Clinical Pharmacokinetic of thenophylline

1. Clinical pharmacokinetic of
theophylline
Lecturer Nin Prapongsena
Huachiew Chalermprakiet University

2. Objective
• Student could apply clinical pharmacokinetic
of theophylline in ambulatory care and acute
care.
– Predicted theophylline plasma concentration
– Evaluated toxicities of theophylline and solved
problems
– Adjusted theophylline dose
– Prepared theophylline injection and co-operated
with nurse

3. Introduction
Theophylline

4. Mechanism of Action
1. Bronchodilator
Therapeutic range 11 – 20 mg/L

5. 2. Anti-inflammation
Mechanism of Action
Therapeutic range 5 – 10 mg/L

6. Toxicities of theophylline
Plasma theophylline
concentration
(mg/L)
ADR Severity
> 10 or
IV infusion rate > 20
mg/min
- Nausea
- Insomnia
- Nervousness
- Headache
Minor

7. Plasma theophylline
concentration (mg/L)
ADR Severity
> 20
- Nausea/vomiting
- Insomnia
- Diarrhea
- Irritability
- Headache
- Tremor
- Tachycardia
Serious
> 35
- Hyper K+ - Hyperglycemia
- Hypotension - Hyperthermia
- Arrythmia
- Respiratory arrest
- Cerebral hypoxia
- Brain injury
- Seizure
Life threatening

8. การเจาะเลือดเพื่อวัดระดับยา
1.Peak concentration level (Cpeak)
concern distribution phase
2.Trough concentration level (Ctrough)
just before next dose
8

9. Slow release
Sampling time
Rapid release
Sampling ≥ 2h post doseSampling ≥ 4h post dose

10. Absorption
Distribution
Metabolism
Excretion

11. Absorption
Salt factor Anhydrous theophylline content
Aminophylline anhydrous 85-86%
Aminophylline hydrous 79-80%
Theophylline monohydrate 91%
Choline theophyllinate 64-65%
Dosage form Bioavailability (F)
IV 1.0
Tablets & capsules (immediated
release)
1.0
Tablets & capsules (extended
release)
0.9-1.0

12. Distribution
•Distributed in to fat-free tissues and body fluid
(Vd = 0.5 L/kg)
•Freely across: Breast milk, cerebrospinal fluid,
placenta, saliva,
•Protein binding 40-60% (especially albumin)
Note: Protein binding decrease in
- lower pH 0.1 = decrease binding 4%
- rises body temperature

13. Vd(L) = 0.5 x IBW* + 0.4 (TBW* - IBW)
Adjusted Body Weight = IBW + [CF x (TBW - IBW)]
. . . where CF = correction factor (usually 20 to 40%)
. . . where WT = patient's total weight
Use when IBW < 30% of actual body weight
1) Vd Calculation
Vd(L) = 0.5 x actual body weight
If obese

14. Metabolism
• CYP 1A2 (53%)
• CYP 2E1 or CYP3A4 (40%)
• CYP 2C9 or CYP 2D6 (7%)
Please !!! Concerned drug interaction

15. Excretion
• Influencing factors of theophylline clearance
– Age
– Smoking
– Hepatic disease
– CHF
– Obesity
– COPD
– Cystic fibrosis
– Infection

16. Clearance of theophylline
Age Half life (h) Vd (L/kg) CL (L/h/kg)
Children (1-9y) 3.5
0.5 L/kg
0.102
Adult (16-65) 8 (6-12) 0.039
Eldery (>65 y) 12 0.025
CLpop = CL* [ABW or IBW(obesity)] * Disease factors

17. CLpop = CL* [ABW or IBW(obesity)] * Disease factors
Clearance of theophylline

18. Adjusment factor for CLtheophylline = 0.75
Drug interaction

19. 2) CLpop calculation
• ผู้ป่วยชาย อายุ 19 ปี น้าหนักตัว 100 kg สูง 165 cm ป่วยเป็น
โรค cirrhosis และ COPD class A ปัจจุบันผู้ป่วยยังคงสูบบุหรี่
14 มวน/วัน ซึ่งขณะนี้ผู้ป่วยกาลังได้รับยา theophylline อยู่
Question? จงหา CL ของยา theophylline ในผู้ป่วยรายนี้
CLpop(L/h) = 0.039*IBW*0.5*1.6

20. 3) Chiou method for CL calculation
***โดยเงื่อนไขพิเศษของ Chiou method คือ
1. ระดับ theophylline ในกระแสเลือดที่วัด ณ 2 จุดเวลา ควรห่างกันไม่เกิน 4-6 ชั่วโมง ในขณะที่ให้
IV infusion
2. วิธีการบริหารยาดังกล่าวจะให้แก่ผู้ป่วยได้ก็ต่อเมื่อผู้ป่วยได้รับ theophylline แล้วไม่น้อยกว่า 12-
16 ชั่วโมง***
ใช้เพื่อปรับขนาดยาก่อนถึง steady state

21. 4) Loading dose (LD) calculation
Initial: Loading dose (LD) = Css ∙ Vd
LD = (Cp(target)-Cp(current)) ∙ Vd
Incremental Loading Dose

22. 5) Maintenance dose (MD) calculation
R0 = K0 = Rate for infusion

23. 6) Cmax & Cmin calculation (steady state)
IV bolus model
ในกรณีที่ยาเข้า steady state แล้ว แต่เราทราบแต่ Cmin เราจะหา Cmax ได้อย่างไร
Answer:
Method of requiring single concentration (Ctrough,ss)

24. Method of requiring single concentration
(Ctrough,ss)
Conc.(mg/L)
Time
(h)
Cmin,ss
(measure)
Cmax,ss
(calculate)
tin
Ƭ
Ƭ-tin
24

25. Method of requiring single
concentration (Ctrough,ss)
Conc.(mg/L)
Time
(h)
tin Ƭ-tin
Ƭ
Cmax,ss = (SFD/Vd)+Cmin,ss
Cmax,ss = (SFD/Cltin)[(1/(1-e-Kt
in)]+Cmin,ss

26. Theophylline dosing flow chart

27. Theophylline dosing flow chart (continue)

28. References
• John E. Murphy. Clinical pharmacokinetics. Bethesda, Maryland :
American Society of Health-System Pharmacists, c2008.
• John E. Murphy. Clinical pharmacokinetics : pocket reference.
Bethesda, Md: American Society of Health-System Pharmacists,
c2001.
• Soraya Dhillon, and Andrzej Kostrzewski. Clinical pharmacokinetics.
London : Pharmaceutical Press, c2006.
• Elliott P, et al. Clinical pharmacokinetics: A Simplified Approach, Part
2. JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 78,
NO. 9,1986.
• สุเพ็ญพร อักษรวงศ์ และคณะ. การใช้ theophylline dosage program ทานายและ
ปรับขนาดยาให้ผู้ป่วยที่มีโรคแทรกซ้อน | นิพนธ์ต้นฉบับ : การบริบาลทางเภสัชกรรม.
Group of Thai Aseptic Dispenasry and Pharmaceutical care
Pharmacists Association of Hospital Pharmacy Community of
Practice. 2006

29. Homework 1
A 42-year-old non-smoker man with a total body weight of 78 kg (180 cm)was
admitted to Hospital complaining of shortness of breath. The diagnosis was
asthma. The physician wanted to start the treatment with theophylline as
soon as possible hence sought your advice. The patient has not been taking
theophylline before. You recommended a 450 mg loading dose of
aminophylline to be injected slowly over 30 minutes followed by a
maintenance dose of 40 mg/h of aminophylline. You also asked for two blood
samples 1 and 5 h after the start of the maintenance dose. The lab results
indicated serum theophylline concentrations of 6.5 and 7.2 for samples
taken 1 and 5 post-dose h, respectively.
1. Comment on the appropriateness of the recommended dose.
2. Estimate the upcoming theophylline steady-state concentration.
3. Recommend an appropriate dose if a target concentration of 12 ug/mL is
desired.