Prediction of optimum oral theophylline dose in patients with obstructive airways disease

The hypothesis that a logarithmic correlation exists between the plasma theophylline concentrations 6 h after a test dose C(6) and the maintenance dose calculated to achieve a desired drug concentration during chronic oral administration (DM,CALC) was tested. A nomogram based on this relationship was evaluated as a means of predicting the optimum dose of theophylline in 14 patients with obstructive airways disease (DM,PRED). Each patient was given 5 mg/kg theophylline intravenously (i.v.) and plasma theophylline concentrations were measured for 12 h thereafter including one exactly 6 h after commencing the i.v. infusion C(6). Pharmacokinetic parameters derived from the plasma concentration-time curve were used to establish DM,CALC for a concentration of 10 micrograms/ml. DM,PRED was obtained from the nomogram using both the optimum and the actual values for C(6). Subsequently oral sustained-release theophylline was administered and the dose adjusted to establish a trough concentration of approximately 10 micrograms/ml. This dose was then corrected arithmetically, assuming a linear relationship between dose and plasma level, to represent that required to achieve a plasma concentration of exactly 10 micrograms/ml (DM,ACT). The correlation between C(6) and log DM,CALC was confirmed (r = 0.97 P less than 0.001), validating the hypothesis. DM,ACT was found to correlate significantly with DM,PRED (r = 0.90, P less than 0.01) substantiating the value of the nomogram. In nine of the 14 patients, DM,ACT corresponded satisfactorily to DM,PRED. In the remaining five, for whom DM,ACT lay outside the 95% confidence limits for the predicted dose, DM,PRED in general underestimated DM,ACT, an advantage in a drug with a low therapeutic index. The predictive error for DM,PRED was lower than that for DM,CALC, and the bias using either method was not significant. The results suggest that a single plasma theophylline assay following a test dose, and the nomogram may be useful in simplifying optimal theophylline administration.