Dose dependency for absorption and elimination rates of theophylline. Implications for studies of bioavailability

Dose dependency for absorption and elimination rates of theophylline were examined by administering 2-mg/kg and 6-mg/kg doses of a theophylline solution to 8 adult volunteers. The area under the concentration-time curve extrapolated to infinity after the lower dose was 84% of that calculated after the higher dose. This is associated with a decrease in the slope of the terminal portion of the elimination curve to varying degrees after the higher dose in all 8 patients (p less than 0.001). A significantly smaller fraction of the higher dose was absorbed at 15 minutes (0.46 vs. 0.77, p less than 0.002), but the differences were trivial by 30 to 45 minutes. Dose dependency for elimination may cause changes in a steady-state serum concentration during multiple dosing that is disproportionately larger than changes in dosage. In addition, the slower elimination at higher serum concentrations may confound the assessment of bioavailability of slow-release formulations when the doses used result in a substantial disparity in the range of serum concentrations attained for the slow-release formulation and the reference. The use of unequal doses adjusted to provide similar peak serum concentrations appears to minimize this potential error.