Theophylline kinetics: dose dependency and single sample prediction of clearance

Area of Science:

• Pharmacokinetics
• Drug Metabolism
• Clinical Pharmacology

Background:

• Theophylline is a common medication with a narrow therapeutic index.
• Understanding theophylline clearance is crucial for safe and effective dosing.
• Factors influencing theophylline clearance require further investigation.

Purpose of the Study:

• To investigate the relationship between theophylline dose and its clearance in healthy adults.
• To evaluate a simplified method for estimating theophylline clearance using single plasma concentrations.
• To assess the utility of this method in quantifying drug interactions, specifically with cimetidine.

Main Methods:

• Theophylline clearance was measured in 10 healthy adults at three intravenous doses (2, 4, and 6 mg/kg).
• A simplified clearance estimation method was tested using single theophylline plasma concentrations and a fixed volume of distribution (0.5 L/kg).
• The simplified method's accuracy was validated by comparing its results with measured clearance and its application in assessing cimetidine's impact.

Main Results:

• Theophylline clearance significantly decreased as the dose increased from 2 mg/kg (0.064 L/h/kg) to 6 mg/kg (0.052 L/h/kg) (p < 0.02).
• The simplified estimation method provided accurate results when plasma samples were collected at 12 hours post-dose for 2 mg/kg and 24 hours post-dose for 4 mg/kg intravenous theophylline.
• This simplified method successfully quantified the impact of cimetidine on theophylline clearance.

Conclusions:

• Theophylline clearance exhibits dose-dependent behavior in young, healthy adults.
• A simplified, single-point method can reliably estimate theophylline clearance under specific sampling conditions.
• This validated method aids in understanding drug-drug interactions affecting theophylline pharmacokinetics.