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Individualized aminophylline therapy in patients with obstructive airway disease: Oral dosage prediction from an intravenous test dose

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Summary

Theophylline disposition after an intravenous test dose of aminophylline was determined in 83 subjects: 7 patients with and 58 without congestive heart failure (CHF), and 18 healthy controls. Based on the pharmacokinetics of theophylline in the individual, the oral dosage of aminophylline was scheduled to attain steady-state trough theophylline concentrations (Cpred) near the therapeutic margin. Significant differences in theophylline clearance with a relatively constant volume of distribution were observed between various groups divided by age, smoking habit and CHF; the significantly different (p<0.001) mean clearance values were: 0.042±0.0161/h/kg (mean ± SD) in patients without CHF (n=58) as opposed to 0.016±0.001 l/h/kg in patients with CHF(n=7), 0.038±0.013 l/h/kg in non-smokers (n=59) versus 0.054±0.015 l/h/kg in smoking subjects (n=17), and 0.030±0.010 l/h/kg in elderly (>60 years) non-smoking patients (n=7) versus 0.057±0.017 l/h/kg in smoking patients (n=5) aged 40 to 59 years. No gender-related difference was detected in theophylline disposition. For all subjects together (n=83), there was no significant correlation between age and clearance (r=-0.111, p>0.1). The multivariate analysis indicated that the overall variability in theophylline clearance was affected first by the smoking habit (t=4.960; p<0.001) and second by CHF (t=-3.052; p<0.001), but not by age (t=1.140) or by sex (t=0.069). 78% of the patients who did not have CHF required a daily dose of aminophylline of 600 to 900 mg, whereas a dose of 300 to 450 mg was the rule in patients with CHF. The measured steady-state minimum concentration (Cmeas) ranged from 5.4 to 14.6 µg/ml (9.0±2.2 µg/ml: mean ± SD) which was in good agreement with the Cpred (5.6 to 13.6, 9.0±1.6 µg/ml) in all patients (n=60) who received the oral dose of aminophylline calculated from the test dose. The overall prediction error was -0.08±1.83 µg/ml (−1.42±19.90%); only 3 of 60 measurements were found to be outside±2 SD. It is concluded that using a test dose to individualize aminophylline therapy is likely to remain the most reliable means to assure the maximum therapeutic benefit in patients with airway obstruction.

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Authors and Affiliations

  1. Division of Clinical Pharmacology, Clinical Research Institute, Tokyo, Japan

    Y. Horai, T. Ishizaki, T. Sasaki, M. Watanabe & J. Kabe

  2. Division of Respiratory Disease, Department of Medicine, National Medical Center, Tokyo, Japan

    Y. Horai, T. Ishizaki, T. Sasaki, M. Watanabe & J. Kabe

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  1. Y. Horai
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  2. T. Ishizaki
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  3. T. Sasaki
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  4. M. Watanabe
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Horai, Y., Ishizaki, T., Sasaki, T. et al. Individualized aminophylline therapy in patients with obstructive airway disease: Oral dosage prediction from an intravenous test dose. Eur J Clin Pharmacol 23, 111–121 (1982). https://doi.org/10.1007/BF00545964

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