1 Neonatal Intensive Care Unit, Department of Paediatrics, University Hospital, Gasthuisberg, Leuven, Belgium. 2 Department of Paediatric Surgery and 3 Department of Paediatrics, Erasmus Medical Centre, Sophia's Children Hospital, Rotterdam, The Netherlands. 4 Department of Anaesthesiology, University of Auckland, Auckland, New Zealand. 5 Center for Clinical Pharmacology, University Hospital, Gasthuisberg, Leuven, Belgium. 6 Division of Pediatric Clinical Pharmacology, Children's National Medical Center, Washington, DC, USA. 7 Departments of Pediatrics, Pharmacology and Physiology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA
* Corresponding author: Neonatal Intensive Care Unit, Department of Paediatrics, University Hospital, Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium. E-mail: karel.allegaert{at}uz.kuleuven.ac.be
Accepted for publication May 9, 2005.
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Abstract |
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Methods. A population pharmacokinetic analysis of tramadol and M1 timeconcentration profiles was undertaken using non-linear mixed-effects models (NONMEM), based on newly collected data on tramadol and M1 timeconcentration profiles in neonates and young infants (n=20) and published studies on intravenous tramadol in children and adults. M1 formation served as a surrogate for CYP2D6 activity.
Results. Tramadol clearance was described using a two-compartment linear model with zero-order input and first-order elimination. Clearance increased from 25 weeks post-conception age (PCA) (5.52 litre h1 [70 kg]1) to reach 84% of the mature value by 44 weeks PCA (standardized to a 70 kg adult using allometric 1/4 power models). The central volume of distribution decreased from 25 weeks PCA (256 litre [70 kg]1) to reach 120% of its mature value by 87 weeks PCA. Formation clearance to M1 contributed 43% of tramadol clearance, but had no relationship with PCA. There was a weak non-linear relationship between PCA and M1 metabolite clearance.
Conclusions. Maturational clearance of tramadol is almost complete by 44 weeks PCA. A target concentration of 300 µg litre1 is achieved after a bolus of tramadol hydrochloride 1 mg kg1 and can be maintained by infusion of tramadol hydrochloride 0.09 mg kg1 h1 at 25 weeks PCA, 0.14 mg kg1 h1 at 30 weeks PCA, 0.17 mg kg1 h1 at 35 weeks PCA, 0.18 mg kg1 h1 at 40 weeks, 0.19 mg kg1 h1 at 50 weeks PCA to 1 yr, 0.18 mg kg1 h1 at 3 yr and 0.12 mg kg1 h1 in adulthood. CYP2D6 activity was observed as early as 25 weeks PCA, but the impact of CYP2D6 polymorphism on the variability in pharmacokinetics, metabolism and pharmacodynamics of tramadol remains to be established.
Keywords: analgesics opioid, tramadol ; drug, tramadol, age factors ; pharmacokinetics, tramadol, maturation, CYP2D6 activity
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Introduction |
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In general, the phenotypic variation in drug metabolism is based on constitutional, genetic and environmental factors.5 6 However, age-related tramadol and O-demethyl tramadol metabolite pharmacokinetics in neonates and young children have not been previously quantified. In addition, it is anticipated that phenotypic variation reflects isoenzyme-specific ontogeny to a greater degree, but observations on phenotypic CYP2D6 activity in the first year are very limited and mainly based on in vitro studies.710
Therefore tramadol disposition was used to assess maturation of in vivo CYP2D6 activity in early neonatal and paediatric life, based on a population-based approach that included size as the primary covariate in an effort to disentangle age-related from size-related factors.
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Methods |
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Tramadol was administered by the intravenous route (loading dose 2 mg kg1 over 30 min, followed by continuous administration of tramadol hydrochloride 5 mg kg1 [24 h]1). Infants with associated renal dysfunction (>1 mg dl1 creatinaemia), hepatic dysfunction (direct bilirubinaemia >2 mg dl1) or peripartal asphyxia (blood lactate >2 mg dl1) were excluded from this pharmacokinetic study. Clinical characteristics and indications to initiate treatment were registered prospectively. The serumtime profiles for one neonate included in the present study were recently described as part of the evaluation of the bloodbrain barrier for tramadol.12
Blood samples (0.2 ml) were taken from an arterial line 0.5, 1, 2, 4, 6, 9, 12, 15, 18 and 24 h after initiation of intravenous administration. The number of samples taken from the smallest infants was lower because the cumulative blood volume collected in a single infant was limited to 1 ml kg1. Blood samples were centrifuged (3 min, 10 000 r.p.m., 4°C) shortly after collection and plasma samples were stored at 20°C until analysis. Plasma concentrations of tramadol and O-demethyl tramadol were determined by high-performance liquid chromatography (HPLC) in low volume plasma samples (see Appendix).13 14
Paediatric pharmacokinetic study
Concentrationtime profiles from the study involving neonates and young infants were combined with data on the pharmacokinetics of intravenous tramadol in nine children with mean weight 13.2 (SD 4.8) kg and age 2.4 (range 1.176.6) yr following single i.v. bolus administration (tramadol hydrochloride 2 mg kg1) as reported by Murthy and colleagues.15
Children received this drug after either elective limb or thoracic surgery. Venous blood samples were collected for up to 20 h after i.v. bolus administration. Samples were centrifuged and stored at 20°C until assay. Serum concentrations of tramadol and its metabolite O-demethyl tramadol (M1) were measured simultaneously by non-stereoselective gas chromatography with nitrogen-selective detection.15
Adult pharmacokinetic study
To assess the maturational aspects of tramadol disposition further, concentrationtime profiles for 20 healthy adults, as reported by Lintz and colleagues16 following single i.v. bolus administration (tramadol hydrochloride 100 mg), were also included. The mean (SD) weight was 70 (10.5) kg and mean age was 40.4 (2357) yr. Venous blood samples were collected up to 24 h after tramadol administration. Samples were centrifuged and stored at 20°C until assay. Serum concentrations of tramadol were determined twice by means of gas chromatography-mass spectrometry.16 17
Population pharmacokinetics
A two-compartment linear model (central compartment V1 and peripheral compartment V2) with zero-order input and first-order elimination fitted the data better than a single-compartment pharmacokinetic model. The model parameters were central volume (V1), peripheral volume (V2), clearance (CL) and intercompartment clearance (Q). Population parameter estimates were obtained using non-linear mixed-effects modelling (NONMEM).18
There were three sources of data for this population analysis and between-study variability was accounted for by giving each study a separate residual error. The quality of fit of the pharmacokinetic models to the data was assessed by visual examination of plots of observed vs predicted concentrations. Models were nested, and an improvement in the objective function was referred to the 2 distribution to assess significance; for example, an objective function change (
OBJ) of 3.84 is significant at
=0.05.
Parameter values were standardized for a body weight of 70 kg using allometric models in order to compare neonatal estimates with those from adults. While body weight is used most commonly in the clinical setting, it is recognized that there is a non-linear relationship between weight and dose. Therefore an allometric 3/4 power model might be a more appropriate scaling to study maturational aspects of drug clearance, based on the observation that the logarithmic plot of basal metabolic rate against weight produces a straight line with a slope of 3/4 in homeotherms, poikilothems and unicellular organisms. This allometric 3/4 power model can be used to scale metabolic processes such as drug clearance.1924
Covariate analysis included a model investigating age-related changes for parent tramadol clearance and volume of distribution using an exponential function.
Population parameter estimations for metabolite (O-demethyl tramadol) pharmacokinetics
Data for studying O-demethyl tramadol (M1) metabolism were available in neonates, infants and children only because no adult metabolite data were collected.1517 M1 tramadol metabolite data were converted to tramadol milligram equivalents using a molecular weight of 249.38 mg mmol1 for M1 and 263.38 mg mmol1 for tramadol (molar ratio 0.947). A two-compartment model (parent drug and metabolite compartments) with zero-order input and first-order elimination was used with NONMEM. Differential equations were used to describe the pharmacokinetics of tramadol and O-demethyl tramadol (see Appendix).
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Results |
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The O-demethyl tramadol (M1) timeconcentration profiles were not determined in the adult population; consequently the pooled paediatric metabolite PK analysis comprised 29 subjects and 545 drug assay samples. Parameter estimates for the two-compartment analysis are shown in Tables 6 and 7. Figure 3 shows the quality of fit for the M1 metabolite data. Figure 4 shows the relationship between PCA and M1 metabolite formation (CL2M1), tramadol clearance by other routes (CL other) and M1 metabolite elimination clearance (CLM1). We were able to demonstrate a non-linear relationship between PCA and CLM1 only, but parameter estimates had high SE values (Table 6), suggesting a poor relationship. There was no relationship between PCA and M1 metabolite formation clearance (CL2M1) or tramadol clearance by other routes (CL other).
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Discussion |
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A two-compartment model produced a better fit than the single-compartment model commonly used for this drug.1 2 Pooled data were from three protocols; sampling techniques and tramadol assay methods varied.12 1517 These differences were monitored by allocating separate residual errors to each study. We were reassured to note that these residual errors were similar in each study. Total clearance was only 23% that of the adult value at 25 weeks PCA but the maturation half-time was 10 weeks and therefore clearance was 84% of the mature value by 44 weeks PCA (Fig. 2B). The estimates of tramadol clearance observed in the present population PK analysis of 24 (CV 43.5%) litre h1 (70 kg)1 (5.7 ml min1 kg1) in adults and 2.7 ml min1 kg1 in children are similar to those reported by others.1 2 1517 25 The central volume of distribution had a longer maturation half-time (34.2 weeks) than the clearance. These findings reflect the slower changes in body composition compared with clearance enzyme maturation that occur with age.
There was no relationship between PCA and M1 metabolite formation (CL2M1) or tramadol clearance by other routes (CL other). There was a relationship between PCA and elimination clearance of M1 (CLM1), but parameter estimates had high SE values and we have less confidence in this relationship, although our CLM1 estimate of 117 litre h1 (70 kg)1 is close to the observations of Campanero and colleagues19 in adults (105 litre h1 [70 kg]1).
The current study included sick neonates and young infants after surgical interventions that included cardiac surgery, and it is possible that surgery may contribute to clearance variability. Morphine clearance in neonates is reduced after cardiac surgery.26
A target tramadol concentration of 300 µg litre1 has been suggested in adult patients given fentanyl 5 µg kg1 intraoperatively or 600 (590) µg litre1 in adults not given supplementary analgesics.1 Based on this suggestion, an age-dependent dose regimen has been developed, although the minimal effective analgesic serum tramadol concentration in adults is uncertain because of differences in tramadol metabolism since the M1 metabolite (CYP2D6 mediated) is a much more potent analgesic. Postulated infusion rates in this current study achieve a mean tramadol concentration only and do not take into account the effect of CYP2D6 polymorphism and activity that has a dramatic influence on the analgesic effect mediated through M1 metabolite production.3 4
The pharmacodynamic impact of CYP2D6 polymorphism is not only limited to adulthood. Abdel-Rahman and colleagues27 recently described the impact of the number of functional CYP2D6 alleles on tramadol metabolism in a paediatric population (n=21, mean 6.8 yr, SD 1.6) of extensive metabolizers. We had anticipated that we could use M1 metabolite formation as a reliable marker of in vivo phenotypic CYP2D6 activity since plasma pharmacokinetics of tramadol have been used as a rapid and simple CYP2D6 genotyping assay in adults.28
We were unsuccessful in describing a maturational relationship between M1 metabolite formation (CYP2D6 activity) and PCA in this cohort of neonates and infants (Fig. 4A), but observed that significant CYP2D6 activity is already present in early neonatal life. It is likely that CYP2D6 polymorphism contributes to the analgesic effect in neonatal life.3 4
In vitro CYP2D6 activity has been evaluated in fetal, neonatal, infant, paediatric and adult liver tissue to study the ontogeny of CYP2D6.710 Treluyer and colleagues7 detected limited CYP2D6 protein and activity in 30% of fetal livers.7 CYP2D6 activity was more frequently documented after spontaneous abortion than after medically induced abortion.7 In the first month of life, CYP2D6 protein and activity increased further, and between 1 month and 5 yr of age protein levels were reported to be approximately two-thirds of adult levels.7 Another study reported no additional significant differences in protein levels of CYP2D6 in infants older and younger than 1 yr, suggesting that CYP2D6 ontogeny is complete by age 1 yr.710 This is consistent with the rapid maturation of total clearance reported here, to which CL2M1 contributed 43%.
Data on in vivo phenotypic CYP2D6 activity are mainly based on the dextromethorphan/dextrorphan (DM/DX) ratio but such data are only reported in adult and paediatric populations and have not yet been reported in neonates. In a large adult population, the DM/DX ratio was 0.01 (SD 0.022) in extensive metabolizers compared with 0.014 (0.021) in heterogeneous genotypes and 3.6 (3.8) in poor metabolizers.29 In a paediatric population (n=21, 6.8 yr, SD 1.6) of extensive metabolizers, the DM/DX ratio was 0.01 (0.011), suggesting CYP2D6 activity at an adult level.29 30
In conclusion, this is the first report on the disposition of tramadol in neonates. By comparing neonatal data with PK data for tramadol in children and adults, we were able to demonstrate rapid maturation of tramadol clearance. These estimates were used to calculate age-dependent dose suggestions. The impact of CYP2D6 polymorphism on the variability in pharmacokinetics and dynamics of tramadol in the first years of life remains to be established, but we were able to document in vivo CYP2D6 activity in early neonatal life.
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Appendix |
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Population pharmacokinetic modelling
Population parameter estimations for parent tramadol
A two-compartment linear model (central compartment V1 and peripheral compartment V2) with zero-order input and first-order elimination was used, parameterized in terms of central volume (V1), peripheral volume (V2), clearance (CL) and intercompartment clearance (Q). Population parameter estimates were obtained using non-linear mixed-effects modelling (NONMEM).18 This model accounts for population parameter variability (between and within subjects) and residual variability (random effects) as well as parameter differences predicted by covariates (fixed effects). The population parameter variability in model parameters was modelled by a proportional variance model. The residual unknown variability was characterized by a proportional term. The population mean parameters between subject variance and residual variance were estimated with the first-order conditional interaction estimate method using ADVAN3 TRANS4 of NONMEM V. The convergence criterion was three significant digits. A Compaq Digital Fortran Version 6.6A compiler with Intel Celeron 333 MHz CPU (Intel Corporation, Santa Clara, CA) under MS Windows XP (Microsoft Corporation, Seattle, WA) was used to compile NONMEM. The population parameter variability is modelled in terms of random effect variables . Each of these variables is assumed to have zero mean and a variance denoted by
2, which is estimated. The covariance between two elements of
(e.g. CL and V) is a measure of statistical association between these two variables. Their covariance is related to their correlation R, i.e.
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Population parameter estimations for metabolite pharmacokinetics
A two-compartment model (parent drug and metabolite compartments) with zero-order input and first-order elimination was used with NONMEM. An additive and a proportional term characterized the residual unknown variability for tramadol and M1 metabolite concentrations. The first-order conditional estimate method with the interaction option and ADVAN 6 with Tol=5 was used for estimation. Differential equations were used to describe the pharmacokinetics of tramadol and O-demethyl tramadol:
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Covariate analysis
The parameter values were standardized for a body weight of 70 kg using an allometric model:20 21
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Covariate analysis included a model investigating age-related changes for parent tramadol clearance and volume of distribution using an exponential function:
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Similar models were used for the metabolite analysis.
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Acknowledgments |
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References |
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