Prediction of Theophylline Clearance in Various Stages of Liver
Cirrhosis by Child-Pugh and MELD Scores: A Population Pharmacokinetic
Analysis
Abstract
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.