Theophylline dosing

I. Introduction

Theophylline was once the cornerstone in the management of both the acute and chronic phases of reversible airway obstruction. However, it has fallen out of favor and is seldom used these days. One reason may be that it has a narrow therapeutic index. Fortunately, theophylline serum levels correlate well with both therapeutic and toxic effects. Concentrations of 10-20 mg/l are needed to produce bronchodilation with a minimum of side effects. Serum levels exceeding 20 mg/l are associated with an unacceptable incidence of adverse reactions. Theophylline levels above 35 mg/l increase the incidence of seizures and cardiac arrythmias.

The clearance of theophylline is affected by many variables which necessitate carefully individualized dosage. Age, smoking, congestive heart failure, other diseases and drug interactions all contribute to a change in the metabolism of theophylline. These factors all necessitate dosage adjustments in order to achieve and maintain therapeutic serum levels and avoid toxicity.

So wide is the variation in clearance rates that no dose which will produce effective levels of theophylline in most patients will fail to produce toxic levels in a few. Serum theophylline measurements are essential for accurate dosage adjustment.

There have been clinical reports suggesting dose-dependent elimination of theophylline in some patients, especially at the higher end of the therapeutic range and most obviously at concentrations greater than 20 mg/l. For these patients, small increases in doses may result in dramatic increases in serum concentrations. Such patients have not been well characterized. Therefore, to minimize the risk of toxicity, doses of theophylline should be increased cautiously, especially at the upper levels of the therapeutic range.

II. Monitoring Parameters

1. An accurate and thorough patient history is essential for proper dosing of theophylline.
   Take special note the following conditions:
   1. Smoking history
   2. Previous theophylline therapy
   3. CHF or other serious cardiac disease
   4. Hepatic disease
   5. Drug interactions: macrolide antibiotics, quinolones, cimetidine.

2. Serum theophylline level monitoring
   
   1. If the patient has taken a theophylline product within the previous 24 hours, obtain a level before administering any IV theophylline.
   2. Monitoring IV theophylline
      Obtain theophylline levels at 1, 7 and 24 hours after initiating IV therapy and every 24 hours while receiving IV theophylline.
   3. Monitoring oral theophylline
      When initiating oral therapy obtain theophylline levels daily until stable.

3. Other monitoring parameters
   1. pulse and blood pressure four times a day
   2. Signs of toxicity daily (nausea, insomnia, etc.)

4. The traditional therapeutic range of theophylline has been 10 to 20 mcg/ml, however there is recent trend to lower the target range to 5 to 15 mcg/ml. This lower target range may be especially suited to outpatients in order to avoid potential toxicity.

III. Precautions

1. Adjust dosage carefully
   Theophylline has a relatively long half-life in certain patient populations (the elderly and CHF patients), consequently it may take several days to reach steady state. Dosage increases should be made with caution. The patient must be followed closely for signs of toxicity.
   

2. Proper serum sampling is important when monitoring oral theophylline. Suggested serum sampling times:
   
   • Rapid release: at least 2 hours post dose.
   • Slow release : at least 4 hours post dose.

3. Factors affecting theophylline elimination
   
   1. Hepatic disease
      Patients with decompensated cirrhosis, acute hepatitis, and, possible, cholestasis have reduced theophylline clearance. A correlation between slow hepatic metabolism and serum albumin and bilirubin concentration has been made in patients with cirrhosis.

   2. Cardiac disease
      Patients with CHF have decreased theophylline clearance due to diminished blood flow to the liver. With treatment of CHF, theophylline clearance increases.

   3. Fever
      Acute illnesses associated with fever have been reported to prolong theophylline half-life. If fever is high and sustained, e.g., >102 for >24 hours, dosage should be reduced.

   4. Diet
      Ingestion of a high protein, low carbohydrate diet accelerates theophylline metabolism presumably by increasing liver enzyme activity. Dietary intake of methylxanthines, caffeine in particular, decreases theophylline metabolism by acting as a substrate for metabolizing enzymes.

   5. Cigarette smoking
      Smoking of cigarettes has a profound effect on theophylline metabolism. There is a dose-related increase in theophylline clearance, with heavy smokers metabolizing theophylline twice as fast as nonsmokers.

   6. Drug interactions are of major clinical importance
      Cimetidine, macrolide antibiotics, and quinolones significantly decrease theophylline metabolism.
      Phenytoin, phenobarbital, and rifampin significantly increase theophylline metabolism.

   7. Age
      Most studies report slower clearance in the elderly.

IV. Program procedure

Before calculating an initial dose or adjusting the maintenance dose the program must know the dosage form, whether the patient is in acute congestive failure and whether any interacting drugs are being concurrently administered.

1. Initial dosing
   The program calculates an ideal loading dose and maintenance dose based on lean body weight and the presence or absence of various factors which affect theophylline metabolism. The user then chooses a practical dose and the program calculates an estimated steady-state serum level.

2. Dosage adjustment based on serum levels
   For IV dosage adjustment, the program utilizes either the linear method or the Chiou method. For oral dosage adjustment, only the linear method may be used. The program checks against population averages to see if the most recent serum level is drawn at steady-state. If the patient is not close to steady-state, the program will utilize the alternate method of dosing which gives more conservative dosage recommendations.

V. Theophylline dosing flow chart

VI. Pharmacokinetic formulas

The theophylline model is not hard-coded into the program. The parameters are found in the drug model database and are fully user-editable. You can tailor each drug model to fit your patient population, or you can create your own models. See the Edit drug models section of the help file for further information.

1. Initial dosing
   
   1. Determine loading dose of IV aminophylline.
      
      • No theophylline within 24 hrs = 6 mg/kg LBW
      • Any theophylline within 24 hrs = 3 mg/kg LBW
      • If theophylline is selected, multiply by 0.8
   2. Determine initial maintenance dose of IV aminophylline, using LBW.
      ko = 0.5 x LBW x Smoking x Age factor x CHF/Liver x Drug factor
      Factors
      • Smoker = 1.5
      • Age > 70 = 0.8
      • Acute CHF or Liver failure = 0.6
      • Interacting drugs = 0.75
      • If theophylline is selected, multiply by 0.8

2. Dosage adjustment before Steady State
   
   1. Chiou Method
      Two serum levels are required, the first level drawn one hour after the constant infusion started, and the second drawn at least one half-life later. The rate of infusion must be constant during the time between the two levels and the patient should not have received any oral theophylline 6 to 12 hours prior to the IV dose.
      
      1. Calculate Clearance (CL)
         CL = [(2 x ko) / (Cp1 + Cp2)] + [(2 x Vd x (Cp1 - Cp2)) / (Cp1 + Cp2) x (t2 -t1)]
         

         where ko = administration rate (mg/hr)
         Cp1 = level (mg/l) drawn 1 hour after start of infusion
         Cp2 = level (mg/l) 6 hours later
         Vd = 0.5 l/kg LBW
         t1 = time Cp1 drawn
         t2 = time Cp2 drawn
         

      2. Calculate Incremental Loading Dose (ILD) OR Temporary Interruption (TI)
         
         • If Cpdes > 1.5 x Cpmeas then calculate Incremental Loading Dose
           ILD = [Cpdes - Cpmeas] x Vd
         • If Cpdes < 0.8 x Cpmeas then calculate Temporary Interruption
           TI = -[ln Cpdes / Cpmeas ] / Ke
      3. Determine new infusion rate (ko')
         ko' = Cpdes x CL
         where ko' = new rate (mg/hr)
         Cpdes= desired level (mg/l)
         CL = clearance (l/hr)
         

   2. Alternate method
      If serum level data does not meet the strict conditions required for the Chiou method, the following general dosage recommendations are made:
      
      • >20 mg/l: Temporary Interruption and decrease infusion rate by 20%.
      • 10-20 mg/l: Continue same.
      • <10 mg/l: Calculate incremental loading dose then increase infusion rate by 20%.

3. Dosage adjustment at Steady State
   
   1. Calculate Clearance (CL)
      CL = ko / Cpss
      where: ko = administration rate (mg/hr)
      Cpss= steady state level (mg/l)
   2. Calculate Incremental Loading Dose (ILD) OR Temporary Interruption (TI)
      -Same as above
   3. Determine new infusion rate (ko')
      -Same as above

4. Converting IV therapy to oral Theo-Dur
   Daily dose = Cpdes x (CL x 24 hr)
   where CL = Clearance (l/hr)
   Cpdes = desired level (mg/l)
   

5. Converting from oral Theo-Dur to IV therapy
   
   1. Calculate Clearance (CL)
      CL = (Daily Dose/24) / Cpss
      where: Daily dose = mg/day of theophylline
      Cpss = steady state level (mg/l)
      
   2. Calculate Incremental Loading Dose (ILD) OR Temporary Interruption (TI)
      -Same as above
      
   3. Determine new infusion rate (ko')
      -Same as above

VII. Bibliography

1. Mitenko P, Ogivie R. Rational intravenous doses of theophylline. N Engl J Med 1973;289:600-603.
2. Lesko LJ. Dose-dependent elimination kinetics of theophylline. Clin Pharmacokinetics 1979;4:449-459.
3. Hendeles L, Weinberger M. Theophylline: a state of the art review. Pharmacotherapy 1983: 3:2-44.
4. Mungall DE, et al. Individualizing theophylline therapy: the impact of a clinical pharmacotherapeutics on patient outcome: Ther Drug Monit 1983; 5:95-101.
5. Iafrate RP, et al. Computer simulated conversion from intravenous to sustained release oral theophylline. DICP 1982;16:19-25.
6. Stein GE, et al. Conversion from intravenous to oral dosing using sustained-release theophylline tablets. DICP 1982;16:772-774.
7. Coleman RW, Hedberg RL. Comparison of three methods for estimating theophylline pharmacokinetics. Clin Pharm 1983;2:148-52.
8. Hatton RC, et al. Conversion from intravenous aminophylline to sustained-release theophylline: computer simulation versus in vivo results. Clin Pharm 1983; 2:347-352.
9. Dunn G, Rybak MJ. Nonlinear theophylline kinetics (letter). DICP 1984;18:155.
10. Johnson MH, Burkle WS. Evaluation of Chiou method for determining theophylline dosages. Clin Pharm 1984; 3:174-8.
11. Hendeles L, et al. Update on pharmacodynamics and pharmacokinetics of theophylline. Chest 1985; 88:10S-111S.
12. Ellis E, Hendeles L. "Theophylline", in Taylor WJ, Caviness MH (eds): A Textbook for the Clinical Application of Therapeutic Drug Monitoring. Irving, Texas. Abbott Laboratories, 1986; pp. 185-201.
13. Hendeles L, et al. "Theophylline" In: Applied Pharmacokinetics, Second Edition. Spokane, WA: Applied Therapeutics, Inc., 1986. pp 1105-1188.
14. Leoni J, Carasiti ME. Practical guidelines for intravenous theophylline dosing. Res Staff Physician 1987;Oct 153-155.
15. Donahue T, et al. Pharmacist-based IV theophylline therapy. Hosp Pharm 1989;24:440-448,460.