Population pharmacokinetics of doxapram in low-birth-weight Japanese infants with apnea.

Abstract

UNLABELLED:

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.

CONCLUSION:

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: Yuki Ogawa, Mitsuru Irikura, Yuka Kobaru, Mayu Tomiyasu, Yoshie Kochiyama, Mamiko Uriu, Yoichi Ishitsuka, Yuki Kondo, Eiji Yukawa, Noboru Kamada, Hitoshi Ohno, Toshio Yamazaki, Tetsumi Irie
• Journal: European journal of pediatrics (Eur J Pediatr) Vol. 174 Issue 4 Pg. 509-18 (Apr 2015) ISSN: 1432-1076 [Electronic] Germany
• PMID: 25248340 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Central Nervous System Stimulants
• Cytochrome P-450 Enzyme System
• Doxapram

Topics

• Apnea (drug therapy, metabolism)
• Asian People
• Central Nervous System Stimulants (pharmacokinetics)
• Chromatography, High Pressure Liquid
• Cytochrome P-450 Enzyme System
• Double-Blind Method
• Doxapram (pharmacokinetics)
• Female
• Humans
• Infant, Low Birth Weight
• Infant, Newborn
• Infant, Premature
• Japan
• Male
• Mass Spectrometry
• Models, Biological