation based on postmenstrual age. RESULTS: Postnatal age had a short-term effect on the time course of clearance distinguishable from the well-known slower maturation based on postmenstrual age. While elimination might be relatively reduced by 15%-45% at birth, there is a rapid increase in elimination for 1-3 weeks after birth to be 15% greater than that predicted by postmenstrual age alone. CONCLUSION: Birth is associated with a small increase in clearance in addition to that described by postmenstrual age for common analgesic drugs cleared by glucuronide conjugation (morphine, paracetamol) or by the P450 cytochrome oxidase (tramadol) and renal systems. While the increase is of biological interest, it would not be expected to have any clinically relevant impact on renal function or drug dosing. The processes of maturation described by these models are potentially applicable to any drug elimination process.

Why standards are useful for predicting doses.

Germovsek and colleagues have recently concluded that a standard approach to modelling pharmacokinetics is not wrong and appears to be at least as useful as other ad hoc methods for describing drug concentrations. There are other advantages of this approach including learning about biology, comparing different studies, detecting errors and rationalizing dose prediction. A standard approach to size and maturation is not a panacea but provides the framework for challenging new ideas and supports a consistent method of dosing in patients of all ages.

Dexmedetomidine pharmacokinetics in the obese.

PURPOSE: This study aims to characterize the influence of body weight and composition on the pharmacokinetics of dexmedetomidine. METHODS: Twenty obese patients and 20 non-obese patients scheduled for elective laparoscopic surgery were given dexmedetomidine infusion schemes. Venous blood samples were taken during and after dexmedetomidine administration. Population pharmacokinetic modeling was undertaken to investigate fat free mass (FFM) and normal fat mass (NFM) as size descriptors of volumes and clearances using non-linear mixed effects modeling. NFM partitions total body weight into FFM and fat mass calculated from total body weight (TBW) minus FFM. The relative influence of fat mass compared to FFM is described by the fraction of fat mass that makes fat equivalent to FFM (Ffat). RESULTS: Theory-based allometric scaling using FFM best described weight and body composition differences in clearances and volumes A negative effect of fat mass of with an exponential parameter of -0.00541/kg (95 % CI -0.0118 to -0.00246) was estimated for clearance which indicates increased fat mass is associated with impairment of clearance. CONCLUSIONS: The use of theory-based allometry with predictions of fat free mass has been able to separate the influences of weight and body composition and indicates that size-normalized clearance of dexmedetomidine is impaired in patients who are obese.

Postoperative analgesia using diclofenac and acetaminophen in children.

BACKGROUND: Diclofenac dosing in children for analgesia is currently extrapolated from adult data. Oral diclofenac 1.0 mg·kg(-1) is recommended for children aged 1-12 years. Analgesic effect from combination diclofenac/acetaminophen is unknown. METHODS: Children (n = 151) undergoing tonsillectomy (c. 1995) were randomized to receive acetaminophen elixir 40 mg·kg(-1) before surgery and 20 mg·kg(-1) rectally at the end of surgery with diclofenac suspension 0.1 mg·kg(-1) , 0.5 mg·kg(-1) , or 2.0 mg·kg(-1) before surgery or placebo. A further 93 children were randomized to receive diclofenac 0.1 mg·kg(-1) , 0.5 mg·kg(-1) , or 2.0 mg·kg(-1) only. Postoperative pain was assessed (visual analogue score, VAS 0-10) at half-hourly intervals from waking until discharge. Data were pooled with those from a further 222 children and 30 adults. One-compartment models with first-order absorption and elimination described the pharmacokinetics of both medicines. Combined drug effects were described using a modified EMAX model with an interaction term. An interval-censored model described the hazard of study dropout. RESULTS: Analgesia onset had an equilibration half-time of 0.496 h for acetaminophen and 0.23 h for diclofenac. The maximum effect (EMAX ) was 4.9. The concentration resulting in 50% of EMAX (C50 ) was 1.23 mg·l(-1) for diclofenac and 13.3 mg·l(-1) for acetaminophen. A peak placebo effect of 6.8 occurred at 4 h. Drug effects were additive. The hazard of dropping out was related to pain (hazard ratio of 1.35 per unit change in pain). Diclofenac 1.0 mg·kg(-1) with acetaminophen 15 mg·kg(-1) achieves equivalent analgesia to acetaminophen 30 mg·kg(-1) . CONCLUSIONS: Combination therapy can be used to achieve similar analgesia with lower doses of both drugs.

Understanding dosing: children are small adults, neonates are immature children.

Paediatric dose cannot be scaled down directly from an adult using weight (eg, mg/kg). This results in a dose too small in infants and children because elimination does not change in direct proportion to weight, and a dose too large in neonates whose drug elimination pathways are immature. The goal of treatment is a desired response (the target effect). An understanding of the concentration-response relationship (pharmacodynamics) can be used to predict the target concentration required to achieve this target effect. Pharmacokinetic knowledge then determines the target dose that will achieve the target concentration. Variability associated with both pharmacokinetics and pharmacodynamics can be reduced by demographic information (covariates), which can be used to help predict the target dose in a specific child. The covariates of size, maturation and organ function are the three principle contributors to pharmacokinetic variability. Children (2 years postnatal age or older) are essentially similar to adults (ie, mature) and differ only in size. Maturation processes are only important in neonates and infants, therefore, this cohort can be viewed as immature children. Paediatric pharmacodynamic studies are fewer than pharmacokinetic studies, but are required to elucidate the target concentration and consequent dose. The lack of pharmacodynamic studies is a serious challenge for rational dosing.

Prediction of morphine dose in humans.

BACKGROUND: Morphine is widely used throughout the human life span. Several pharmacokinetic models have been proposed to predict how morphine clearance changes with weight and age. This study uses a large external data set to evaluate the ability of pharmacokinetic models to predict morphine doses. METHODS: A data set of morphine clearance estimates was created from published reports in premature neonates, full-term neonates, infants, children, and adults. This external data set was used to evaluate published models for morphine clearance as well as other models proposed for use in neonates and infants. Morphine clearance predictions were used to predict morphine dose rates to achieve similar target concentrations in all age groups. RESULTS: An allometric ¾ power model using weight combined with a sigmoid maturation model using postmenstrual age successfully predicted the morphine dose rate (within 25% of target) in all age groups except infants [predicted dose 30% under target (95% CI, 7-46%)]. Other published models based on empirical allometric scaling all made unacceptable predictions (>100% of target) in at least one age group. CONCLUSIONS: Clearance based on empirical allometric scaling predicted unacceptable doses. Theory-based allometric scaling combined with a maturation function has been confirmed by external evaluation to provide a sound basis for describing clearance and predicting morphine doses in humans of all ages.

Interpreting the results of Parkinson's disease clinical trials: time for a change.

Randomized clinical trials testing putative disease-modifying agents in Parkinson's disease (PD) have yielded controversial results that have not influenced evidence-based recommendations for the treatment of PD. We argue that the failure of these clinical trials may be linked to end point-based statistical analyses that must make prior assumptions about the magnitude and the time course of wash-in and wash-out of drug effects. Many of these shortcomings may be avoided with quantitative modeling of the entire time course of the clinical trial and examining evidence for three concomitant processes, disease progression, symptomatic drug effects and disease modifying effects. The power of this approach is illustrated by modeling of DATATOP and ELLDOPA trial data.

Tips and traps analyzing pediatric PK data.

Pharmacokinetic (PK) and pharmacodynamic (PD) modeling has elucidated aspects of developmental pharmacology of value to the anesthetic community. The increasing sophistication of modeling techniques is associated with pitfalls that may not be readily apparent to readers or investigators. While size and age are considered primary covariates for PK models, the impact of birth on clearance maturation is poorly documented, dose in obese children is poorly investigated, pharmacologic implications of physiologic changes poorly portrayed, disease progression on drug response poorly depicted and the impact of metabolites on effect poorly illustrated. This review identifies some of these pitfalls and suggests ideas to circumvent or investigate these hazards.

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.

Dexmedetomidine hemodynamics in children after cardiac surgery.

BACKGROUND: Dexmedetomidine has opposing effects on the cardiovascular system. Action in the central nervous system produces sympatholysis and a reduction in blood pressure, while peripherally it causes vasoconstriction leading to an increase in blood pressure. The purpose of our study is to define the concentration-response profile for these hemodynamic effects in children after cardiac surgery. METHODS: A simultaneous pharmacokinetic-pharmacodynamic analysis of data from 29 children given a single bolus of dexmedetomidine 1-4 mcg.kg(-1) following cardiac surgery was undertaken using mixed effects modeling. There were four dexmedetomidine concentrations available from each patient, and mean arterial blood pressure (MAP) was recorded electronically every 5 min for 5 h after drug administration. A composite Emax model was used to relate mean arterial pressure changes to plasma dexmedetomidine concentration. RESULTS: Children had a mean age of 2.67 years (range 4 days-14 years) and a mean weight of 12.34 (range 3.4-48.4) kg. The peripheral vasopressor effect was directly related to plasma concentration with an Emax(pos) of 50.3 (CV 44.50%) mmHg, EC(50pos) 1.1 (48.27%) microg.l(-1) and a Hill(pos) coefficient of 1.65. The delayed central sympatholytic response was described with an Emax(neg) of -12.30 (CV 37.01%) mmHg, EC(50neg) 0.10 (104.40%) microg.l(-1) and a Hill(neg) coefficient of 2.35. The equilibration half-time (T(1/2)keo) was 9.66 (165.23%) min. CONCLUSIONS: Dexmedetomidine administered as a single bolus dose following cardiac surgery produces a biphasic effect on MAP. A plasma dexmedetomidine concentration of above 1.0 microg.l(-1) was associated with a 20% increase in MAP in this specific cohort. A dosage regimen involving a small bolus dose (0.5 microg.kg(-1)) followed by a continuous infusion should be used to avoid initial increases in MAP.

Mechanistic basis of using body size and maturation to predict clearance in humans.

Growth and development are two major aspects of children not readily apparent in adults. Clearance in the paediatric population should be investigated using models that describe size, maturation and organ function influences. Size is the primary covariate and although lean body weight is argued as a better measure than total body weight, the use of different fractions of fat mass to explain how pharmacokinetic parameters vary with body composition has been proposed. Allometric scaling using an empiric power exponent of 3/4 is superior to scaling using body surface area. The sigmoid hyperbolic model has proven useful to describe maturation. An extra parameter that describes asymmetry can be incorporated into this model. These descriptors are used to illustrate creatinine, morphine and paracetamol clearance in children. Simultaneous investigation of pooled GFR, paracetamol and morphine data enabled testing for shared common features of maturation processes. Results suggest that GFR matures before paracetamol or morphine clearance, consistent with phase II conjugation processes that convert xenobiotics to water soluble forms that can subsequently be eliminated from the body through the renal system. The use of such mechanistic approaches improves understanding of paediatric pharmacokinetics; improving dosing predictions and allowing projection in exploratory drug development.

Human renal function maturation: a quantitative description using weight and postmenstrual age.

This study pools published data to describe the increase in glomerular filtration rate (GFR) from very premature neonates to young adults. The data comprises measured GFR (using polyfructose, (51)Cr-EDTA, mannitol or iohexol) from eight studies (n = 923) and involved very premature neonates (22 weeks postmenstrual age) to adulthood (31 years). A nonlinear mixed effects approach (NONMEM) was used to examine the influences of size and maturation on renal function. Size was the primary covariate, and GFR was standardized for a body weight of 70 kg using an allometric power model. Postmenstrual age (PMA) was a better descriptor of maturational changes than postnatal age (PNA). A sigmoid hyperbolic model described the nonlinear relationship between GFR maturation and PMA. Assuming an allometric coefficient of 3/4, the fully mature (adult) GFR is predicted to be 121.2 mL/min per 70 kg [95% confidence interval (CI) 117-125]. Half of the adult value is reached at 47.7 post-menstrual weeks (95%CI 45.1-50.5), with a Hill coefficient of 3.40 (95%CI 3.03-3.80). At 1-year postnatal age, the GFR is predicted to be 90% of the adult GFR. Glomerular filtration rate can be predicted with a consistent relationship from early prematurity to adulthood. We propose that this offers a clinically useful definition of renal function in children and young adults that is independent of the predictable changes associated with age and size.