title: Population pharmacokinetics of doxapram in low-birth-weight Japanese infants with apnea.
abstract: This study aimed to determine the population pharmacokinetics of doxapram in low-birth-weight (LBW) infants. A total of 92 serum concentration measurements that were obtained from 34 Japanese neonates were analyzed using nonlinear mixed-effect modeling (NONMEM). Estimates generated by NONMEM indicated that clearance of doxapram (CL; L/kg/h) was affected by postmenstrual age (PMA; weeks), body weight (BW; g), and aspartate aminotransferase (AST; IU/L). In addition, the volume of distribution (Vd; L/kg) was affected by gestational age (GA; weeks). The final pharmacokinetic model was as follows: CL = BW / PMA × 0.0453 × serum AST(-0.373); Vd = 2.54 (if GA >28 weeks) and Vd = 2.54 × 2.11 (if GA ≤28 weeks). The interindividual variabilities in CL and Vd were 39.9 and 83.0 %, respectively, and the residual variability was 20.9 %. To clarify the reasons for large interindividual variations, the enzymes involved in the metabolic pathway of doxapram were also determined. We found that doxapram was metabolized by CYP3A4/5.
  
  
  CONCLUSIONS
  We report the population pharmacokinetics of doxapram in neonates and the involvement of CYP3A4/5 in its metabolism. The final model of population pharmacokinetics may be useful for formulating a safe and effective dosage regimen and for predicting serum doxapram concentrations in neonates.
authors.affiliation: Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto, 862-0973, Japan, 099p1011@st.kumamoto-u.ac.jp.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ogawa
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Irikura
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kobaru
authors.forename: Mayu
authors.initials: M
authors.lastname: Tomiyasu
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Kochiyama
authors.forename: Mamiko
authors.initials: M
authors.lastname: Uriu
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Ishitsuka
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kondo
authors.forename: Eiji
authors.initials: E
authors.lastname: Yukawa
authors.forename: Noboru
authors.initials: N
authors.lastname: Kamada
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ohno
authors.forename: Toshio
authors.initials: T
authors.lastname: Yamazaki
authors.forename: Tetsumi
authors.initials: T
authors.lastname: Irie
mesh_terms: D001049:Apnea / Q000188:drug therapy / Q000378:metabolism*; D044466:Asian People; D000697:Central Nervous System Stimulants / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System; D004311:Double-Blind Method; D004315:Doxapram / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007230:Infant, Low Birth Weight; D007231:Infant, Newborn; D007234:Infant, Premature; D007564:Japan; D008297:Male; D013058:Mass Spectrometry; D008954:Models, Biological
chemical_list: D000697:Central Nervous System Stimulants; D003577:Cytochrome P-450 Enzyme System; D004315:Doxapram