Clinical Pharmacokinetics

THEOPHYLLIN
KELAS A/KELOMPOK 12

AYU ANDARINI (1511014017)

ARINI INTAN MUTIA (1511014018)
BEBA SHIAMI (1511014019)
MARHANI DWITHANIA (1511014020)
SITI SARI K. (1511014021)
 INTRODUCTION
Theophyllin is a drug of the metylxanthin group used
for the asma treatment, chronic obstructive
pulmonary, and apnea premature. The primary key
of the disease is broncospasm. Theophyllin use has
different profiles for everyone, although some
people exhibit mixed disease with reversible airway
component. Theophyllin is now regarded as
adjunctive therapy, since asthmais also considered
an inflammatory disease that can be treat with
corticosteroid.

Baur, 2008 : 745

 THEURAPETIC AND TOXIC
CONCENTRATION
• Treatment asthma : 10-20 µg/ml
• Premature apnea : 6-13 µg/ml
• Pulmonary disease : 5- 15 µg/ml ( suggest of
guideline)
upper end of the theurapetic range (>15 µg/ml) some
patient will experience the side effect (nausea,
vommiting, dyspepsia, insomnia, nervousness and
headache)
Concentration 20-30 µg/ml : tachiarrythmia
Concentration >40 µg/ml : ventricular arrythmias
(Baur, 2008 : 746)
 PARAMETER CLINICAL MONITORING
• Measurment pulmonary function test
• Forced expiratory volume 1 second
• Peak- flow meter
• Spirometric test
• Clinical signs and symptoms ( dyspneas,
coughing,wheezing, impairmant in normal
activity)

(Baur, 2008 : 746- 747)

 BASIC CLINICAL PHARMACOKINETIC
PARAMETERS
• Primarily eliminated by hepatic metabolism
(>90%)
• Hepatic metabolism is 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

(Bauer, 2008 : 748-749)

• There’s 3 different forms of theophylline
• Aminophylline is the ethylenediamine salt of
theophylline, and anhydrous aminophylline
contains about 85% theophylline while
aminophylline dihydrate contains about 80%
theophylline (oral and IV injection use)
• Oxtriphylline is the choline salt of theophylline
and contains about 65% theophylline (only
oral use)

(Bauer, 2008 : 749)

• The oral bioavailability of all three
theophylline-based drugs is very good and
generally equals 100%
• Theophylline plasma protein binding is only
40%
• Theophylline serum concentrations increase in
a patient more than expected after a dosage
increase for an unidentifiable reason (Non
Linear Pharmacokinetics)

(Bauer, 2008 : 749)

 EFFECTS OF DISEASE STATES AND CONDITIONS ON
THEOPHYLLINE PHARMACOKINETICS AND DOSING
• Most disease states and conditions that
change theophylline pharmacokinetics and
dosage requirements alter clearance but
volume of distribution remains stable at ~0.5
L/kg
• Tobacco and marijuana smoke causes
induction of hepatic CYP1A2 which accelerates
the clearance of theophylline (people who
smoke these has t 1/2 is 5 hr)

(Bauer, 2008 : 749)

• Patients with liver cirrhosis or acute hepatitis have
reduced theophylline clearance which results in a
prolonged average theophylline half-life of 24 hours

(Bauer, 2008 : 750)

(Bauer, 2008 : 750)
(Bauer, 2008 : 751)
(Bauer, 2008 : 751)
• Heart failure causes reduced theophylline clearance because
of decreased hepatic blood flow secondary to compromised
cardiac output
• Venous stasis of blood within the liver may also contribute to
the decrease in theophylline clearance found in heart failure
patients
• Patients with mild heart failure (New York Heart Association
or NYHA Class I or II) have an average theophylline half-life
equal to 12 hours (range: 5–24 hours) while those with
moderate to severe heart failure (NYHA class III or IV) or cor
pulmonale have an average theophylline half-life of 24 hours
(5–50 hours)

(Bauer, 2008 : 752)

(Bauer, 2008 : 752)
• Premature neonates have average theophylline half-
lives equal to 30 hours 3–15 days after birth and 20
hours 25–57 days after birth
• Newborns have decreased theophylline clearance
• Children (1–9 y.o) have accelerated theophylline
clearance rates resulting in an average half-life of 3.5
hours (range: 1.5–5 hours)
• The breast milk to serum ratio for theophylline is 0.7

(Bauer, 2008 : 753)

 DRUG INTERACTIONS
• Serious inhibition drug interactions are those that decrease theophylline Cl more
than 30%.
• Clinicians should consider an arbitrary decrease in theophylline dose of 30–50%
for patients receiving these agents until the actual degree of hepatic enzyme
inhibition can be assessed using theophylline serum concentration monitoring.
• Cimetidine given at higher doses (≥1000 mg/d) on a multiple daily dosage
schedule decreases theophylline Cl by 30–50%.
Other cimetidine doses (≤800 mg/d) given once or twice daily decrease
theophylline clearance by 20% or less.
• Ciprofloxacin and enoxacin, both quinolone antibiotics, and troleandomycin, a
macrolide antibiotic, also decrease theophylline Cl by 30–50%.
• Estrogen and estrogen-containing oral contraceptives, propranolol, metoprolol,
mexiletine, propafenone, pentoxifylline, ticlopidine, tacrine, thiabendazole,
disulfiram, nefazodone, interferon, zileuton, and fluvoxamine can also decrease
theophylline Cl by this extent.

(Bauer, 2008 : 753-754)

• many clinicians believe that a routine decrease in
theophylline dose is unnecessary for patients with Css
theophylline below 15 μg/mL, but should be considered
on a case-by-case basis for those with concentrations
above this level. Should a decrease be warranted in a
patient, theophylline doses can be cut by 20% to avoid
adverse effects.
• Patients should be actively monitored for the signs and
symptoms of theophylline toxicity.
• The CCB, verapamil, and diltiazem, have been reported to
cause decreases in theophylline Cl by 15–25%.
• Clarithromycin and erythromycin, both macrolide
antibiotics, and norfloxacin, a quinolone antibiotic, can
also decrease theophylline Cl by this magnitude. At doses
of 600 mg/d or above, allopurinol has been reported to
decrease theophylline clearance by 25%.

(Bauer, 2008 : 754)

 INITIAL DOSAGE DETERMINATION
METHODS
• Pharmacokinetic Dosing Method
The goal of initial dosing of theophylline is to compute the best
dose possible for the patient given their set of disease states and
conditions that influence theophylline pharmacokinetics and the
pulmonary disorder being treated

• HALF-LIFE AND ELIMINATION RATE CONSTANT ESTIMATE

Theophylline is predominately metabolized by liver.
Unfortunately, there is no good way to estimate the elimination
characteristics of liver metabolized drugs using an endogenous marker of
liver function in the same manner that serum creatinine and estimated
creatinine clearance are used to estimate the elimination of agents that
are renally eliminated. Because of this, a patient is categorized according
to the disease states and conditions that are known to change
theophylline t1/2, and the t1/2 previously measured in these studies is
used as an estimate of the current patient’s t1/2

(Bauer, 2008 : 755)

• VOLUME OF DISTRIBUTION ESTIMATE
Theophylline Vd is relatively stable in patients regardless of the
disease states and conditions that are present. Vd is assumed to equal
0.5 L/kg for nonobese patients.
For obese patients (>30% above ideal body weight), ideal body weight
is used to compute theophylline volume of distribution
• SELECTION OF APPROPRIATE PHARMACOKINETIC MODEL AND
EQUATIONS
When given by continuous iv infusion or orally, theophylline
follows a onecompartment pharmacokinetic model (Figures 18-1, 18-3,
18-4). When oral therapy is required, most clinicians utilize a
sustained-release dosage form that has good bioavailability (F = 1),
supplies a continuous release of theophylline into the GI tract, and
provides a smooth theophylline serum concentration/time curve that
emulates an iv infusion after once or twice daily dosing.
Because of this, a very simple pharmcokinetic equation that
computes the average theophylline (Css in μg/mL = mg/L) is widely
used and allows maintenance dosage calculation:
Css = [F ⋅ S (D/τ)]/Cl or
D = (Css ⋅ Cl ⋅ τ)/(F ⋅ S),

(Bauer, 2008 : 755)

• (F = 1 for most oral theophylline sustained-release products),
• S is the fraction of the theophylline salt form that is active
theophylline (S = 1 for theophylline, S = 0.85 for anhydrous
aminophylline, S = 0.80 for aminophylline dihydrate, S = 0.65
for oxtriphylline),
• D is the dose of theophylline salt in milligrams, and τ is the
dosage interval in hours.
• Cl is theophylline Cl in L/h and is computed using estimates of
theophylline elimination rate constant (k) and Vd : Cl = k.Vd
(Bauer, 2008 : 755-756)
• When intravenous therapy is required, a similar pharmacokinetic
equation that computes the theophylline Css (Css in μg/mL =
mg/L) is widely used and allows dosage calculation for a
continuous infusion: Css = [S ⋅ k0]/Cl or k0 = (Css ⋅ Cl)/S,
• (S = 1 for theophylline, S = 0.85 for anhydrous aminophylline, S =
0.80 for aminophylline dihydrate) and k0 is the dose of
theophylline salt in mg
• Cl is theophylline Cl/h and is computed using estimates of
theophylline elimination rate constant (k) and Vd : Cl = kV.

(Bauer, 2008 : 756)

• STEADY-STATE CONCENTRATION SELECTION
• The generally accepted therapeutic ranges for theophylline are 10–
20 μg/mL for the treatment of asthma or chronic obstructive
pulmonary disease, or 6–13 μg/mL for the treatment of premature
apnea.
• Recent guidelines suggest that for initial treatment of pulmonary
disease, clinical response to theophylline concentrations between
5–15 μg/mL should be assessed before higher concentrations are
used.
• Many patients requiring chronic theophylline therapy will derive
sufficient bronchodilatory response with a low likelihood of adverse
effects at concentrations of 8–12 μg/mL.
• However, theophylline therapy must be individualized for each
patient in order to achieve optimal responses and minimal side
effects.

(Bauer, 2008 : 757)

• Literature-Based Recommended Dosing
• Because of the large amount of variability in theophylline pharmacokinetics, In
general, the expected theophylline Css used to compute these doses was 10
μg/mL.
• For obese individuals (>30% over ideal body weight), ideal body weight should be
used to compute doses. Because the doses are given in terms of theophylline,
doses for other theophylline salt forms need to be adjusted accordingly (S = 0.85
for anhydrous aminophylline, S = 0.8 for aminophylline dihydrate, S = 0.65 for
oxtriphylline).
• If theophylline is to be given orally, the dose given in Table 18-4 (in mg/kg/h) must
be multiplied by the appropriate dosage interval for the dosage form being used: D
= (theophylline dose ⋅ Wt ⋅ τ)/S, where Wt is patient weight, τ is the dosage
interval, and S is the appropriate salt form correction factor for aminophylline or
oxtriphylline.
• If theophylline is to be given as a continuous iv infusion the following equation is
used to compute the infusion rate: k0 = (theophylline dose ⋅ Wt)/S, where Wt is
patient weight and S is the appropriate salt form correction factor for
aminophylline.
• When more than one disease state or condition is present in a patient, choosing
the lowest dose suggested by Table 18-4 will result in the safest, most conservative
dosage recommendation. If an iv loading dose is necessary, theophylline 5 mg/kg
or aminophylline 6 mg/kg is used; ideal body weight is used to compute loading
doses for obese patients (>30% over ideal body weight).

(Bauer, 2008 : 776-777)

(Bauer, 2008 : 776)
CHIOU METHOD

BAUER, 2008 : 770

 BAYESIAN PHARMACOKINETIC
COMPUTER PROGRAMS
The most reliable computer programs use a nonlinear regression
algorithm that incorporates components of Bayes’ theorem.
Nonlinear regression is a statistical technique that uses an iterative
process to compute the best pharmacokinetic parameters for a
concentration/time data set.

Briefly, the patient’s drug dosage schedule and serum

concentrations are input into the computer. The computer program
has a pharmacokinetic equation preprogrammed for the drug and
administration method (oral, intravenous bolus, intravenous
infusion, etc.).

Typically, a one-compartment model is used,

BAUER. 2008 : 772

Bayes’ theorem is used in the computer algorithm to
balance the results of the computations between values
based solely on the patient’s serum drug concentrations
and those based only on patient population parameters.

Some clinicians use Bayesian pharmacokinetic computer

programs exclusively to alter drug doses based on serum
concentrations.

An advantage of this approach is that consistent dosage

recommendations are made when several different
practitioners are involved in therapeutic drug monitoring
programs.

BAUER. 2008 : 772

DOSING STRATEGIES

BAUER. 2008 : 774

 USE OF THEOPHYLLINE BOOSTER
DOSES TO IMMEDIATELY INCREASE
SERUM CONCENTRATIONS
A modified loading dose equation is used to
accomplish computation of the booster dose
(BD) which takes into account the current
theophylline concentration present in the
patient:

BAUER. 2008 : 775

Where :
C desired : the desired theophylline
concentration,
C actual : the actual current
theophylline concentration for the patient,
S : the fraction of the
theophylline salt form that is active
theophylline,
V : the volume of distribution
for theophylline.

BAUER. 2008 : 775

 CONVERSION OF THEOPHYLLINE
DOSES FROM INTRAVENOUS TO ORAL
ROUTE OF ADMINISTRATION
Occasionally there is a need to convert a patient stabilized on theophylline
therapy from the oral route of administration to an equivalent continuous
infusion or vice versa. In general, oral theophylline dosage forms, including
most sustained-release tablets andcapsules, have a bioavailability equal to
one. Assuming that equal theophylline serum concentrations are desired, this
makes conversion between the intravenous
[k0 = (Css ⋅ Cl)/S] and oral [D = (Css ⋅ Cl ⋅ τ)/(F ⋅ S)]
routes of administration simple equivalent doses of drug (corrected for
theophylline salt form) are prescribed:
k0 = Dpo/(24 h/d ⋅ Siv) or Dpo = Siv ⋅ k0 ⋅ 24 h/d
where k0 is the equivalent intravenous infusion rate for the theophylline salt
in milligrams per hour, Dpo is equivalent dose of oral theophylline in
milligrams per day, and Siv is the fraction of the intravenously administered
theophylline salt form that is active theophylline.
REMOVAL OF THEOPHYLLINE BODY
STORES IN MANAGEMENT OF
THEOPHYLLINE OVERDOSE
Extracorporeal methods to remove theophylline in emergency
situations include hemodialysis and charcoal hemoperfusion.
Hemoperfusion is a technique similar to hemodialysis except
the blood is passed through a column of activated charcoal
instead of through an artificial kidney.
Theophylline can also be removed from the body using oral
doses of activated charcoal. Activated charcoal physically
adsorbss theophylline rendering it nonabsorbable from the
gastrointestinal tract.

BAUER. 2008 : 776

 REFERENCES
• Bauer, Larry A. 2008. Applied Clinical
Pharmacokinetics. First Edition.USA : The
McGraw-Hill Companies.