Pharmacokinetics of rectal paracetamol after repeated dosing in children

T. W. Hahn1,*, S. W. Henneberg2, R. J. Holm-Knudsen2, K. Eriksen2, S. N. Rasmussen3 and M. Rasmussen1

1Department of Pharmaceutics and 3Department of Pharmacology, The Royal Danish School of Pharmacy, Universitetsparken 2, DK-2100 Copenhagen, Denmark. 2Department of Anaesthesiology, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark

Accepted for publication:March 8, 2000


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Twenty-three children(aged between 9 weeks and 11 yr) were given paracetamol suppositories 25 mgkg–1 every 6 h (maximum 5 days) after major surgery andserum and saliva concentrations were measured. There was a good correlation(r=0.91, P<0.05) between saliva andserum concentrations. A one-compartment linear model withfirst-order elimination and absorption and lag-time was fitted tothe data (ADAPT II). At steady state, the mean (SD)concentration was 15.2 (6.8) mg litre–1. Mean (SD) time to reach 90% of the steady state concentrationwas 11.4 (8.6) h. Body weight, age and body surface area were wellcorrelated (P<0.05) with clearance and apparent volume ofdistribution. There was no evidence of accumulation leading tosupratherapeutic concentrations during this dosing schedule for a mean ofapproximately 2–3 days.

Br J Anaesth 2000; 85: 512–9

Keywords:analgesics non-opioid, paracetamol; children; pharmacokinetics,paracetamol


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Paracetamol has gained wideacceptance as a simple and safe antipyretic and analgesic in children. Whenoral administration is impractical, paracetamol is frequently givenrectally. The administration of paracetamol to children is most commonlybased on body weight.1 Based on acomputer simulation, it has been suggested that a rectal loading dose of 50mg kg–1 followed by 30 mg kg–1 every 6 hshould be the preferred regimen in children.2 Several single dose studies have been carriedout to investigate the pharmacokinetics of rectal paracetamol inchildren.3–13 However, there is very limited clinicalknowledge about the pharmacokinetics after repeated therapeutic doses inchildren,14 partly as a result of bloodsampling limitations and ethical considerations.

Paracetamol has beenfound to pass readily from blood to saliva via the salivary glandsresulting in similar concentrations in adult volunteers15 and patients.16

The purpose of this study was to confirmthe correlation between serum and saliva concentrations and to investigatethe pharmacokinetics of paracetamol after repeated rectal administration of25 mg kg–1 every 6 h for 5 days inchildren.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Patientsand protocol
Twenty-three children (ASA physical statusI–II, aged between 9 weeks and 11 yr), scheduled for surgery with ananticipated need for analgesia for several days postoperatively werestudied. The study protocol was approved by the regional Ethics Committeeand the Danish Medicines Agency. Verbal and written information was given,and written informed consent was obtained from the parents. The childrenprovided verbal assent to participate when possible and were excluded ifthey had received paracetamol 24 h prior to the time of surgery, had ahistory of liver disease, or paracetamol intolerance.

Anaesthesia wasinduced intravenously or with an inhalational agent and nitrousoxide/oxygen. Post- operatively, some children were given epiduralbupivacaine/fentanyl and others had i.v. morphine either as patientcontrolled analgesia (PCA) or on a ‘as required’ basis. Afterinduction of anaesthesia, the first dose of paracetamol 25 mgkg–1 was given. One or two of the five availablesuppository doses (50, 125, 250, 500, 1000 mg) were used to administer adose as close as possible to 25 mg kg–1 for each child.Subsequent doses of paracetamol 25 mg kg–1 were given atapproximately 6 hourly intervals for up to 5 dayspostoperatively.

Saliva and blood samples were obtained immediatelybefore insertion of suppositories and at 1, 2, 3 and 4 h after theadministration of the first dose. On the following days, blood and/orsaliva samples were taken before administration of the morning dose and at1, 2, 3 and 4 h after these morning doses. Paracetamol was administered forup to 5 days. Blood samples were drawn from a central venous catheter or aperipheral vein. Saliva samples were obtained using the Salivette citrusdevice (Sarstedt Laboratories, Nümbrecht, Germany) developedespecially for saliva sampling. The Salivette citrus consists of a cottonwool swab (containing 25 mg citric acid to stimulate saliva production),which is placed in the oral cavity for 2–3 min.17 A string was attached to the swab to avoidaccidental swallowing. Binding of paracetamol to the swab was investigatedprior to this study and was found to be a maximum of 2% whencompared with saliva samples collected by spitting. Citric acid did notinterfere with the analysis and stimulation of saliva production and had noinfluence on the concentration of paracetamol in saliva.18 The exact dose and time of administration wasnoted along with the time of collection of blood and salivasamples.

Analysis ofsamples
Saliva samples were kept refrigerated at 4°C for amaximum 1 h until the saliva was centrifuged out of the swab. Blood sampleswere allowed to clot for 1 h before serum was separated by centrifugation.Immediately after centrifugation, saliva and serum samples were frozen at–20°C until assayed. Saliva and serum samples were stable at–20°C for at least 6 months. After thawing, 60 µl of samplewas mixed with 120 µl of a protein precipitating solution (2%ZnSO4.7H2O in 1:1 methanol/water) containing theinternal standard (metacetamol, 6 mg litre–1) andwhirl-mixed for 30 s before centrifugation at 10 000 g for 10 min.

Paracetamol concentration was determined byhigh performance liquid chromatography (HPLC). The HPLC system consisted ofa Merck Hitachi automatic integrated system with a L-7100 pump,L-7400 UV-detector, L-7200 autosampler and a D-7500integrator. A Spherisorb RP-18 (250x4.6 mm, 5 µm) columnand a LiChrospher 100 RP-18 (5 µm) pre-column were used.The chromatographic conditions were as follows: wavelength 248 nm, mobilephase flow 1 ml min–1, the mobile phase consisted ofacetonitrile–0.1 M sodium acetate pH=4 (20:80 v/v).Triethylamine 150 µl was added per litre of mobile phase. Theinjection volume was 20 µl. Standard curves were linear in the range0–40 mg litre–1. The intra day coefficient ofvariation was 6.7% at 0.05 mg litre–1 and0.4% at 40 mg litre–1. The between-daycoefficient of variation was 0.8–2.2% when concentrationsranged from 1–40 mglitre–1.

Statistics andpharmacokinetic modelling
Data are presented as mean values withSD, median and ranges as appropriate. Pearson’scorrelation was used for analysis of saliva–serum correlations and toevaluate the influence of demographic data on pharmacokinetic parameters.Statistical significance was defined as P<0.05.

Pharmacokinetic modelling was performed usingthe computer program ADAPT II, release three (D.Z. D’argenio and A.Schumitzky, University of Southern California, USA, 1992).

Aone-compartment linear model with first-order elimination andabsorption and lag-time was fitted to the data. The goodness of fitwas evaluated by visual inspection of predicted vs observeddata and from plots of residuals.

The absorption rate constant (ka), lag-time (tlag),elimination rate constant (ke), eliminationhalf-life (t1/2), apparent volume ofdistribution (Vd/F, F=absorption fraction), and apparent clearance (CL/F)were estimated by the ADAPT II program for each patient. The maximumconcentration Cmax(1) and the time to reach theCmax(1) Tmax(1) in thefirst dosing interval was calculated by Cmax(1)=[(D·F/Vd)(ka/ke)(ke/(ke–ka))] and Tmax(1)=[(1/(ka–ke))(ln(ka/ke))]respectively [19], where D represents thedose.

The average concentration at steady state (Css) was calculated for each patient by using the vanRossum’s equation20 Css=[(D/{tau})/(CL/F)], where {tau} is the dosinginterval. The median of {tau} for each patient was used for thispurpose.

In each case the time to reach 90% of the steadystate concentration (TCss(90%)) was calculated using the equation [21] TCss(90%)=3.3·t1/2.

Simulation of the recommended dosingschedule was done in Quattro Pro 6.0 using the equation,


where n represents the number of dosesgiven.19


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Twenty-threechildren were included in the study. Two were excluded because ofmishandling of saliva and serum samples. Patient characteristics of theremaining 21 children, individual doses and length of paracetamol treatment(LOT), which was determined as the time from first to last paracetamol doseaccording to the protocol was administered, are shown in Table 1.


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Table 1 Patient and clinical data for all patients. BMI=body mass index22 calculated as [(body weight in kilograms)/(height in metres)2], BSA (in m2)=body surface area23 calculated as [(body weight in kilograms)0.425 (height in centimetres)0.725x71.84x10–4], LOT=length of treatment, determined as the time from first to last administration of paracetamol suppositories. *Patients are not included in calculation of mean (SD), median, or range. **Only one dose was given (see text for details)
 
No paracetamol was detected in the serum or salivasamples taken before administration of the first studydose.

Saliva–serumcorrelation
Thirty-two paired samples (n=64) were available for correlation analysis. Thesamples were obtained from 12 different children aged between 11 weeks and11 yr. The data are depicted in Figure 1A. Regression analysis resulted in a Pearson’s Correlationcoefficient (r) of 0.91 (P<0.001). Theconstant of the regression line was not significantly different from zero(P=0.6) and the data were then fitted to the simplermodel forcing through the origin. The relationship between serum and salivaconcentrations could be described by the following equation (mglitre–1):



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Fig 1 (A) Plot of saliva vs serum concentrations. The line indicates the line of regression: concentrationsaliva=0.92xconcentration serum. (B) Ratio between saliva and serum concentrations. The mean ratio was 0.92 (SD 0.26). The line indicates the line of unity.

 
        concentrationsaliva=0.92xconcentrationserum

Theratio between saliva and serum was calculated to be 0.92±0.26 (Fig.1B).

Pharmacokineticmodelling
Data from 17 children were used in the followingmodelling as four children (8, 11, 12 and 15 in Table 1) were excluded because of insufficientdata.

Individual parameters of ka, tlag, ke, t1/2, Vd/F, CL/F, Css and TCss(90%) are given in Table 2.


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Table 2 Pharmacokinetic data. ka=absorption rate constant; tlag=lag time; ke=elimination rate constant; t1/2=elimination half-life; Vd/F=apparent volume of distribution; Cmax(1)=maximum concentration in the first dosing interval; Tmax(1)=time to reach Cmax(1); CL/F= apparent clearance, F=absorption fraction; {tau}=dosing interval; Css=average concentration in steady state; TCss (90%)=time to reach 90% of Css. *Patient is not included in the calculation of mean, SD, median, or range (see text for details)
 
In Figure 2A aserum concentration–time profile for a typical patient is shown. Onepatient (14) among the 17 patients subjected to pharmacokinetic modellingwas excluded from average estimates in Table 2because this patient exhibited very different parameter values and did notreach steady state within the 75 h of sampling. The serumconcentration–time profile for this patient is shown in Figure2B.



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Fig 2 Observed vs predicted serum concentration time-profiles of paracetamol. (A) A typical patient (no. 19). (B) An atypical patient (no. 14).

 
The Pearson’sCorrelation coefficients (r) between the apparent volume ofdistribution (Vd/F) and age,height, body weight, and body surface area (BSA)23 were found to be 0.57, 0.70, 0.67 and 0.69respectively. The Pearson’s Correlation coefficients (r) for the relationship between the apparent clearance(CL/F) and the patient characteristics mentioned above were 0.74, 0.79,0.83 and 0.82. All correlations were statistically significant (P<0.05) and are depicted in Figure 3AD. There was no correlation between bodymass index (BMI)22 and Vd/F or CL/F. Patients 8, 11,12, 14 and 15 were excluded from calculations of Pearson’scorrelation coefficients.



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Fig 3 Volume of distribution (Vd/F) and clearance (CL/F) compared to age, weight, height and BSA. The lines indicate lines of regression. Correlation coefficients (r) between Vd/F and weight, height, and BSA were 0.57, 0.70, 0.67 and 0.69, respectively, and between CL/F and the parameters mentioned above correlation coefficients were 0.74, 0.79, 0.83 and 0.82. All correlations were statistically significant (P<0.05).

 
Concomitant administration of drugs wasregistered for all patients (Table 3). There areno reports on interactions between paracetamol and any of thesedrugs24 and regional anaesthetictechniques are not known to affect paracetamolpharmacokinetics.


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Table 3 Concomitant drug administration during study period. Numbers refer to patient numbers in Tables 1 and 2
 

    Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Salivasampling represents a non-invasive method, which is not associatedwith pain and the risk of infection present in blood sampling. It isespecially advantageous when multiple samples are required. The goodcorrelation between saliva and serum concentrations of paracetamol found inthe children in our study is in agreement with findings in another study ofadult postoperative patients,16 wherethe correlation coefficient (r) after rectal administrationof paracetamol was 0.99 compared with 0.91 in our study. Al-Obaidy andcolleagues25 found a correlationcoefficient (r) of 0.95 after oral dosing in six paediatricpatients. This suggests that saliva samples can replace blood samples inassessment of paracetamol concentrations in children in the postoperativeperiod. Saliva sampling has been observed to result in cost savingscompared to blood sampling and to be more acceptable to parents andchildren.26

After administrationof paracetamol suppositories, the absorption rate was faster than or equalto the rate of elimination in all children, but large variations were seenin the absorption phase and the resulting steady state concentrations. Theabsorption rate constant (ka) observed in ourstudy was 1.4 (2.2) h–1. After administration ofsuppositories to children, Birmingham and colleagues3 reported a typical kaof 0.3 h–1 and Coulthard and colleagues8 found a mean ka of 1.4h–1.

Various explanations have been offered for thisunpredictable absorption pattern from paracetamol suppositories, but nonehave been proven. Premature defaecation would reduce the amount of drugavailable for absorption, but no premature defaecation was observed in ourstudy. Rectal pH and rectal contents may also influence the absorptionpattern of rectally administered drugs [27]. In children, therectal pH varies from 7.8–11.4 (95%-confidenceinterval).28 For paracetamol(pKa=9.5) this may influence bioavailability, since onlyundissociated drug passes biological membranes and the degree ofdissociation for paracetamol will vary from 2 to 99% in this pHrange (% molar dissociation=[100/(1+antilogpKa–pH)]).29

Childrenseem to absorb paracetamol from suppositories faster and to a greaterextent than adults. Using the same type of suppositories in a single doseof 26–36 mg kg–1 in adults after minorgynaecological laparoscopic surgery,16the highest mean (SD) observed concentration was 8.4 (3.5)mg litre–1 compared with the Cmax after the first dose in our study which was 10.7(3.1) mg litre–1 after administration of 21–27 mgkg–1. Giving 23.9 (4.2) mg kg–1 tochildren younger than 160 days, Hansen and colleagues30 observed a Cmax of10.9 mg litre–1. In a study of adults,16 Tmax was not reachedwithin 4 h after administration. In contrast, Tmax in the first dosing interval for the children inour study was 2.4 (1.1) h. Values of Tmax foundby other investigators after single dose administration of paracetamolsuppositories to children are between approximately 1 and 3 h.3 4 8 10 3032 In pre-term neonates, the absorptionseems to be slower, van Lingen and colleagues found Tmax values of 3.9–5.1 h in children28–36 weeks of gestational age.33

The limited space in the rectum ofinfants and small children compared with suppository size may favour a moreefficient contact with the rectal mucosa and, consequently, improvedabsorption. Also, the rectal mucosa and colonic blood flow may be alteredin children, but this has not been proven.

Differences in theconcentration reached in individual patients may also be explained by avariability of venous drainage from the rectum. Paracetamol undergoesvariable hepatic first-pass metabolism.31 34 If adrug is administered in the upper part of rectum it will be subject to thehepatic first pass effect whereas drugs in the lower part of the rectumwill bypass the liver via the inferior vena cava.35 Administration of multiple suppositories, aswas the case for some children in our study, could also contribute to thevariable absorption.36 The degree ofrectal anastotomic channels has been proposed to counteract the rectalvenous drainage pattern.7

Thevolume of distribution (Vd/F)in our study is in agreement with values found in other paediatricstudies.11 32 37 Thelower correlation coefficient (r=0.57) between ageand Vd/F implies thatcalculation of a loading dose should not be based on age but rather onweight, height or BSA, which show higher correlations to the apparentvolume of distribution (r=0.67–0.70).

Only 4% of paracetamolis excreted unchanged in the urine in both neonates, children and adults.The rest is metabolized to paracetamol-sulphate and glucoronide invarying amounts depending on age.3839 Even though neonates, infants andchildren under 12 yr have a limited ability to conjugate phenolic drugsthey are able to compensate for this by a well-developed capabilityfor sulphate conjugation, resulting in overall paracetamol eliminationhalf-lifes after single doses similar to adult values.39 40 In ourstudy t1/2, after repeated dosing, wasbetween 1.1 and 11.5 h with a mean (SD) of 3.5 (2.6) h, andfor one patient (14) the t1/2 was as long as20.8 h, but the predicted steady state concentration for this patient wasin the therapeutic range. The long t1/2 mayreflect a very slow rate of absorption, i.e. a flip-flop model, andnot a reduced clearance, as the steady state concentration for this patientwas comparable with the steady state concentration of the other patients.Repeated doses to children aged between 6 months and 6 yr in a study byNahata and colleagues resulted in a t1/2 of2.2 h.14

The relatively goodcorrelation (r=0.72, P<0.05)between CL/F and age suggests that the ability to eliminate paracetamoldoes increase slightly with age (Fig. 3A). However, body weight (Fig. 3B) and BSA (Fig. 3D) seemto correlate better with elimination capacity (r=0.83and 0.82, P<0.05). In six pharmacokinetic studies ofparacetamol including a total of 270 children between 2 months and 17 yrthe terminal half-life after single doses ranged from 1.7 to 4.7h.4 811 3032 37In pre-term neonates the half-life seems to be prolonged. Forexample, van Lingen33 observed a t1/2 of 4.8–11.0 h in this agegroup.

The average concentration reached at steady state (Css) in our study (15.2 (6.8) mglitre–1) is well above the lower limit for the acceptedantipyretic concentration range, which has been suggested to be 10–20mg litre–1.4143 Only one patient did not approach thisconcentration range at steady state. Although no solid link has been provento exist between serum concentration of paracetamol and degree of analgesiaproduced, the analgesic effect of paracetamol is believed to be related,directly, to its serum concentration44because of its high lipid solubility and low protein binding in thetherapeutic concentration range. After tonsillectomy in children twostudies have reported relationships between paracetamol concentration anddegree of postoperative pain. Anderson and colleagues2 observed that 50% of children experiencedsatisfactory analgesia at a concentration of 17 mglitre–1, and in another study,13 acceptable pain scores were associated with aparacetamol concentration above 10 mg litre–1.

Thesafety of repeated dosing of paracetamol in children has beenquestioned,14 33 45 andcases of toxicity after repeated therapeutic doses46 47 andsupratherapeutic doses48 have beenreported. In our study the highest predicted concentration at steady statewas 36.9 mg litre–1 which is well below the limit oftoxicity49 50 at 120 mg litre–1. However,care should be taken when situations of malnutrition are present, becausedepletion of glutathione stores could make children susceptible whensulphation and glucoronidation pathways are saturated.5153

The maximum daily dose of paracetamol iscontroversial,54 but the current oralpaediatric dosing recommendation for paracetamol is a loading dose of 20 mgkg–1 and a maintenance dose of 15 mg kg–1every 4 h55 with an upper limit of 90 mgkg–1 per day.56Rectally 15–20 mg kg–1 is given every 4 hcommonly,57 but this may produceinadequate concentrations.58 59

To reduce the time to reach steady stateconcentrations, which in our study were not reached until nearly 12 h afteradministration of the first dose, a loading dose should be given.

Weused mean parameter values found in this study (ka=1.4 h–1, tlag=0.5 h, ke=0.3 h–1, Vd/F=1.3 litrekg–1, CL/F=0.3 litrekg–1h–1) to simulate a paracetamol dosingschedule with a loading dose of 35 mg kg–1 and amaintenance dose of 25 mg kg–1 administered assuppositories every 6 h (Fig. 4).



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Fig 4 Simulation of serum concentration time-profile showing a dosing schedule with a loading dose of 35 and 25 mg kg–1 administered as suppositories every 6 h. Parameter values used were ka=1.4 h–1; tlag=0.5 h; ke=0.3 h–1; Vd/F=1.3 litre kg–1; CL/F=0.3 litre kg–1 h–1. Simulation was done using the equation:

where n represents the number of doses given.19

 
Inconclusion, after administration of paracetamol suppositories to childrenblood samples can be replaced by saliva samples in the postoperativeperiod, and a loading dose of 35 mg kg–1 followed by 25 mgkg–1 rectal paracetamol every 6 h for 2–3 days tochildren aged between 9 weeks and 11 yr produces steady stateconcentrations in the anticipated antipyretic and analgesic range with nosign of accumulation or adverse effects. This dosing schedule isrecommended for otherwise healthy infants and children in the postoperativeperiod. A more cautious dosing regimen should probably be followed inchildren who have been fasted for a longer period or with concomitantdiseases.


    Acknowledgements
 
Theauthors wish to thank all the participating children and their parents,Karina Marinheiro and Annette Poulsen, and the medical and the nursingstaff. The study was supported by SmithKline Beecham,Denmark.


    Footnotes
 
* Corresponding author Back


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 Methods
 Results
 Discussion
 References
 
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