Pharmacolinetic and pharmacodynamic data analysis of theophylline for three different drug forms

Theophylline, which is widely used in asthmatics, should be maintained within narrow plasma limits to achieve maximum therapeutic benefit with minimum adverse effects. For the evaluation of drug input schemes it is essential to know the pharmacokinetic parameters and their variation for different dosage forms. Apart from absorption and elimination rates, an appropriate dosage schedule is determined by the extent of bioavailability. The objectives of the study presented here are the assessment of bioavailability, the estimation of pharmacokinetic parameters, and the investigation of the relationship between plasma drug levels and cardiac side effects. Additionally, it was checked whether drug levels in saliva could be used for monitoring drug levels in plasma. The time course of theophylline in plasma and saliva was measured in twelve healthy volunteers on different drug forms: intravenous injection as well as oral application of a fast and a slow release form of theophylline. Pharmacokinetic parameters were estimated using a three-compartment model for the distribution of theophylline. The extent of bioavailability was estimated via the area under the curves and by numerical evaluation of the invasion function. By simultaneous measurements of heart rate and c-AMP levels the drug response was monitored. The results show the following: i) The slow and fast release dosage forms do not differ with respect to extent of bioavailability, whereas bioavailability rates are slower for the sustained release form. ii) Apart from the initial phase (less than or equal to 1 h) plasma and saliva drug levels run approximately parallel. However, the mean concentration ratio has a large variance. iii) The time courses of heart rate are closely related to the time courses of drug level. iv) When the sustained release form is used for a long-term therapy, it is possible to evaluate dosage schedules and dosage regimens that reduce cardiac side effects caused by the fast release form. This was shown by computer simulation carried out on the basis of pharmacokinetic parameters that were estimated from the experimental curves.