THEOPHYLLIN

E
Maria Andriyani P.D - 260220207504

Konsentrasi Biokimia Klinik

Program Studi Farmasi Klinik
Fakultas Farmasi
UNIVERSITAS PADJAJARAN
2021
 INTRODUCTI
ON
Theophylline is a methylxanthine compound that is used for
the treatment of asthma,
chronic obstructive pulmonary disease (COPD; chronic
bronchitis and emphysema), and
premature apnea. Theophylline therapy must be
individualized for each patient in order to achieve optimal
responses and minimal side effects.
 THERAPEUTIC AND
TOXIC
CONCENTRATIONS

THERAPEUTIC TOXIC
RANGES CONCENTRATIONS

• 10–20 μg/mL for the treatment of asthma • (>15 μg/mL) effects include nausea, vomiting,
or COPD dyspepsia, insomnia, nervousness, and headache

• 6–13 μg/mL for the treatment of premature • 20–30 μg/mL sinus tachycardia
apnea • above 40 μg/mL ventricular arrhythmias
• 5–15 μg/mL initial treatment of pulmonary (premature ventricular contractions, ventricular
disease tachycardia or fibrillation) or seizures

• 8–12 μg/mL chronic theophylline therapy • 25 μg/mL seizures caused by theophylline

therapy have been reported to occur in patients at
theophylline concentrations as low as

serum concentration monitoring is

mandatory for patients receiving theophylline.
 CLINICAL MONITORING
PARAMETERS

• Theophylline serum concentration monitoring is mandatory in

patients receiving the drug.
• For dose adjustment purposes, theophylline serum concentrations
should be measured at steady state after the patient has received a
consistent dosage regimen for 3–5 drug half-lives.
• Theophylline half-life varies from 3 to 5 hours in children and
tobacco-smoking individuals to 50 hours or more in patients with
severe heart or liver failure.
 BASIC CLINICAL
PHARMACOKINETIC
PARAMETERS
• Theophylline is primarily eliminated by hepatic metabolism (>90%), mainly via the
CYP1A2 enzyme system with a smaller amount metabolized by CYP3A and CYP2E1.
• About 10% of a theophylline dose is recovered in the urine as unchanged drug.
• Three different forms of theophylline are available.
 Aminophylline : the ethylenediamine salt of theophylline
anhydrous aminophylline contains about 85% theophylline
aminophylline dihydrate contains about 80% theophylline
 Oxtriphylline is the choline salt of theophylline and contains about 65%
theophylline
• The recommended dose of theophylline or one of its salt forms is based on the
concurrent disease states and conditions present in the patient that can influence
theophylline pharmacokinetics.
Disease States and Conditions That
Alter Theophylline
Pharmacokinetics
 Parameter Utama

Konsentrasi Terapeutik 5 - 15 mg/L

Bioavailabilitas (F) 100%
Bentuk garam (S) 1 for theophylline,
S = 0.85 for anhydrous
aminophylline, S = 0.80 for
aminophylline dihydrate,
S = 0.65 for oxtriphylline
Volume Distribusi (V) 0,5 L/kg
Klirens (Cl) 0,04 L/kg/jam
Waktu Paruh (t1/2) 8 jam
fu (fraksi bebas tak terikat dalam 0,6
plasma)
 BIOAVAILABILITAS (F)

•  Oral: Rapid and complete (90 – 100% bioavailability), dosage-form dependent

•  Food does not affect absorption of fast-release products and most sustained-
release products; however, food may induce a sudden release (dose-dumping) of
once-daily sustained release product.
 VOLUME DISTRIBUTION (V)

• (≥ 1 year), adolescents, adults, elderly 0,5 L/kg

• Infants (4 weeks – 1 year) 0.5 – 0.7 L/kg
• Neonates (< 4 weeks) 0.8 L/kg
• Fibrosis sistik 0,6 L/kg
 KLIRENS (Cl)

• Klirens teofilin rerata adalah 0,04 L/kg/jam, didasarkan pada berat badan tanpa
lemak atau berat badan ideal.
• Faktor klinis yang memengaruhi kirens teofilin, yaitu :
• Obesitas
• Merokok
• Penyakit
• Diet/ Makanan
• Interaksi Obat
 HALF-LIFE (T1/2)

• The half-life for theophylline depends on age and renal function.

• Half-life for normal adults without disease states/conditions with normal liver
function: 8 hours (range: 6 – 12 hours)
 Study Case 1

LK is a 50-year-old, 75-kg (5 ft 10 in) male with chronic bronchitis who requires therapy with oral theophylline. He currently smokes 2
packs of cigarettes daily, and has normal liver and cardiac function. Suggest an initial theophylline dosage regimen
designed to achieve a steady-state theophylline concentration equal to 8 μg/mL. (Note: μg/mL = mg/L and this concentration unit was
substituted for Css in the calculations so that unnecessary unit conversion was not required.)

1. Estimate half-life and elimination rate constant according to disease states and conditions
present in the patient.
Cigarette smoke induces the enzyme systems responsible for theophylline metabolism,
and the expected theophylline half-life (t1/2) is 5 hours. The elimination rate constant is
computed using the following formula:

k = 0.693= 0.693 = 0.139 h−1

t1/2 5 h
 Study Case 1
2. Estimate volume of distribution and clearance The patient is not obese, so the estimated theophylline volume of distribution will be
based on actual body weight: V = 0.5 L/kg.75 kg = 38 L.
Estimated theophylline clearance is computed by taking the product of the volume of distribution and the elimination rate constant:

Cl = kV = 0.139 h−1 . 38 L = 5.28 L/h.

3. Compute dosage regimen.

Oral sustained-release theophylline tablets will be prescribed to this patient (F = 1, S = 1). Because the patient has a rapid theophylline
clearance and short half-life, the initial dosage interval (τ) will be set to 8 hours. (Note: μg/mL = mg/L and this concentration unit
was substituted or Css in the calculations so that unnecessary unit conversion was not required.) The dosage equation for oral
theophylline is:

D = (Css ⋅ Cl ⋅ τ) = (8 mg/L ⋅ 5.28 L/h ⋅ 8h) = 338 mg, rounded to 300 every 8 hours.
(F ⋅ S) (1 ⋅ 1)

A steady-state trough theophylline serum concentration should be measured after steady state is attained in 3–5 half-lives. Since the
patient is expected to have a half-life equal to 5 hours, the theophylline steady-state concentration could be obtained anytime after
the first day of dosing (5 half-lives = 5.5 h = 25 h).
 Study Case 2

OI is a 60-year-old, 85-kg (6 ft 1 in) male with emphysema who requires therapy with oral theophylline. He has liver cirrhosis (Child-
Pugh score = 11) and normal cardiac function. Suggest an initial theophylline dosage regimen designed to achieve a
steady-state theophylline concentration equal to 10 μg/mL.

1. Estimate half-life and elimination rate constant according to disease states and conditions present in the patient.
Patients with severe liver disease have highly variable theophylline pharmacokinetics and dosage requirements. Hepatic disease destroys
liver parenchyma where hepatic drug–metabolizing enzymes are contained, and the expected theophylline half-life (t1/2) is 24
hours. The elimination rate constant is computed using the following formula:

k = 0.693= 0.693 = 0.029 h−1

t1/2 24 h
 Study Case 2
2. Estimate volume of distribution and clearance. The patient is not obese, so the estimated theophylline volume of distribution will be
based on actual body weight: V = 0.5 L/kg ⋅ 85 kg = 43 L. Estimated theophylline clearance is computed by taking the product of
the volume of distribution and the elimination rate constant:

Cl = kV = 0.029 h−1 .43 L = 1.25 L/h.

3. Compute dosage regimen.

Oral sustained-release theophylline tablets will be prescribed to this patient (F = 1, S = 1). The initial dosage interval (τ) will be set to 12
hours. (Note: μg/mL = mg/L and this concentration unit was substituted for Css in the calculations so that unnecessary unit
conversion was not required.) The dosage equation for oral theophylline is

D = (Css ⋅ Cl ⋅ τ) = (10 mg/L ⋅ 1.25 L/h ⋅ 12h) = 150 mg, every 12 hours.
(F ⋅ S) (1 ⋅ 1)

A steady-state trough theophylline serum concentration should be measured after steady state is attained in 3–5 half-lives. Since the
patient is expected to have a half-life equal to 24 hours, the theophylline steady-state concentration could be obtained anytime after
the fifth day of dosing (5 half-lives = 5 ⋅ 24 h = 120 h or 5 days).
 Study Case 3
OI is a 60-year-old, 85-kg (6 ft 1 in) male with emphysema who is receiving a 20 mg/h continuous infusion of theophylline. He has liver
cirrhosis (Child- Pugh score = 11) and normal cardiac function. The current steady-state theophylline concentration equals 15
μg/mL, and he is experiencing some minor caffeine-type adverse effects (insomnia, jitteriness, nausea). Compute a theophylline
dose that will provide a steady-state concentration of 10 μg/mL.

1. Compute new dose to achieve desired serum concentration. The patient has severe liver disease and would be expected to achieve
steady-state conditions after 5 days (5 t1/2 = 5 ⋅ 24 h = 120 h or 5 d) of therapy. Using linear pharmacokinetics, the new infusion
rate to attain the desired concentration should be proportional to the old infusion rate that produced the measured concentration:

Dnew = (Css,new/Css,old)Dold = (10 μg/mL / 15 μg/mL) 20 mg/h = 13 mg/h, round to 15 mg/h

The new suggested dose would be 15 mg/h of theophylline as a continuous infusion. If necessary, the infusion could be temporarily
stopped for 12–24 hours until theophylline adverse effects subsided. A steady-state trough theophylline serum concentration should
be measured after steady state is attained in 3–5 half-lives.
Since the patient is expected to have a half-life equal to 24 hours, the theophylline steady-state concentration could be obtained anytime
after the fifth day of dosing (5 half-lives = 5 ⋅ 24 h = 120 h or 5 d).
 Study Case 4
YU is a 64-year-old, 80-kg (5 ft 9 in) male with COPD who smokes 11/2 packs of cigarettes per day. He is started on a 40-mg/h
theophylline infusion after being administered an intravenous loading dose at 0900 H. The theophylline concentration was 11.6
μg/mL at 1000 H and 8.1 μg/mL at 1600 H. What theophylline infusion rate is needed to achieve Css = 10 μg/mL?

1. Compute theophylline clearance and dose.

(Note: μg/mL = mg/L and this concentration unit was substituted for concentrations so that unnecessary unit conversion was not required.
Additionally, the time difference between t2 and t1 was determined and placed directly in the calculation.)

k0 = (Css ⋅ Cl)/S = (10 mg/L ⋅ 6.43 L/h) / 1 = 64 mg/h, round to 65 mg/h of theophylline
 THANKS

Bauer L.A. 2008. Applied Clinical Pharmakokinetics, 2nd Ed., McGraw-Hill Companies, Inc. USA.
Winter M. 2004. Basic Clinical Pharmakokinetics, 5th Ed., Lippincott William & Wilkins, USA.