Evaluation of theophylline therapeutic drug monitoring service

Neža Rugelj; Katja Čvan Trobec; Mitja Pišlar; Pika Meško Brguljan; Mitja Košnik; Aleš Mrhar

doi:10.6016/ZdravVestn.1174

Neža Rugelj Faculty of Pharmacy, University of Ljubljana
Katja Čvan Trobec University Clinic of Respiratory and Allergic Diseases Golnik
Mitja Pišlar Faculty of Pharmacy, University of Ljubljana
Pika Meško Brguljan University Clinic of Respiratory and Allergic Diseases Golnik
Mitja Košnik University Clinic of Respiratory and Allergic Diseases Golnik
Aleš Mrhar Faculty of Pharmacy, University of Ljubljana

DOI: https://doi.org/10.6016/ZdravVestn.1174

Keywords: theophylline pharmacokinetic, narrow therapeutic range, serum levels measurements, individualized dosage schedule

Abstract

Background

Therapeutic monitoring of theophylline serum levels is required due to its narrow therapeutic range and marked interindividual pharmacokinetic variability. We evaluated therapeutic drug monitoring service for theophylline in Slovenian clinical setting, which currently includes no pharmacokinetic evaluation of measured theophylline serum concentrations.

Methods

We retrospectively evaluated 127 randomly selected theophylline serum level determinations performed in 2010 in a tertiary clinical setting in Slovenia. Demographic data, information on theophylline dosing and blood sampling was collected from patients’ data files. Authors evaluated the appropriateness of the following procedures: indications for theophylline serum concentration measurement, timing of blood sampling and dosage adjustments made after theophylline levels had been reported. On the basis of collected data, population pharmacokinetic model for theophylline was built and further used for the evaluation of dosage adjustments.

Results

Out of 127 cases, 107 (84.3%) had clinically justified indication for theophylline serum level measurement. Near half of measurements (44.9%) were performed before the steady state of theophylline concentrations was established. 65% of measured concentrations were subtherapeutic and the average measured concentration was below therapeutic range (53.1 μmol/L). Despite subtherapeutic concentrations the dose of theophylline was mainly not increased. Pharmacokinetic model enabled the calculation of average optimal daily dose which was significantly higher than the average actual daily dose used (876 mg vs. 572 mg, p < 0.001).

ConclusionsTheophylline TDM service should be optimized and pharmacokinetic interpretation of theophylline serum levels should be integrated into clinical practice.

Downloads

Download data is not yet available.

Author Biographies

Neža Rugelj, Faculty of Pharmacy, University of Ljubljana

MPharm

Katja Čvan Trobec, University Clinic of Respiratory and Allergic Diseases Golnik

PhD, MPharm

Mitja Pišlar, Faculty of Pharmacy, University of Ljubljana

MPharm

Pika Meško Brguljan, University Clinic of Respiratory and Allergic Diseases Golnik

BSc in Chemistry, PhD, specialist in medical biochemistry

Mitja Košnik, University Clinic of Respiratory and Allergic Diseases Golnik

MD, PhD

Aleš Mrhar, Faculty of Pharmacy, University of Ljubljana

PhD, MPharm

References

Touw D, Neef C, Thomson A, Vinks A. Cost-effectiveness of therapeutic drug monitoring: a systematic review. Ther Drug Monit 2005; (27): 10-7.

Jaquenoud Sirot E, van der Velden J, Rentsch K, Eap C, Bauman P. Therapeutic drug monitoring and pharmacogenetic test as tool in pharmcovigilance. Drug Saf 2006; 29(9): 735-68.

Jellife R. Some comments and suggestions concerning population pharmacokinetic modeling, especially of digoxin, and its relation to clinical therapy. Ther Drug Monit 2012; 34(4): 368-77.

El Deskoy E, Meinshausen J, Buhl K, Engel G, Harings-Kaim A, Drewelow B, et al.. Generation of pharmacokinetic data during routine therapeutic drug monitoring: Bayesian approach vs. pharmacokinetic studies. Ther Drug Monit 1993; 15(4): 281-8.

Kang J, Lee M. Overview of therapeutic drug monitoring. Korean J Intern Med 2009; 24(1): 1-10.

Gross A. Best practice in therapeutic drug monitoring. Br J Clin Pharmacol 2001; 52: 5-10.

Halloworth M, Watson I. Therapeutic drug monitoring and laboratory medicine; 2008.

Touv D, Neef C, Thomson A, Vinks A. Cost-effectiveness of therapeutic drug monitoring: an update. Ther Drug Monit 2005; 27(1): 10-7.

Global initiative for chronic obstructive pulmonary disease. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease. December 2011. Dosegljivo 1.12.2012 s spletne strani: www.goldcopd.com

Method Sheet Theo 2, Roche Diagnostics.

Cosio B, Iglesias A, Rios A, Noguera A, Sala E, Ho K, et al.. Low-dose theophylline enhances the anti-inflammatory effects of steroids during exacerbations of COPD. Thorax 2009; 64(5): 424-9.

Ford P, Durham A, Russel R, Gordon F, Adcock I, Barnes P. Treatment effects of low-dose theophylline combined with an inhaled corticosteroid in COPD. Chest 2010; 137(6): 1338-44.

Culpitt S, de Matos C, Russel R, Donnelly L, Rogers D, Barnes P. Effects of theophylline on induced sputum inflammatory indices and neutrophil chemotaxis in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002; 165: 1371-6.

Johnston I. Difficult drugs to use, few clinical indications. Br Med J. 1990; 300.

Affolter N, Krahenbuhl S, Schlienger R. Appropriateness of serum level determinations of antiepileptic drugs. Swiss Med Wkly 2003; 133: 591-7.

Mordasini M, Krähenbühl S, Schlienger R. Appropriatness of digoxin level monitoring. Swiss Med Wkly 2002; 132: 506-12.

Ratanajamit C, Soorpan S, Doang-ngern T, Waenwaisart W, Suwanchavalit L, Suwansiri S, et al.. Appropriateness of therapeutic drug monitoring for lithium. J Med Assoc Thai 2006; 89(11): 1954-60.

Sharma S, Joshi S, Mukherji S, Bala K, Tripathi C. Therapeutic drug monitoring: appropriateness and clinical utility in neuropsychiatry practice. Am J Ther 2009; 16(1): 11-6.

Irshaid Y, Hamdi A, Al Homrany M. Evaluation of therapeutic drug monitoring of antiepileptic drugs. Int J Clin Pharmacol Ther 2003; 41(3): 126-31.

Babaei A, Eslamai M. Evaluation of therapeutic drug level monitoring of phenobarbital, phenytoin and carbamazepine in Iranian epileptic patients. Int J Clin Pharmacol Ther 2007; 45(2): 121-5.

Urbaniak G, Plous S. Research Randomizer (version3.0), Computer software. 2011. Dosegljivo 23.3.2012 s spletne strani: www.randomizer.org

Beal S, Sheiner LB, Boechmann A, Bauer RJ. NONMEM User's Guides. Icon Development Solutions. Ellicott City, MD; 2011.

Mušič E, Paulin A, Šuškovič S. Clinical study of Theotard capsules. 1986.

Jonsson E, Karlsson M. Automated covariate model building with NONMEM. Pharm Res 1998; 15: 1463-8.

Hallynck T, Soep H, Thomis JA, Boelaert J, Daneels R, Dettli L. Should clearance be normalised to body surface or to lean body mass? Clin Pharmacol 1981; 11: p. 523-6.

James W. Research on obesity. London; 1976.

Mosteller R. Simplified calculation of body surface area. N Engl J Med 1987; 317(17): 1098.

Trepanier E, Nafziger A, Amsden G. Effect of terbinafine on theophylline pharmacokinetics in healthy volunteers. Antimicrob Agents Chemother 1998; 42(3): 695-7.

Tanigawara Y, Komada F, Shimizu T, Iwakawa S, Iwai T, Maekawa H, et al.. Population pharmacokinetics of theophylline. III. Premarketing study for a once-daily administered preparation. Biol Pharm Bull 1995; 18(11): 1590-8.

Yano I, Tanigawara Y, Yasuhara M, Okumura K, Kawakatsu K, Hori R. Population pharmacokinetics of theophylline. II: Intravenous infusion to patients with stable chronic airway obstruction. Biol Pharm Bull 1993; 16(5): 501-5.

Antal E, Kramer P, Merick S, Chapron D, Lawson I. Theophylline pharmacokinetics in advanced age. Br J Clin Pharmacol 1981; 12(5): 637-45.

Steinijans V, Eicke R, Ahrens J. Pharmacokinetics of theophylline in patients following short-term intravenous infusion. Eur J Clin Pharmacol 1982; 22(5): 417-22.

Qiu F, Wang G, Zhao Y, Sun H, Mao G, Sun J. Effect of danshen extract on pharmacokinetics of theophylline in healthy volunteers. Br J Clin Pharmacol 2008; 65(2): 270-4.

Kinzig-Schippers M, Fuhr U, Cesana M, Müller C, Staib A, Rietbrock S, et al. Absence of effect of rufloxacin on theophylline pharacokinetics in steady state. Antimicrob Agents Chemother 1998; 42(9): 2359-64.

McKay S, Howie C, Thomson A, Whiting B, Addis G. Value of theophylline treatment in patients handicapped by chronic obstructive pulmonary disease. Thorax 1993; 48: 227-32.

Milavetz G, Vaughan L, Weinberger M, Harris J, Mullenix T. Relationship between rate and extent of absorption of oral theophylline from Uniphyl brand of slow-release theophylline and resulting serum concentrations during multiple dosing. J Allergy Clin Immunol 1987; 80(5): 723-9.

Lagas M, Jonkman J. Influence of food on the rate and extent of absorption of theophylline after single dose oral administration of a controlled release tablet. Int J Clin Pharmacol Ther Toxicol 1985; 23(8): 424-6.