PLASMA PARACETAMOL CONCENTRATIONS AND PHARMACOKINETICS FOLLOWING RECTAL ADMINISTRATION IN NEONATES AND YOUNG INFANTS.

Hansen TG, et al. Acta Anaesthesiol Scand 1999 Sep;43(8):855-9.

BACKGROUND: Despite widespread use in children pharmacokinetic data about paracetamol are relatively scarce, not the least in the youngest age groups. This study aimed to describe plasma paracetamol concentrations and pharmacokinetics of a single rectal paracetamol dose in neonates and young infants.

METHODS: Perioperatively, 17 neonates and infants < or =160 days of age received one rectal paracetamol dose (mean 23.9 mg/kg (+/-4.2 mg/kg)). Blood samples were drawn at 60, 120, 180, 240, 300 and 360 min, according to the infants' weights. Plasma paracetamol concentrations were measured by a Colorometric Assay, Ectachem Clinical Chemistry Slides (Johnson & Johnson Clinical Diagsnostics).

RESULTS: The plasma paracetamol concentrations were mainly below the therapeutic (i.e. antipyretic) range of 66-132 micromol/l and did not exceed 160 micromol/l in any infant. The mean maximum plasma concentration (Cmax) was 72.4 micromol/l (+/-33.5 micromol/l) and the time to Cmax, i.e. the mean Tmax was 102.4 min (_+59.1 min). The mean "apparent" terminal half-life (n=10) was 243.6 min (+/-114.1 min).

CONCLUSION: The absorption of rectal paracetamol (mean dose 23.9 mg/kg, +/-4.2mg/kg) in young infants <160 days is variable and often prolonged and achieves mainly subtherapeutic plasma concentrations.

RELATIVE BIOAVAILABILITY AND PLASMA PARACETAMOL PROFILES OF PANADOL SUPPOSITORIES IN CHILDREN.

Coulthard KP, et al. J Paediatr Child Health 1998 Oct;34(5):425-31

OBJECTIVE: To determine the relative bioavailability and plasma paracetamol concentration profiles following administration of a proprietary formulation of paracetamol suppositories to postoperative children.

METHODOLOGY AND RESULTS: Study A-eight children undergoing minor surgery had blood samples collected following the rectal administration of either a 250 mg or 500 mg paracetamol suppository on one day and an equivalent oral dose on the following day. A mean dose of 13 mg/kg gave a mean Cmax (Tmax) of 7.7 mg/L (1.6 h) and 4.9 mg/L (2.0 h) following oral and rectal administration, respectively. The mean relative rectal bioavailability was 78% (95% confidence interval of 55-101%). Study B-20 children undergoing tonsillectomy and/or adenoidectomy were randomly assigned to receive a postoperative dose of 500 mg of paracetamol either as 2 x 250 mg liquid filled or 1 x 500 mg hard wax Panadol suppository. A mean dose of 25 mg/kg produced mean maximum plasma paracetamol concentrations of 13.2 mg/L and 14.5 mg/L at 2.1 and 1.9 h for the hard and liquid filled suppository, respectively. The absorption rate constants and areas under the curves suggested no difference in the rate or extent of absorption between the two formulations.

CONCLUSION: Absorption of paracetamol following rectal administration of Panadol suppositories to postoperative children is slower and reduced as compared to oral therapy. The hard wax and liquid filled products have similar absorption characteristics. The usually quoted antipyretic therapeutic range for paracetamol is 10-20 mg/L, although 5 mg/L may be effective. A single rectal dose of 25 mg/kg will obtain this lower concentration within 1 h of administration and maintain it for up to 6 h. When given in an appropriate dose for analgesia, maximum plasma paracetamol concentrations would be available in the immediate postoperative period if the rectal dose was given 2 h before the planned end of the procedure.

TWENTY-FOUR-HOUR PHARMACOKINETICS OF RECTAL ACETAMINOPHEN IN CHILDREN: AN OLD DRUG WITH NEW RECOMMENDATIONS.

Birmingham PK, et al. Anesthesiology 1997 Aug;87(2):244-52.

BACKGROUND: Rectal acetaminophen is often administered during operation to provide supplemental analgesia or antipyresis in children. Recent studies examining current dose guidelines are limited by short sampling times. The authors extended the drug sampling period to more clearly define acetaminophen pharmacokinetics in children having surgery.

METHODS: Children (n = 28) were randomized to receive a single dose of 10, 20, or 30 mg/kg rectal acetaminophen after induction of anesthesia. Venous blood samples were taken every 30 min for 4 h, every 60 min for 4 h, and every 4 h for 16 h. Data were analyzed using a mixed-effects modeling technique (using NONMEM software) to determine the volume of distribution and clearance normalized for bioavailability. Additional models accounted for suppository dissolution followed by acetaminophen absorption.

RESULTS: Age, weight, estimated blood loss, volume of intravenous fluid administered, and anesthesia time were similar in the three groups. Most patients did not achieve peak or sustained serum values in the 10-20 microg/ml serum concentration range associated with antipyresis. The volume of distribution was 385 ml/kg, and clearance normalized for bioavailability, F, was 5.46 ml x kg(-1) x min(-1). Pharmacokinetic models suggest that absorption of acetaminophen is a function of zero-order dissolution of suppositories and first-order absorption from the rectum. Suppository dose size also may affect absorption characteristics.

CONCLUSIONS: The current recommended rectal acetaminophen dose of 10-15 mg/kg yields peak serum concentrations less than the antipyretic serum concentration of 10-20 microg/ml. Based on the observed kinetics, the authors recommend that the initial dose should be approximately 40 mg/kg.

PLASMA CONCENTRATIONS AFTER HIGH-DOSE (45 MG.KG-1) RECTAL ACETAMINOPHEN IN CHILDREN.

Montgomery CJ, et al. Can J Anaesth 1995 Nov;42(11):982-6.

BACKGROUND: Although the recommended dose of rectal acetaminophen (25-30 mg.kg-1) is twice that for oral administration (10-15 mg.kg-1), the literature justifies the use of a higher dose when acetaminophen is administered via the rectal route.

SETTING & RESULTS: We measured venous plasma acetaminophen concentrations resulting from 45 mg.kg-1 of rectal acetaminophen in ten ASA 1, 15 kg paediatric patients undergoing minor surgery with a standardized anaesthetic. After induction of anaesthesia, a single 650 mg suppository (Abenol, SmithKline Beecham Pharma Inc.) was administered rectally. Plasma was sampled at t = 0, 15, 30, 45, 60, 90, 120, 180, 240 min in the first five patients and at t = 0, 30, 60, 90, 120, 180, 240, 300, 420 min in the subsequent five. Acetaminophen plasma concentrations were determined using a TDxFLx fluorescence polarization immunoassay (Abbott Laboratories, Toronto, Ontario). The maximum plasma concentration was 88 +/- 39 mumol.L-1 (13 +/- 6 micrograms.ml-1) and the time of peak plasma concentration was 198 +/- 70 min (mean +/- SD). At 420 min, the mean plasma concentration was 46 +/- 18 mumol.L-1 (7.0 +/- 0.9 micrograms.ml-1). No plasma concentrations associated with toxicity (> 800 mumol.L-1) were identified. A 45 mg.kg-1 rectal dose of acetaminophen resulted in peak plasma concentrations comparable with those resulting from 10-15 mg.kg-1 of oral acetaminophen at three hours after suppository insertion.

CONCLUSION: It is concluded that the delayed and erratic absorption of acetaminophen after rectal administration leads to unpredictable plasma concentrations. Rectal acetaminophen will not be consistently effective for providing rapid onset of analgesia in children.

COMMENTS: Rectal acetaminophen doses should be 40-45 mg/kg. This still does not guarantee a therapeutic plasma level, but it’s better than nothing.