Theophylline

Question 1

What are the indications for theophylline?

Answer 1

Traditionally used as a bronchodilator (3rd line now) to help manage COPD, bronchitis, emphysema

Also used in pediatrics for the prevention of apnea or bradycardia

Question 2

What is an average theophylline dosing range?

Answer 2

30-80 micromol/L for adult asthma

Question 3

Why do pharmacists need to conduct TDM on theophylline?

Answer 3

• Narrow TI range
• Good correlation between Cp and response
• Wide interpatient variability in PK
• Possible non-linear PK

Question 4

What are the two main forms of theophylline?

Answer 4

Theophylline (oral) = 100% theophylline
Aminophylline (parenteral)= 80% theophylline

Question 5

What are some oral absorption characteristics of theophylline?

Answer 5

Absorption:
- Well absorbed (high F, F=1)
- Ka can be affected by food and antacids (tmax = 1.4h)

Question 6

Can different sustained-release theophylline formulations be susbstituted for another?

Answer 6

No, there are differences in the release rate of theophylline between the SR formulations

Question 7

What are some distribution characteristics of theophylline?

Answer 7

Considered a two-compartent model drug
Vd:
- Not a very large Vd (0.45L/kg), larger in neonates
- Use IBW when dosing in obese patients
Plasma protein binding:
- NOt highly protein bound (0.4-0.5)
- Changes in fu(b) are usually not clinically significant
Tissue Distribution:
- Delayed distribution to lungs
- Can distribute into the CNS

Question 8

What are some elimination characteristics of theophylline?

Answer 8

• Largely eliminated hepatically (85-90%), particularly by CYP1A2
• Low E drug (fu(b) and Clint are principal determinants)
• In neonates, CYP1A2 enzymes are immature, so 50% is eliminated by the kidneys

Question 9

What is the main enzyme in the liver that metabolizes Theophylline?

Answer 9

CYP1A2

Question 10

What are some CYP1A2 substrates that can either induce or inhibit Cls?

Answer 10

See slide 10

Question 11

What are some physiological or environmental influences on Cls?

Answer 11

• Duration of therapy (Cls can shift over time)
• Age (Cls reduced significantly in neonates and elderly)
• Cirrhosis or CHF (Cls reduced by 40-60%)
• Diet (Cls increases with high protein, low carbs, charbroiled meat)
• Cigarette Smoking (enzyme induction by polyaromatic substances released when organic materials burn)
• Thyroid Disease (reduced in Hypo, increased in hyper)
• Obesity (use IBW)
• CF (increases Cls)
• Infection (Decreases Cls)

Question 12

What are the population PK parameters for Theophylline?

Answer 12

Vd = 0.45l/kg
Cls = 0.04L/h/kg
t1/2= 8 to 9 hours
F = 1

Question 13

Review slides 14 to 16 for individualization of theophylline dosing