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Theophylline Absorption from Sustained‐Release Products: Comparative Steady‐State Bioavailability of Once‐Daily Theo‐Dur, Theo‐24, and Uniphyl
Author(s) -
Hurwitz Aryeh,
Karim Aziz,
Burns Thomas S.
Publication year - 1987
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/j.1552-4604.1987.tb05579.x
Subject(s) - theophylline , aminophylline , bioavailability , pharmacokinetics , chemistry , zoology , steady state (chemistry) , absorption (acoustics) , dosing , pharmacology , medicine , biochemistry , physics , acoustics , biology
Theophylline absorption from three sustained‐release formulations was evaluated in 18 healthy men. First, a 600‐mg oral dose of aminophylline, a rapidly absorbed formulation, was studied to confirm that theophylline clearance was in the expected range (mean ± SD, 0.710 ± 0.096 mL/min/kg), t 1/2 = 6.9 ± 1.1 hr. Then each of the three sustained‐release formulations was given at one hour before breakfast for eight days to achieve steady state. Multiple blood samples were drawn on days 7 and 8 over two complete dosing intervals. After a six‐day drug‐free period each subject was crossed over to the next product. At steady state, mean fluctuations of serum theophylline levels were more than 200% with Theo‐Dur (Key Pharmaceuticals, Miami, FL), more than 150% with Uniphyl (Purdue‐Frederick, Norwalk, CT), and about 75% with Theo‐24 (Searle Laboratories, Chicago, IL). Theophylline C max levels averaged 16.5 μg/mL after 900 mg Theo‐Dur, with 8% exceeding 20 μg/mL. Despite these high peak levels, nearly half of the C min levels were below 5 pg/mL. Uniphyl administration resulted in three‐fourths of trough levels to be at 5 μg/mL or lower. Peak levels from 800‐mg daily doses of Uniphyl were also low, with 42% never reaching 10 pg/mL. With Theo‐24 only 17% of trough levels were below 5 μg/mL, as compared to 47% with Theo‐Dur and 72% with Uniphyl. The three products differed in the areas under the serum concentration‐time curves (AUC), which reflect bioavailability. Theo‐Dur AUC was nearly equivalent to that of rapidly absorbed aminophylline (when adjusted for dosage). AUC from Theo‐24 was 80% relative to Theo‐Dur, and Uniphyl was 67%, when adjusted for dose. These data show the limitations in once‐daily administration of sustained‐release theophylline, even in normal and slow metabolizers. Serum levels fluctuated widely with Theo‐Dur and Uniphyl, whereas the latter had incomplete bioavailability. Of the three products approved in the United States for once‐daily dosing, only Theo‐24 consistently yielded serum theophylline levels within the desired range while providing acceptable bioavailability.