Clinical pharmacokinetic of theophylline

Lecturer Nin PrapongsenaHuachiew Chalermprakiet University

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

Introduction

Theophylline

Mechanism of Action1. Bronchodilator

Therapeutic range 11 – 20 mg/L

2. Anti-inflammation

Mechanism of Action

Therapeutic range 5 – 10 mg/L

Toxicities of theophylline

Plasma theophyllin

e concentrat

ion (mg/L)

ADR Severity

> 10 or IV infusion rate > 20 mg/min

- Nausea- Insomnia- Nervousness- Headache

Minor

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

การเจาะเลื�อดเพื่��อวั�ดระด�บยา1.Peak concentration level (Cpeak)

concern distribution phase2.Trough concentration level (Ctrough)

just before next dose

8

Slow release

Sampling time

Rapid release

Sampling ≥ 2h post dose Sampling ≥ 4h post dose

AbsorptionDistributionMetabolism

Excretion

AbsorptionSalt 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

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

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 CalculationVd(L) = 0.5 x actual body weight

If obese

Metabolism

• CYP 1A2 (53%)

• CYP 2E1 or CYP3A4 (40%)

• CYP 2C9 or CYP 2D6 (7%)

Please !!! Concerned drug interaction

Excretion

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

Clearance of theophylline

Age Half life (h)

Vd (L/kg

)

CL (L/h/k

g)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

CLpop = CL* [ABW or IBW(obesity)] * Disease factors

Clearance of theophylline

Adjusment factor for CLtheophylline = 0.75

Drug interaction

2) CLpop calculation• ผู้��ป่�วัยชาย อาย� 19 ป่� น้ำ��าหน้ำ�กตั�วั 100 kg สู�ง 165

cm ป่�วัยเป่ น้ำ โรค cirrhosis แลืะ COPD class A ป่$จจ�บ�น้ำผู้��ป่�วัยย�งคงสู�บบ�หร%� 14 มวัน้ำ/ วั�น้ำ ซึ่(�งขณะน้ำ%�

ผู้��ป่�วัยก�าลื�งได�ร�บยา theophylline อย�,

Question? จงหา CL ของยา theophylline ในผู้�� ป่�วยรายน��

CLpop(L/h) = 0.039*IBW*0.5*1.6

3) Chiou method for CL calculation

***โดยเง��อน้ำไขพื่-เศษของ Chiou method ค�อ 1 .ระด�บ theophylline ใน้ำกระแสูเลื�อดที่%�วั�ด ณ 2 จ�ดเวัลืา ควัรห,างก�น้ำไม,เก-น้ำ

4-6 ช��วัโมง ใน้ำขณะที่%�ให� IV infusion2. วั-ธี%การบร-หารยาด�งกลื,าวัจะให�แก,ผู้��ป่�วัยได�ก4ตั,อเม��อผู้��ป่�วัยได�ร�บ theophylline แลื�วัไม,น้ำ�อยกวั,า 12- 16 ช��วัโมง***

ใช้�เพื่��อป่ร�บขนาดยาก่�อนถึ�ง steady state

4) Loading dose (LD) calculation

Initial: Loading dose (LD) = Css Vd∙

LD = (Cp(target)-Cp(current)) Vd∙

Incremental Loading Dose

5) Maintenance dose (MD) calculation

R0 = K0 = Rate for infusion

6) Cmax & Cmin calculation (steady state)

IV bolus model

ใน้ำกรณ%ที่%�ยาเข�า steady state แลื�วั แตั,เราที่ราบแตั, Cmin เราจะหา Cmax ได�อย,างไรAnswer: Method of requiring single concentration (Ctrough,ss)

Method of requiring single concentration (Ctrough,ss)

Conc.(mg/L)

Time(h)

Cmin,ss

(measure)

Cmax,ss (calculate

)

tin

ƬƬ-tin

24

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-Ktin)]

+Cmin,ss

Theophylline dosing flow chart

Theophylline dosing flow chart (continue)

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.

•   สู�เพื่4ญพื่ร อ�กษรวังศ6 แลืะคณะ.  ก่ารใช้� theophylline dosage program ทำ านาย และป่ร�บขนาดยาให�ผู้��ป่�วยทำ��มี�โรคแทำรก่ซ้�อน |  น(พื่นธ์*ต้�นฉบ�บ : ก่ารบร(บาล

ทำางเภสั�ช้ก่รรมี. Group of Thai Aseptic Dispenasry and Pharmaceutical care Pharmacists Association of Hospital Pharmacy Community of Practice. 2006

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 bloodsamples 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.