Nonlinear Theophylline Pharmacokinetics: A Preventable Cause of latrogenic Theophylline Toxic Reactions

When theophylline is used for the treatment of patients with obstructive pulmonary diseases, most clinicians attempt to maintain serum levels between 55 and 110 μmol/L because higher levels are associated with an increased risk of serious toxic effects. Nonlinear theophylline kinetics are known to occur in animals, in some pediatric patients, and at very high toxic levels in adults. However, within the usual therapeutic range of serum levels, first-order kinetics are assumed to operate, and, thus, a one-compartment model or a model-independent approach is routinely used for dose adjustments. We have recently encountered two adult patients in whom nonlinear theophylline kinetics existed within the subtherapeutic and therapeutic range of serum levels. In both cases this was not immediately recognized by the clinician, resulting in prolonged use of subtherapeutic doses of theophylline. In addition, in one case our empiric attempts to achieve therapeutic serum levels resulted in serious theophylline toxicity. We present only the data from this latter patient to be used as a case study. Based on this example and a review of the literature, we propose that to avoid such a potentially fatal complication the following steps should be taken when dealing with a patient in whom serum theophylline levels fail to rise as expected with increasing oral doses: (1) supervised administration of oral theophylline to rule out noncompliance; (2) discontinuation of further empirical increases of the oral dose of theophylline; (3) obtention of steady-state serum levels on at least two different oral doses of theophylline; and (4) calculation of the appropriate maintenance dose of theophylline for that individual patient using any of the methods cited in this report.