Population pharmacokinetics of theophylline. II: Intravenous infusion to patients with stable chronic airway obstruction.
The population pharmacokinetics of theophylline were studied in 55 patients with stable chronic airway obstruction. Two hundred and seventy six theophylline serum concentrations after intravenous short infusion were analyzed using a nonlinear mixed-effect model. The influence of hepatic dysfunction, smoking habit, age and the measurement of arterial blood gases (oxygen tension: PaO2, carbon dioxide tension: PaCO2, blood pH) and clinical laboratory tests (serum albumin concentration, haematocrit) on the pharmacokinetic parameters of theophylline was examined by the likelihood ratio test. Assessment of each factor was made by a forward selection method. In the final regression model, the total body clearance (CL, l/h/kg) was related to the value of PaCO2 as well as to the presence of hepatic dysfunction, and the volume of distribution (Vd, l/kg) was related with the PaCO2 value as expressed in the following equations: CL = exp(-3.78 - 0.525.HF + 0.0233.PaCO2) and Vd = exp(-1.12 + 0.00934.PaCO2), where HF is a categorical variable with a value of unity if a patient has hepatic dysfunction otherwise zero. The interactions among blood gas measurements were observed and the CL and Vd of theophylline would be inversely correlated with PaO2 or pH, if we selected PaO2 or blood pH to be a more important factor than PaCO2. The inter-individual variabilities in CL and Vd were 38.5% and 12.5%, respectively, and the residual variability in theophylline serum concentrations was 10.6% as a coefficient of variation. This final model and the population parameters of theophylline will be useful for individualization of a drug dosage regimen by means of the Bayesian method.(ABSTRACT TRUNCATED AT 250 WORDS)
Yano
I
I
Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Japan.
Tanigawara
Y
Y
Yasuhara
M
M
Okumura
K
K
Kawakatsu
K
K
Nishimura
K
K
Hori
R
R
D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000402:Airway Obstruction / Q000378:metabolism* / Q000503:physiopathology; D001784:Blood Gas Analysis; D002908:Chronic Disease; D005260:Female; D006801:Humans; D007206:Individuality; D007262:Infusions, Intravenous; D008107:Liver Diseases / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D012044:Regression Analysis; D012907:Smoking / Q000378:metabolism; D013806:Theophylline / Q000008:administration & dosage / Q000493:pharmacokinetics*
D013806:Theophylline