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Objective <p>To systematically evaluate how the Child–Pugh classification is applied in Japanese prescription drug labeling and to characterize the pharmacokinetic features and evidentiary basis underlying contraindications and dose-related recommendations for hepatic impairment.</p> Methods <p>We conducted a cross-sectional review of Japanese prescription drug package inserts available as of October 1, 2025. Drugs explicitly referring to the Child–Pugh classification in Section&#xa0;2 (“Contraindications”) and/or Section&#xa0;7 (“Precautions for Dosage and Administration”) were identified using the Pharmaceuticals and Medical Devices Agency database. Absolute bioavailability, systemic clearance, plasma protein binding, and urinary excretion of unchanged drug were extracted from package inserts and interview forms. Hepatic extraction ratio was approximated and analyzed descriptively.</p> Results <p>Fifty-one active ingredients were identified, including 35 with Child–Pugh-based contraindications and 29 with dose-related recommendations. Most drugs showed high plasma protein binding, low urinary excretion of unchanged drug, and low hepatic extraction. Median values were 0.62 for bioavailability, 11.5 L/h for clearance, 94.7% for plasma protein binding, 1.0% for urinary excretion of unchanged drug, and 0.12 for hepatic extraction ratio. Pharmacokinetic evidence supporting Child–Pugh class C labeling was available for 23 of 51 drugs overall and 14 of 35 drugs with Child–Pugh-based contraindications.</p> Conclusions <p>Child–Pugh-based labeling in Japan was broadly consistent with hepatic clearance principles, particularly protein binding, renal contribution, and hepatic extraction. However, limited direct pharmacokinetic evidence in severe hepatic impairment indicates the need for clearer justification of whether future recommendations derive from clinical data, modeling, or precautionary inference.</p>

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Application of the Child–Pugh Classification in Japanese Drug Labeling: A Cross-Sectional Analysis of Contraindications, Dose Recommendations, and Pharmacokinetic Rationale

  • 期刊论文

  • 发表日期：

    2026年7月11日

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  • Masahiro Kobayashi,
  • Moeka Ogawa,
  • Tatsuya Okuwaki,
  • Mika Maeda,
  • Katsuya Otori

摘要

Objective

To systematically evaluate how the Child–Pugh classification is applied in Japanese prescription drug labeling and to characterize the pharmacokinetic features and evidentiary basis underlying contraindications and dose-related recommendations for hepatic impairment.

Methods

We conducted a cross-sectional review of Japanese prescription drug package inserts available as of October 1, 2025. Drugs explicitly referring to the Child–Pugh classification in Section 2 (“Contraindications”) and/or Section 7 (“Precautions for Dosage and Administration”) were identified using the Pharmaceuticals and Medical Devices Agency database. Absolute bioavailability, systemic clearance, plasma protein binding, and urinary excretion of unchanged drug were extracted from package inserts and interview forms. Hepatic extraction ratio was approximated and analyzed descriptively.

Results

Fifty-one active ingredients were identified, including 35 with Child–Pugh-based contraindications and 29 with dose-related recommendations. Most drugs showed high plasma protein binding, low urinary excretion of unchanged drug, and low hepatic extraction. Median values were 0.62 for bioavailability, 11.5 L/h for clearance, 94.7% for plasma protein binding, 1.0% for urinary excretion of unchanged drug, and 0.12 for hepatic extraction ratio. Pharmacokinetic evidence supporting Child–Pugh class C labeling was available for 23 of 51 drugs overall and 14 of 35 drugs with Child–Pugh-based contraindications.

Conclusions

Child–Pugh-based labeling in Japan was broadly consistent with hepatic clearance principles, particularly protein binding, renal contribution, and hepatic extraction. However, limited direct pharmacokinetic evidence in severe hepatic impairment indicates the need for clearer justification of whether future recommendations derive from clinical data, modeling, or precautionary inference.