title: Tramadol and o-desmethyl tramadol clearance maturation and disposition in humans: a pooled pharmacokinetic study.
abstract: OBJECTIVE
  We aimed to study the impact of size, maturation and cytochrome P450 2D6 (CYP2D6) genotype activity score as predictors of intravenous tramadol disposition.
  
  
  METHODS
  Tramadol and O-desmethyl tramadol (M1) observations in 295 human subjects (postmenstrual age 25 weeks to 84.8 years, weight 0.5-186 kg) were pooled. A population pharmacokinetic analysis was performed using a two-compartment model for tramadol and two additional M1 compartments. Covariate analysis included weight, age, sex, disease characteristics (healthy subject or patient) and CYP2D6 genotype activity. A sigmoid maturation model was used to describe age-related changes in tramadol clearance (CLPO), M1 formation clearance (CLPM) and M1 elimination clearance (CLMO). A phenotype-based mixture model was used to identify CLPM polymorphism.
  
  
  RESULTS
  Differences in clearances were largely accounted for by maturation and size. The time to reach 50 % of adult clearance (TM50) values was used to describe maturation. CLPM (TM50 39.8 weeks) and CLPO (TM50 39.1 weeks) displayed fast maturation, while CLMO matured slower, similar to glomerular filtration rate (TM50 47 weeks). The phenotype-based mixture model identified a slow and a faster metabolizer group. Slow metabolizers comprised 9.8 % of subjects with 19.4 % of faster metabolizer CLPM. Low CYP2D6 genotype activity was associated with lower (25 %) than faster metabolizer CLPM, but only 32 % of those with low genotype activity were in the slow metabolizer group.
  
  
  CONCLUSIONS
  Maturation and size are key predictors of variability. A two-group polymorphism was identified based on phenotypic M1 formation clearance. Maturation of tramadol elimination occurs early (50 % of adult value at term gestation).
authors.affiliation: Neonatal Intensive Care Unit and Center for Clinical Pharmacology, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium, karel.allegaert@uz.kuleuven.ac.be.
authors.forename: Karel
authors.initials: K
authors.lastname: Allegaert
authors.forename: Nick
authors.initials: N
authors.lastname: Holford
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Anderson
authors.forename: Sam
authors.initials: S
authors.lastname: Holford
authors.forename: Frank
authors.initials: F
authors.lastname: Stuber
authors.forename: Alain
authors.initials: A
authors.lastname: Rochette
authors.forename: Iñaki F
authors.initials: IF
authors.lastname: Trocóniz
authors.forename: Horst
authors.initials: H
authors.lastname: Beier
authors.forename: Jan N
authors.initials: JN
authors.lastname: de Hoon
authors.forename: Rasmus S
authors.initials: RS
authors.lastname: Pedersen
authors.forename: Ulrike
authors.initials: U
authors.lastname: Stamer
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011110:Polymorphism, Genetic; D014147:Tramadol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000701:Analgesics, Opioid; C080580:O-demethyltramadol; D014147:Tramadol; D019389:Cytochrome P-450 CYP2D6