title: Population Pharmacokinetic Model of Sublingual Buprenorphine in Neonatal Abstinence Syndrome.
abstract: OBJECTIVE
  Neonatal abstinence syndrome (NAS)--a clinical entity of infants from in utero exposure to psychoactive xenobiotic and buprenorphine--has been successfully used to treat NAS. However, nothing is known about the pharmacokinetics (PK) of buprenorphine in neonates with NAS. To our knowledge, this is the first study to investigate the population pharmacokinetic of sublingual buprenorphine in neonates with NAS.
  
  
  METHODS
  A retrospective population PK analysis of: (1) neonates with NAS treated with sublingual buprenorphine in randomized, double blinded clinical study and (2) data from healthy adults from a previously published pharmacokinetic study.
  
  
  METHODS
  Neonatal intensive care unit and general clinical research unit.
  
  
  METHODS
  Twenty-four neonates with NAS and five healthy adults.
  
  
  METHODS
  All participants received sublingual buprenorphine per study protocol.
  
  
  RESULTS
  A total of 303 PK data from 29 neonates and adults were used for model development. A population pharmacokinetic analysis was conducted using a first order conditional estimation with interaction in the NONMEM software program. A two-compartment linear PK model with first-order absorption process best described the pharmacokinetics of sublingual buprenorphine in neonates. The apparent clearance (CL) of buprenorphine was linearly related to body weight and matured with increasing age via two distinct saturated pathways. A typical neonate with NAS (body weight, 2.9 kg; postnatal age; 5.4 days) had a CL of 3.5 L/kg/hour and elimination half-life of 11 hours. Phenobarbital did not affect the clearance of buprenorphine compared to neonates of similar age and weight.
  
  
  CONCLUSIONS
  This is the first study to investigate the population PK of sublingual buprenorphine in neonatal NAS. To our knowledge, this is also the first report to describe the age-dependent changes of buprenorphine PK in this patient population. No buprenorphine dose adjustment is needed for neonates with NAS treated with buprenorphine and concurrent phenobarbital.
authors.affiliation: Clinical Pharmacology and Therapeutics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.|Department of Pediatrics, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Chee M
authors.initials: CM
authors.lastname: Ng
authors.affiliation: Clinical Pharmacology and Therapeutics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Erin
authors.initials: E
authors.lastname: Dombrowsky
authors.affiliation: Clinical Pharmacology and Therapeutics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Hopi
authors.initials: H
authors.lastname: Lin
authors.affiliation: Department of Pediatrics and Neurology, Mt. Sinai School of Medicine, New York, New York.
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Erlich
authors.affiliation: Center of Human Toxicology, Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah.
authors.forename: David E
authors.initials: DE
authors.lastname: Moody
authors.affiliation: Clinical Pharmacology and Therapeutics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.|Department of Pediatrics, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Barrett
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Walter K
authors.initials: WK
authors.lastname: Kraft
mesh_terms: D000286:Administration, Sublingual; D000328:Adult; D002047:Buprenorphine / Q000493:pharmacokinetics* / Q000627:therapeutic use; D017321:Clinical Trials, Phase I as Topic; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008954:Models, Biological; D009357:Neonatal Abstinence Syndrome / Q000188:drug therapy*; D016032:Randomized Controlled Trials as Topic; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors*; D017450:Receptors, Opioid, mu / Q000819:agonists*
chemical_list: D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D002047:Buprenorphine
keywords: Neonatal Abstinence Syndrome; buprenorphine; pharmacokinetics