Clinical pharmacology of ibuprofen in preterm infants: A meta-analysis of published data

Pacifici, Gian Maria

doi:10.5935/MedicalExpress.2014.02.02

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REVIEWS • MedicalExpress (São Paulo, online) 1 (2) • Apr 2014 • https://doi.org/10.5935/MedicalExpress.2014.02.02 copy

Clinical pharmacology of ibuprofen in preterm infants: A meta-analysis of published data

Authorship SCIMAGO INSTITUTIONS RANKINGS

OBJECTIVES:

Ibuprofen is a non-selective anti-inflammatory cyclooxygenase inhibitor drug of the propionic acid class of non-steroidal agents, available without prescription in the USA. In preterm infants, ibuprofen is used to close the Patent Ductus Arteriosus and it was found to be more effective than indomethacin. This metaanalysis determined whether differences exist in the closure rate of Patent Ductus Arteriosus following the oral vs. intravenous ibuprofen administration to preterm infants; it examines metabolism, pharmacokinetics and adverse renal effects of ibuprofen.

METHOD:

The bibliographic search was performed using PubMed and EMBASE databases as search engines. In addition, the books "Neofax: a Manual of Drugs Used in the Neonatal Care" by Young and Mangum and the "Neonatal Formulary" were consulted.

RESULTS:

Patent Ductus Arteriosus closure was 89% with oral ibuprofen (9 reports) vs. 75% with intravenous ibuprofen (13 reports); p = 0.011. The half-life (t_1/2) of ibuprofen is 43.1 and 26.8 hours in infants on the 3^rd and 5^th day of life, respectively. In adults, the half-life of ibuprofen is 2 hours. The rapid shortening of ibuprofen t_1/2 is due to the rapid increase of cytochromes CYP2C9 and CYP2C8 activities, which metabolize ibuprofen and which surge in the liver during the first weeks of life. Ibuprofen reduces the renal glomerular filtration and the sodium tubular transport rates.

CONCLUSION:

Oral ibuprofen is more effective than intravenous ibuprofen to close patent ductus arteriosus. Ibuprofen has fewer renal adverse effects than intravenous ibuprofen and has the most favourable risk/benefit ratio.

KEYWORDS:
adverse-effects; ibuprofen; metabolism; neonate; pharmacokinetics

GA (Weeks)	BW (g)	Number of cases	Dose of ibuprofen (mg)	Route of administration	%PDA closed	Reference
22.4-31.0	565-1460	34	10-5-5	Intravenous	100	⁷7 Varvarigou A, Bardin CL, Beharry K, Chemtob S, Papageorgiou A, Aranda JV. Early ibuprofen administration to prevent patent ductus arteriosus in premature newborn infants. JAMA. 1996;275(7):539-44.
28.1±1.1	934±288	23	10-5-5	Intravenous	87.0	⁴³43 De Carolis MP, Romagnoli C, Polimeni V, Piersigilli F, Zecca E, Papacci P, et al. Prophylactic ibuprofen therapy of patent ductus arteriosus in preterm infants. Eur J Pediatr. 2000;159(5):364-8.
28.1±1.7	1048±315	205	10-5-5	Intravenous	84.0	³⁴34 Van Overmeire B, Allegaert K, Casaer A, Debauche C, Decaluwé W, Jespers A. et al. Prophylactic ibuprofen in premature infants: a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2004;364(9449):1945-9.
25.6±1.4	757±127	160	10-10	Intravenous	85.0	⁶⁴64 Richards J, Johnson A, Fox G, Campbell M. A second course of ibuprofen is effective in the closure of a clinically significant PDA in ELBW infants. Pediatrics. 2009;124(2):e287-93.
27.0±2.9	853±383	22	10-5-5	Intravenous	72.7	⁴²42 Zanardo V, Vedovato S, Lago P, Trevisanuto D, Favaro F, Faggian D, et al. Urinary ET-1, AVP and sodium in premature infants treated with indomethacin and ibuprofen for patent ductus arteriosus. Pediatr Nephrol. 2005;20(11):1552-6.
26^a a mean, SD is not available; na = not available;	857^a a mean, SD is not available; na = not available;	22	10-5-5	Intravenous	72.7	⁶⁵65 Zanardo V, Vedovato S, Lago P, Piva D, Faggian D, Chiozza L. Effects of ibuprofen and indomethacin on urinary antidiuretic hormone excretion in preterm infants treated for patent ductus arteriosus. Fetal Diagn Ther. 2005;20(6):534-9.
26.6^a a mean, SD is not available; na = not available;	994^a a mean, SD is not available; na = not available;	30	10-5-5	Intravenous	94.0	⁶⁶66 Vanhaesebrouck S, Zonnenberg I, Vandervoort P, Bruneel E, Van Hoestenberghe MR, Theyskens C. Conservative treatment for patent ductus arteriosus in the preterm. Arch Dis Child Fetal Neonatal Ed. 2007;92(4):F244-7.
26±1.7	835±215	35	10-5-5	Intravenous	63.0^* * first course of ibuprofen. Barzilay et al. (55) administered only 10 mg/kg ibuprofen.	⁶⁷67 Dani C, Vangi V, Bertini G, Pratesi S, Lori I, Favelli F, et al. High-dose ibuprofen for patent ductus arteriosus in extremely preterm infants: a randomized controlled study. Clin Pharmacol Ther. 2012;91(4):590-6.
26.0±1.7	838±215 20	20	10-5-5	Intravenous	77.0	⁶⁸68 Desfrere L, Zohar S, Morville P, Brunhes A, Chevret S, Pons G. et al. Dose-finding study of ibuprofen in patent ductus arteriosus using the continual reassessment method. J Clin Pharm Ther. 2005;30(2):121-32.
27.7±3.2	1086±572	23	10-5-5	Intravenous	52.6	⁶⁹69 Meißner U, Chakrabarty R, Topf HG, Rascher W, Schroth M. Improved closure of patent ductus arteriosus with high doses of ibuprofen. Pediatr Cardiol. 2012;33(4):586-90.
28.3±1.1	1197±158	32	10-5-5	Intravenous	62.5	⁴¹41 Cherif A, Jabnoun S, Khrouf N. Oral ibuprofen in early curative closure of patent ductus arteriosus in very premature infants. Am J Perinatol. 2007;24(6):339-45.
28.7±2.1	na	50	10-5-5	Intravenous	62.0	¹⁹19 Gokmen T, Erdeve O, Altug N, Oguz SS, Uras N, Dilmen U. Efficacy and safety of oral versus intravenous ibuprofen in very low birth weight preterm infants with patent ductus arteriosus. J Pediatr. 2011;158(4):549-54.
26.3±1.3	872±123	34	10-5-5	Intravenous	61.7	⁷⁰70 Erdeve O, Yurttutan S, Altug N, Ozdemir R, Gokmen T, Dilmen U, et al. Oral versus intravenous ibuprofen for patent ductus arteriosus closure: a randomised controlled trial in extremely low birthweight infants. Arch Dis Child Fetal Neonatal Ed. 2012;97(4):F279-83.
27.5±1.75	979±266	22	10-5-5	Oral	95.5	⁴⁶46 Heyman E, Morag I, Batash D, Keidar R, Baram S, Berkovitch M. Closure of patent ductus arteriosus with oral ibuprofen suspension in premature newborns: a pilot study. Pediatrics. 2003;112(5):e354-8.
na	na	13	10-5-5	Oral	84.6	⁴⁷47 Hariprasad P, Sundarrajan V, Srimathy G, Suthagar B, Ramadevi BS. Oral ibuprofen for closure of hemodynamically significant PDA in premature neonates. Indian Pediatr. 2002;39(1):99-100.
31.2±2.5	1521±398	12	10-5-5	Oral	83.3	⁴⁸48 Aly H, Lotfy W, Badrawi N, Ghawas M, Abdel-Meguid IE, Hammad TA. Oral Ibuprofen and ductus arteriosus in premature infants: a randomized pilot study. Am J Perinatol. 2007;24(5):267-70.
29.4±1.0	1237±198	40	10-5-5	Oral	95.0	⁴¹41 Cherif A, Jabnoun S, Khrouf N. Oral ibuprofen in early curative closure of patent ductus arteriosus in very premature infants. Am J Perinatol. 2007;24(6):339-45.
27.8±2.4	1052±443	13	10	Oral	100	⁵⁵55 Barzilay B, Youngster I, Batash D, Keidar R, Baram S, Goldman M, et al. Pharmacokinetics of oral ibuprofen for patent ductus arteriosus closure in preterm infants. Arch Dis Child Fetal Neonatal Ed. 2012;97(2):F116-9.
<32 weeks	500-1500	33	10-5-5	Oral	93.9	⁴⁵45 Ghanem S, Mostafa M, Shafee M. Effect of oral ibuprofen on patent ductus arteriosus in premature newborns. J Saudi Heart Ass. 2010;22:7-10.
29.3±1.2	1227±188	32	10-5-5	Oral	84.3	¹⁸18 Cherif A, Khrouf N, Jabnoun S, Mokrani C, Amara MB, Guellouze N, et al. Randomized pilot study comparing oral ibuprofen with intravenous ibuprofen in very low birth weight infants with patent ductus arteriosus. Pediatrics. 2008;122(6):e1256-61.
28.5±1.9	na	52	10-5-5	Oral	84.6	¹⁹19 Gokmen T, Erdeve O, Altug N, Oguz SS, Uras N, Dilmen U. Efficacy and safety of oral versus intravenous ibuprofen in very low birth weight preterm infants with patent ductus arteriosus. J Pediatr. 2011;158(4):549-54.
26.4±1.1	892±117	36	10-5-5	Oral	83.3	⁷⁰70 Erdeve O, Yurttutan S, Altug N, Ozdemir R, Gokmen T, Dilmen U, et al. Oral versus intravenous ibuprofen for patent ductus arteriosus closure: a randomised controlled trial in extremely low birthweight infants. Arch Dis Child Fetal Neonatal Ed. 2012;97(4):F279-83.

GA (weeks)	BW(g)	Dose(mg/kg)	n	Cmax (µg/ml)	t_1/2 (hours)	Cl (ml/h/kg)	Vd (l/kg)	AUC (µg.h/ml)	Reference
26.8±0.59^* * mean±SEM;	945±59.9^* * mean±SEM;	10IV	21	181±11.1^d d = plasma concentration 1 h after intravenous administration of 10 mg/kg ibuprofen to 21 preterm infants within the first 3 hours after birth.	30.5±4.2^* * mean±SEM;	2.06±0.33^* * mean±SEM;	0.062.1±0.004^* * mean±SEM;	7698±1096^ the unity is not stated; na = not available; IV = intravenous administration; PO = oral administration;	³⁰30 Aranda JV, Varvarigou A, Beharry K, Bansal R, Bardin C, Modanlou H, et al. Pharmacokinetics and protein binding of intravenous ibuprofen in the premature newborn infant. Acta Paediatr. 1997;86(3):289-93.
28.6±1.9	1250±460	10,5,5^b b = the dose was 10 mg/kg followed by 5 mg/kg after 24 and 48 hours; IV	13	43.5±11.2	43.1±26.1	9.49±6.82	0.24±0.08	524±156	28
30.4±0.33	1262±55	10PO	20	18.3^c c = mean, SD is not available;	30.7^c c = mean, SD is not available;	na	na	403±80	29
27.8±2.4	1052±443	10PO	33	30.7^c c = mean, SD is not available;	na	na	na	618^c c = mean, SD is not available;	55
na	4400±600^a a = the postnatal age was 1 to 7 weeks;	19.0±1.6^a a = the postnatal age was 1 to 7 weeks; (Rectally)	5	na	4.6±5.1^a a = the postnatal age was 1 to 7 weeks;	na	na	299±69^a a = the postnatal age was 1 to 7 weeks;	23
26.6^c c = mean, SD is not available;	855	10,5,5^b b = the dose was 10 mg/kg followed by 5 mg/kg after 24 and 48 hours; IV	62	na	25.5^c c = mean, SD is not available;	na	0.18^c c = mean, SD is not available; (l)	Na	32
25 to 34	na	10,5,5^b b = the dose was 10 mg/kg followed by 5 mg/kg after 24 and 48 hours; IV		38.4^c c = mean, SD is not available;	42.2	9.13^c c = mean, SD is not available;	0.36^c c = mean, SD is not available; (l)	Na	27

	Oral ibuprofen^* * Ibuprofen was administered at the dose of 10 mg/kg, followed by 5 mg/kg after 24 and 48 hours.		Intravenous ibuprofen*
Parameter	Number of infants or valuation	Number of infants	Number of infants or valuation	Number of infants	Statistical significance	Reference
Serum creatinine	5.7±1.2 (mg/dl)	32	10.9±1.2 (mg/dl)	32	p < 0.01	18
Adverse effects^ The authors did not explain how they calculated the %adverse effects.	9.3%	32	31.2%	32	p = 0.02	18
Second course of ibuprofen	612.0%	50	1938.0%	50	p = 0.012	19
Second course of ibuprofen	616.7%	36	1338.2%	34	p = 0.012	20
Bilirubin concentration	5.2±2.7(mg/dl)	36	4.4±1.7(mg/dl)	34	p = 0.03	20
Need for steroid for chronic lung disease	822.2%	36	1750.0%	34	p = 0.01	20

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[1] E-mail: pacifici@biomed.unipi.it