Eur J Pediatr DOI 10.1007/s00431-014-2416-1
ORIGINAL ARTICLE
Population pharmacokinetics of doxapram in low-birth-weight Japanese infants with apnea 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
Received: 6 June 2014 / Revised: 27 August 2014 / Accepted: 28 August 2014 # Springer-Verlag Berlin Heidelberg 2014
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.
Communicated by Patrick Van Reempts Electronic supplementary material The online version of this article (doi:10.1007/s00431-014-2416-1) contains supplementary material, which is available to authorized users. Y. Ogawa : Y. Kobaru : M. Tomiyasu : Y. Kochiyama : M. Uriu : Y. Ishitsuka : Y. Kondo : T. Irie Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan Y. Ogawa e-mail: [email protected] Y. Kobaru e-mail: [email protected] M. Tomiyasu e-mail: [email protected] Y. Kochiyama e-mail: [email protected] M. Uriu e-mail: [email protected] Y. Ishitsuka e-mail: [email protected]
M. Irikura e-mail: [email protected] E. Yukawa e-mail: [email protected] N. Kamada : H. Ohno Pharmacokinetics Research, Kissei Pharmaceutical Co., Ltd., Nagano, Japan N. Kamada e-mail: [email protected] H. Ohno e-mail: [email protected]
T. Yamazaki Department of Pediatrics, School of Medicine, Fujita Health University, Aichi, Japan e-mail: [email protected]
Y. Kondo e-mail: [email protected] M. Irikura : E. Yukawa Laboratory of Evidence-Based Pharmacotherapy, College of Pharmaceutical Sciences, Daiichi University, Fukuoka, Japan
T. Irie (*) Center for Clinical Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan e-mail: [email protected]
Eur J Pediatr
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. Keywords Apnea . NONMEM . Population pharmacokinetics . Premature infants . Doxapram Abbreviations AOP Apnea of prematurity AST Aspartate aminotransferase BW Body weight CL Clearance GA Gestational age HLM Human liver microsomes HPLC High-performance liquid chromatography LBW infants Low-birth-weight infants MAE Mean absolute error ME Mean prediction error MS Mass spectrometry NONMEM Nonlinear mixed-effect modeling PMA Postmenstrual age PNA Postnatal age OBJ Objective function Vd Volume of distribution
Introduction Apnea of prematurity (AOP) is defined as cessation of breathing by a premature infant that lasts for more than 20 s or is accompanied by hypoxia or bradycardia [24]. The incidence of AOP is 25 % in neonates who weigh
ORIGINAL ARTICLE
Population pharmacokinetics of doxapram in low-birth-weight Japanese infants with apnea 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
Received: 6 June 2014 / Revised: 27 August 2014 / Accepted: 28 August 2014 # Springer-Verlag Berlin Heidelberg 2014
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.
Communicated by Patrick Van Reempts Electronic supplementary material The online version of this article (doi:10.1007/s00431-014-2416-1) contains supplementary material, which is available to authorized users. Y. Ogawa : Y. Kobaru : M. Tomiyasu : Y. Kochiyama : M. Uriu : Y. Ishitsuka : Y. Kondo : T. Irie Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan Y. Ogawa e-mail: [email protected] Y. Kobaru e-mail: [email protected] M. Tomiyasu e-mail: [email protected] Y. Kochiyama e-mail: [email protected] M. Uriu e-mail: [email protected] Y. Ishitsuka e-mail: [email protected]
M. Irikura e-mail: [email protected] E. Yukawa e-mail: [email protected] N. Kamada : H. Ohno Pharmacokinetics Research, Kissei Pharmaceutical Co., Ltd., Nagano, Japan N. Kamada e-mail: [email protected] H. Ohno e-mail: [email protected]
T. Yamazaki Department of Pediatrics, School of Medicine, Fujita Health University, Aichi, Japan e-mail: [email protected]
Y. Kondo e-mail: [email protected] M. Irikura : E. Yukawa Laboratory of Evidence-Based Pharmacotherapy, College of Pharmaceutical Sciences, Daiichi University, Fukuoka, Japan
T. Irie (*) Center for Clinical Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan e-mail: [email protected]
Eur J Pediatr
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. Keywords Apnea . NONMEM . Population pharmacokinetics . Premature infants . Doxapram Abbreviations AOP Apnea of prematurity AST Aspartate aminotransferase BW Body weight CL Clearance GA Gestational age HLM Human liver microsomes HPLC High-performance liquid chromatography LBW infants Low-birth-weight infants MAE Mean absolute error ME Mean prediction error MS Mass spectrometry NONMEM Nonlinear mixed-effect modeling PMA Postmenstrual age PNA Postnatal age OBJ Objective function Vd Volume of distribution
Introduction Apnea of prematurity (AOP) is defined as cessation of breathing by a premature infant that lasts for more than 20 s or is accompanied by hypoxia or bradycardia [24]. The incidence of AOP is 25 % in neonates who weigh
