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

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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.

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.

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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

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Acknowledgments

This study was supported by a grant-in-aid for scientific research from the Ministry of Health, Labour and Welfare (Research Project Number: 23590189) and by the doxapram group of the Neonatal Research Network. The following investigators and research staff (no particular order) contributed to the trial. Fujita Health University, Aichi, Japan: Toshio Yamazaki, Tadayoshi Hata, Shuji Hashimoto, and Hiroko Mizutani; Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan: Hiroyuki Kitajima, Masanori Fujimura, and Shinya Hirano; Kumamoto University, Kumamoto, Japan: Tetsumi Irie and Mitsuru Irikura; Kakogawa City Hospital, Hyogo, Japan: Akihito Ishida and Masanori Murase; Toyohashi Municipal Hospital, Aichi, Japan: Norihisa Koyama; Hiroshima City Hospital, Hiroshima, Japan: Michiko Hayashidani; Shiga University of Medical Science, Shiga, Japan: Hirofumi Aotani; National Center for Child Health and Development, Tokyo, Japan: Hidefumi Nakamura; Kagawa University, Kagawa, Japan: Susumu Itoh; and Kissei Pharmaceutical Co., Ltd., Nagano, Japan: Mutsuo Kanzawa. Doxapram used in this study was donated by Kissei Pharmaceutical Co. Ltd.

Ethical standards

This study was approved by the ethics committee at the each institution. Parents of eligible LBW infants gave written informed consent.

Author information

Authors and Affiliations

  1. Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto, 862-0973, Japan

    Yuki Ogawa, Yuka Kobaru, Mayu Tomiyasu, Yoshie Kochiyama, Mamiko Uriu, Yoichi Ishitsuka, Yuki Kondo & Tetsumi Irie

  2. Laboratory of Evidence-Based Pharmacotherapy, College of Pharmaceutical Sciences, Daiichi University, Fukuoka, Japan

    Mitsuru Irikura & Eiji Yukawa

  3. Pharmacokinetics Research, Kissei Pharmaceutical Co., Ltd., Nagano, Japan

    Noboru Kamada & Hitoshi Ohno

  4. Department of Pediatrics, School of Medicine, Fujita Health University, Aichi, Japan

    Toshio Yamazaki

  5. Center for Clinical Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan

    Tetsumi Irie

Authors
  1. Yuki Ogawa
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  2. Mitsuru Irikura
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  3. Yuka Kobaru
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  4. Mayu Tomiyasu
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  5. Yoshie Kochiyama
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  6. Mamiko Uriu
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  7. Yoichi Ishitsuka
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  8. Yuki Kondo
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  9. Eiji Yukawa
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  10. Noboru Kamada
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  11. Hitoshi Ohno
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  12. Toshio Yamazaki
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  13. Tetsumi Irie
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Corresponding author

Correspondence to Tetsumi Irie.

Additional information

Communicated by Patrick Van Reempts

Electronic supplementary material

Below is the link to the electronic supplementary material.

Online Resource 1

(XLSX 13 kb)

Online Resource 2

Assay procedure of doxapram and keto-doxapram. (PPTX 35 kb)

Online Resource 3

(A) Chromatogram of the 10 μM internal standard (a). (B) Chromatogram of the 10 μM internal standard, 6.7 μM doxapram (b), and 7.3 μM keto-doxapram (c). (C) Chromatogram of LBW infants receiving a maintenance dose of 0.20 mg/kg/h after a loading dose of 1.5 mg/kg for 1 h. Values indicate the retention time. (PPTX 77 kb)

Online Resource 4

(A) Chromatogram of keto-doxapram (m/z 393). (B) Chromatogram of midazolam as the internal standard (m/z 326). (PPTX 72 kb)

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Ogawa, Y., Irikura, M., Kobaru, Y. et al. Population pharmacokinetics of doxapram in low-birth-weight Japanese infants with apnea. Eur J Pediatr 174, 509–518 (2015). https://doi.org/10.1007/s00431-014-2416-1

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  • DOI: https://doi.org/10.1007/s00431-014-2416-1

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