Evaluation of the absorption from some commercial sustained-release theophylline products

  • Robert A. Upton
  • Jean-Francois Thiercelin
  • Theodor W. Guentert
  • Lloyd Sansom
  • J. Robert Powell
  • Peter E. Coates
  • Sidney Riegelman
Article

Abstract

Absorption of theophylline from three commercial products labeled as sustained release was compared to the absorption from a standard uncoated tablet (Searle 200-mg aminophylline tablet) in a single-dose study. Aminodur tablets (Cooper) and Slophyllin Gyrocap capsules (Dooner) had bioavailability (100.2%±19.8% and 98.5%±13.8%) statistically indistinguishable from that of the standard but showed significantly slower absorption (peak times of 10,4±2.8 and 4.36±1.35 hr) and lower peak plasma concentrations (13.9±4.5 and 22.6±3.5gmg/ml/g dose) than the standard (tpeak,1.52±0.45 hr; Cpeak,28.l±6.2μg/ml/g dose). The time of the plasma concentration peak (2.47±1.38 hr) after a dose of Tedral S.A. (Warner/Chilcott) was not statistically different from that after the standard, but both the peak concentration (16.0±3.9 gmg/ml/g dose) and bioavailability (76.0±18.4%) were. Multiple-dose projections from single-dose data indicate that of the three test products only Aminodur maintains reasonably constant interdose plasma levels during 12 hourly dosing. With an 8 hourly dosing schedule Gyrocaps also might be satisfactory. Reasonable predictions of the plasma concentrations arising from Aminodur doses have been made using a single-compartment body model and assuming input from an outer followed by an inner layer of the tablet.

Typically a single dose of a preparation designed for constant release of drug over 12 hr should not produce a plasma concentration plateau in subjects with an average 6.1-hr drug half-life. The apparent plateau in the mean plasma profile (i.e., concentrations at each sampling time averaged over all subjects) for Aminodur doses is evaluated. The interpretation commonly being implied in the publication of mean profiles from bioavailability studies is misleading, particularly when applied to sustained-release preparations.

Key words

theophylline absorption bioavailability sustained release tablets plasma concentrations mean plasma concentrations steady-state projections 

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References

  1. 1.
    C. W. Bierman, Theophylline in asthma.Pediatrics 58:623–635 (1976).PubMedGoogle Scholar
  2. 2.
    L. Hendeles, M. Weinberger, and G. Johnson. Monitoring serum theophylline levels.Clin. Pharmacokin. 3:294–312 (1978).CrossRefGoogle Scholar
  3. 3.
    M. H. Jacobs, R. M. Senior, and G. Kessler. Clinical experience with theophylline: Relationship between dosage, serum levels and toxicity.JAMA 235:1983–1986 (1976).PubMedCrossRefGoogle Scholar
  4. 4.
    R. I. Ogilvie. Clinical pharmacokinetics of theophylline.Clin. Pharmacokin. 3:267–293 (1978).CrossRefGoogle Scholar
  5. 5.
    P. R. Yarnell, and N. S. Chu. Focal seizures and aminophylline.Neurology 25:819–822 (1975).PubMedCrossRefGoogle Scholar
  6. 6.
    C. W. Zwillich, F. D. Sutton, T. A. Neff, W. M. Cohn, R. A. Matthay, and M. M. Weinberger. Theophylline induced seizures in adults.Ann. Brt. Med. 82:784–787 (1975).Google Scholar
  7. 7.
    E. F. Ellis, R. Koysooko, and G. Levy. Pharmacokinetics of theophylline in children with asthma.Pediatrics 58:542–547 (1976).PubMedGoogle Scholar
  8. 8.
    J. W. Jenne, E. Wyse, F. S. Rood, and F. M. McDonald. Pharmacokinetics of theophylline: Application to adjustment of the clinical dose of aminophylline.Clin. Pharmacol. Ther. 13:349–360 (1972).PubMedGoogle Scholar
  9. 9.
    J. R. Powell, S. Vozeh, P. Hopewell, J. Costello, L. B. Sheiner, and S. Riegelman. Theophylline disposition in acutely ill hospitalized patients: The effect of smoking, heart failure, severe airways obstruction and pneumonia.Am. Rev. Resp. Dis. 118:229–238 (1978).PubMedGoogle Scholar
  10. 10.
    R. A. Upton, L. Sansom, T. W. Guentert, J. R. Powell, J.-F. Thiercelin, P. E. Coates, and S. Riegelman. Evaluation of the absorption from 15 commercial immediate-release theophylline products.J. Pharmacokin. Biopharm. 8(3) (1980).Google Scholar
  11. 11.
    M. Danhof, and D. D. Breimer. Therapeutic drug monitoring in saliva.Clin. Pharmacokin. 3:39–57 (1978).CrossRefGoogle Scholar
  12. 12.
    S. P. Galant, S. A. Billman, L. H. Cummins, P. P. Kozak, and J. J. Orcutt. Reliability of salivary theophylline as a guide to plasma theophylline levels.Am. J. Dis. Child. 131:970–972 (1977).PubMedGoogle Scholar
  13. 13.
    R. A. Upton, J. R. Powell, T. W. Guentert, J.-F. Thiercelin, L. Sansom, P. E. Coates and S. Riegelman. Evaluation of the absorption from some commercial enteric-release theophylline products.J. Pharmacokin. Biopharm. 8:151–164 (1980).CrossRefGoogle Scholar
  14. 14.
    “Interpolate,” a MLAB procedure available through the PROPHET data analysis system, National Institutes of Health, Washington, D.C.Google Scholar
  15. 15.
    W. L. Chiou. Critical evaluation of the potential error in pharmacokinetic studies of using the linear trapezoidal rule method for the calculation of the area under the plasma level-time curve.J. Pharmacokin. Biopharm. 6:539–546 (1978).CrossRefGoogle Scholar
  16. 16.
    K. C. Yeh, and K. C. Kwan. A comparison of numerical integrating algorithms by trapezoidal, Lagrange and spline approximation.J. Pharmacokin. Biopharm. 6:79–98 (1978).CrossRefGoogle Scholar
  17. 17.
    A. Bostrom. RMEAS, a Program for Repeated Measures Analysis of Variance, Version 3, 1977, Scientific Computing Services, University of California, San Francisco, Calif. 94143.Google Scholar
  18. 18.
    W. J. Westlake. Use of statistical methods in evaluation ofin vivo performance of drug forms.J. Pharm. Sci. 62:1579–1589 (1973).PubMedCrossRefGoogle Scholar
  19. 19.
    D. L. Spangler, D. D. Kalof, F. L. Bloom, and H. J. Wittig. Theophylline bioavailability following oral administration of six sustained-release preparations.Ann. Allergy 40:6–11 (1978).PubMedGoogle Scholar
  20. 20.
    M. Weinberger, L. Hendeles, and L. Bighley. The relation of product formulation to absorption of oral theophylline.New Engl. J. Med. 229:852–857 (1978).CrossRefGoogle Scholar
  21. 21.
    P. Leung, C. Katsampes, and T. Bell. Pharmacokinetics of delayed versus sustained release theophylline formulations following single and repetitive dosing.Ann. Allergy 41:285–287 (1978).PubMedGoogle Scholar
  22. 22.
    J. G. Wagner, and E. Nelson. Kinetic analysis of blood levels and urinary excretion in the absorptive phase after single doses of drug.J. Pharm. Sci. 53:1392–1403 (1964).PubMedCrossRefGoogle Scholar
  23. 23.
    N. H. G. Holford. “Drugfun,” a modeling procedure available through the PROPHET Data Analysis System, National Institutes of Health, Washington, D.C.Google Scholar
  24. 24.
    H. Akaike. An information criterion (A.I.C.).Math. Sci. 14:5–9 (1976).Google Scholar
  25. 25.
    L. B. Sheiner, R. A. Upton, J.-F. Thiercelin, and S. Riegelman. Intra-individual variability in drug pharmacokinetics and its relevance to bioavailability testing. Submitted toJ. Pharmacokin. Biopharm. Google Scholar
  26. 26.
    R. A. Upton, J.-F. Thiercelin, T. W. Guentert, S. M. Wallace, J. R. Powell, L. Sansom, and S. Riegelman. Intra-individual variability in theophylline pharmacokinetics; statistical verification in 39 of 60 healthy young adults. Submitted toJ. Pharmacokin. Biopharm. Google Scholar

Copyright information

© Plenum Publishing Corporation 1980

Authors and Affiliations

  • Robert A. Upton
    • 1
  • Jean-Francois Thiercelin
    • 1
  • Theodor W. Guentert
    • 1
  • Lloyd Sansom
    • 1
  • J. Robert Powell
    • 1
  • Peter E. Coates
    • 1
  • Sidney Riegelman
    • 1
  1. 1.Department of PharmacyUniversity of CaliforniaSan Francisco

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