Food-Induced “Dose-Dumping” from a Once-a-Day Theophylline Product as a Cause of Theophylline Toxicity

      Three slow-release preparations of theophylline have received approval from the U.S. Food and Drug Administration (FDA) for “once-daily” dosing indications, amid controversy regarding the appropriateness of this decision. Because of specific concerns regarding data submitted to the FDA in support of the first of these products to be approved, Theo-24, we examined the absorption characteristics of this newly marketed formulation. Eight healthy volunteers received, in a crossover manner, single doses of a theophylline reference solution and Theo-24, taken both fasting and after a breakfast of bacon and eggs. The concentrations of theophylline were measured up to 60 hours after the dose. Absorption of Theo-24 after an overnight fast was very slow, with only 71 ± 6 percent (mean ± SE) of the dose ultimately absorbed. In contrast, food caused precipitous “dose-dumping,” resulting in dose-normalized peak levels in the serum that averaged 2.3 times higher than after a fasting dose. About half of the dose was absorbed in a four-hour period, generally beginning six to eight hours after the postprandial dose, and complete absorption was then attained within 24 hours (p<0.001). Toxic effects of theophylline occurred in four subjects when they took the dose with food whereas no toxic effects occurred during the fasting regimen. Consequently, doses of Theo-24 that would have attained a predicted peak concentration of 15μg/ml after multiple dosing taken without food would, if taken with food, have resulted in larger fluctuations and in peak concentrations in the potentially toxic range for six of the eight subjects.
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      References

        • Weinberger MM
        • Bronsky EA
        Evaluation of oral bronchodilator therapy in asthmatic children.
        J Pediatr. 1974; 84: 421-427
        • Pollock J
        • Kiechel F
        • Cooper D
        • Weinberger M
        Relationship of serum theophylline concentration to inhibition of exercise-induced bronchospasm and comparison with cromolyn.
        Pediatrics. 1977; 60: 840-844
        • Richer C
        • Mathieu M
        • Bah H
        • Thuillez C
        • Duroux P
        • Giudicelli JF
        Theophylline kinetics and ventilatory flow in bronchial asthma and chronic airflow obstruction: influence of erythromycin.
        Clin Pharmacol Ther. 1982; 31: 579-586
        • Simons FER
        • Luciuk GH
        • Simons KJ
        Sustained-release theophylline for treatment of asthma in preschool children.
        Am J Dis Child. 1982; 136: 790-793
        • Jacobs MH
        • Senior RM
        • Kessler G
        Clinical experience with theophylline: relationships between dosage, serum concentration and toxicity.
        JAMA. 1976; 235: 1983-1986
        • Zwillich CW
        • Sutton FD
        • Neff TA
        • Cohn WM
        • Matthay R
        • Weinberger M
        Theophylline induced seizures in adults; correlation with serum concentrations.
        Ann Intern Med. 1975; 82: 784-787
        • Hendeles L
        • Bighley L
        • Richardson RH
        • Hepler CD
        • Carmichael J
        Frequent toxicity from IV aminophylline infusions in critically ill patients.
        Drug Intell Clin Pharm. 1977; 11: 12-18
        • Hendeles L
        • Weinberger M
        Theophylline: a state of the art review.
        Pharmacotherapy. 1983; 3: 2-44
        • Hendeles L
        • Iafrate P
        • Weinberger M
        A clinical and pharmacokinetic basis for the selection and use of slow-release theophylline products.
        Clin Pharmacokinet. 1984; 9: 95-135
        • Ginchansky E
        • Weinberger M
        Relationship of theophylline clearance to oral dosage in children with chronic asthma.
        J Pediatr. 1977; 91: 655-660
        • Weinberger M
        • Hendeles L
        • Wong L
        • Vaughan L
        Relationship of formulation and dosing interval to fluctuation of serum theophylline concentration in children with chronic asthma.
        J Pediatr. 1981; 99: 145-152
        • Dasta J
        • Mirtallo JM
        • Altman M
        Comparison of standard and sustained-release theophylline tablets in patients with chronic obstructive pulmonary disease.
        Am J Hosp Pharm. 1979; 36: 613-617
        • Weinberger M
        • Hendeles L
        • Bighley L
        The relation of product formulation to absorption of oral theophylline.
        N Engl J Med. 1978; 299: 852-857
        • Weinberger M
        Theophylline QID, TID, BID—and now OD? A report on 24 hour dosing with slow-release theophylline formulations with emphasis on analyses of data used to obtain FDA approval for Searle's Theo-24.
        Pharmacotherapy. 1984; 4: 181-198
        • Barr WH
        The once-daily theophylline controversy.
        Pharmacother. 1984; 4: 167-168
        • Pedersen S
        • Moeller-Petersen J
        Influence of food on the absorption rate and bioavailability of a sustained release theophylline preparation.
        Allergy. 1982; 37: 531-534
        • Thompson PJ
        • Kemp MW
        • McAllister WAC
        • Turner-Warwick M
        Slow release theophylline in patients with airways obstruction with particular reference to the effects of food upon serum levels.
        Br J Dis Chest. 1983; 77: 293-298
        • Pedersen S
        • Moller-Petersen J
        Erratic absorption of a slow-release theophylline sprinkle product caused by food.
        Pediatrics. 1984; 74: 534-538
        • Lagas M
        • Jonkman JHG
        Greatly enhanced bioavailability of theophylline on postprandial administration of a sustained release tablet.
        Eur J Clin Pharmacol. 1983; 24: 761-767
        • Milavetz G
        • Weinberger M
        • Vaughan L
        Dose dependency for absorption and elimination rates of theophylline: implications for studies of bioavailability.
        Pharmacotherapy. 1984; 4: 216-220
        • Hendeles L
        • Weinberger M
        • Bighley L
        Absolute bioavailability of oral theophylline.
        Am J Hosp Pharm. 1977; 34: 525-527
      1. Karim A. Theophylline absorption, controlled-release formulations and food. Presented at the Third Annual Conference on Current Concepts in Biopharmaceutics and Clinical Trials: Pharmacokinetic and Pharcomadynamic Considerations in Designing Bioavailability and Clinical Efficacy Studies, University of Maryland, Baltimore, Oct 2-4, 1984

        • Weinberger M
        • Ginchansky E
        Dose-dependent kinetics of theophylline disposition in asthmatic children.
        J Pediatr. 1977; 91: 820-824
        • Sarrazin E
        • Hendeles L
        • Weinberger M
        • Muir K
        • Riegelman S
        Dose-dependent kinetics for theophylline: observations among ambulatory asthmatic children.
        J Pediatr. 1980; 94: 825-828
        • Weinberger M
        • Hendeles L
        Slow-release theophylline: rationale and basis for product selection.
        N Engl J Med. 1983; 308: 760-764
        • Welling PG
        • Lyons LL
        • Craig WA
        • Trochta GA
        Influence of diet and fluid on bioavailability of theophylline.
        Clin Pharmacol Ther. 1975; 17: 475-480
        • Upton RA
        • Sansom L
        • Guentert TW
        • Powell JR
        • Thiercelin JF
        • Shah VP
        • et al.
        Evaluation of the absorption from 15 commercial theophylline products indicating deficiencies in currently applied bioavailability criteria.
        J Pharmacokinet Biopharm. 1980; 8: 229-242
        • Leeds NH
        • Gal P
        • Purohit AA
        • Walter JB
        • Dijkman JH
        Effect of food on the bioavailability and pattern of release of a sustained-release theophylline tablet.
        J Clin Pharmacol. 1982; 22: 196-200
        • Osman MA
        • Patel RB
        • Irwin DS
        • Welling PG
        Absorption of theophylline from enteric coated and sustained release formulations in fasted and non-fasted subjects.
        Biopharm Drug Dispos. 1983; 4: 63-72
        • Sips AP
        • Edelbroek PM
        • Kulstad S
        • de Wolff FA
        • Dijkman JH
        Food does not affect bioavailability of theophylline from Theolin Retard.
        Europ J Clin Pharmacol. 1984; 26: 405-407
        • Jonkman JHG
        • Schoenmaker R
        • Grimberg N
        • de Zeeuw RA
        A new in vitro dissolution test for controlled-release theophylline tablets.
        Int J Pharmaceutics. 1981; 8: 153-156
      2. Pedersen S, Möller-Pedersen J. Influence of food on the absorption of theophylline from Somophyllin-CRT. Clin Allergy (in press)