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Prediction of Theophylline Clearance in Various Stages of Liver Cirrhosis by Child-Pugh and MELD Scores: A Population Pharmacokinetic Analysis
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  • Yasuo Kurata,
  • Shota Muraki,
  • Takeshi Hirota,
  • Hiroshi Araki,
  • Ichiro Ieiri
Yasuo Kurata
Fukuoka City Hospital

Corresponding Author:[email protected]

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Shota Muraki
Kyushu University
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Takeshi Hirota
Kyushu University Hospital
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Hiroshi Araki
Fukuoka City Hospital
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Ichiro Ieiri
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Aims Theophylline clearance in patients with chronic liver diseases (CLDs), chronic hepatitis (CH) and liver cirrhosis (LC), was evaluated by population pharmacokinetic (PPK) analysis. Methods PPK analysis included 433 minimum steady-state concentrations from 192 Japanese bronchial asthma patients and was performed using NONMEM. The severity of LC was assessed by the Child-Pugh (CP) class and model for end-stage liver disease (MELD) score. Results Two final models (CP and MELD models) were obtained, and described apparent theophylline clearance (CL/F) as follows: CP model: CL/F=0.0473×0.874CH×0.697CPA×0.592CPB×0.441CPC, MELD model: CL/F=0.0472×0.876CH×0.687MELD < 10×0.568MELD 10-14×0.487MELD 15-19×0.417MELD 20-24×0.328MELD ≥ 25. The CP model showed that mean CL/F in patients without CLDs, and with CH, and LC with CP class A, B, and C was 0.0473, 0.0413, 0.0330, 0.0280, and 0.0209 L/h kg-1, respectively. The MELD model predicted that CL/F in patients without CLDs, and with CH, and LC with a MELD score of < 10, 10-14, 15-19, 20-24, and ≥ 25 was 0.0472, 0.0413, 0.0324, 0.0268, 0.0230, 0.0197, and 0.0155 L/h kg-1, respectively. Conclusions CL/F in various stages of LC was evaluated and a change in CL/F was highly dependent on the severity of CLDs in both models. The MELD model classified LC into 5 categories, and subdivided CP class C patients into 3 further categories. The MELD model provided a more accurate and precise description of CL/F than the CP model, particularly in high-severity LC patients.
27 Jul 2021Submitted to British Journal of Clinical Pharmacology
28 Jul 2021Submission Checks Completed
28 Jul 2021Assigned to Editor
28 Jul 2021Reviewer(s) Assigned
24 Sep 2021Review(s) Completed, Editorial Evaluation Pending
07 Nov 2021Editorial Decision: Revise Major
07 Feb 20221st Revision Received
08 Feb 2022Submission Checks Completed
08 Feb 2022Assigned to Editor
08 Feb 2022Review(s) Completed, Editorial Evaluation Pending
26 Feb 2022Editorial Decision: Revise Major
09 Mar 20222nd Revision Received
10 Mar 2022Submission Checks Completed
10 Mar 2022Assigned to Editor
10 Mar 2022Review(s) Completed, Editorial Evaluation Pending
16 Mar 2022Editorial Decision: Accept