Theophylline &

Lithium

Therapeutic Drug Monitoring

Assist Lec. Zainab Abdul Hameed
 Theophylline is a methylxanthine compound that is used for the
treatment of:

• Asthma
• Chronic obstructive pulmonary disease
• Premature apnea.
 The general accepted therapeutic ranges for theophylline
are:
10-20 μg/mL for the treatment of asthma or chronic obstructive
pulmonary disease.
6-13 μg/mL for the treatment of premature apnea.

Clinical guidelines suggest that for initial treatment of pulmonary

disease, clinical response to theophylline concentrations between 5
and 15 μg/mL should be assessed before higher concentrations are
used.
BASIC CLINICAL PHARMACOKINETIC PARAMETERS

• Theophylline is primarily eliminated by hepatic metabolism (>90%).

• About 10% of a theophylline dose is recovered in the urine as

unchanged drug.
Dosage forms
Different forms of theophylline are available:
1- Aminophylline is the ethylenediamine salt of theophylline.
2- Anhydrous aminophylline contains about 85% theophylline.
3- Aminophylline dihydrate contains about 80% theophylline.
4- Oxtriphylline is the choline salt of theophylline, contains about 65%
theophylline. [available only for oral use]

• The oral bioavailability of all three theophylline-based drugs is very

good and generally equals 100% F=1
 INITIAL DOSAGE DETERMINATION METHODS
 The Pharmacokinetic Dosing method

Literature-based recommended dosing

Pharmacokinetic Dosing Method
1- Half-Life and Elimination Rate Constant Estimate

Disease state or condition T 1/2

Adult, normal liver function 8 hours
Patient with COPD who smokes tobacco-containing Cigarettes 5 hours
Patient with moderate heart failure (NYHA CHF class III)
patient with severe liver disease (Child-Pugh score = 12) 24 hours
Elderly < 65 y 12 hour
Patient with mild heart failure (NYHA CHF class I or II)

• Once the correct half-life is identified for the patient, it can be converted into the
theophylline elimination rate constant (ke) using the following equation:
 ke = 0.693/t1/2.
2- Volume of Distribution Estimate
• Volume of distribution 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.

3- Clearance Estimate
Cl =Ke V

Cl : is theophylline clearance in L/h

 4- Selection of Appropriate Pharmacokinetic Model and Equations
• When given by continuous intravenous infusion or orally, theophylline
follows a one compartment pharmacokinetic model.
• F is the bioavailability fraction for the oral dosage form (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 mg

• τ is the dosage interval in hours {8hr for smoker while in normal or

liver dysfunction 12 hr}

• Cl is theophylline clearance in L/h.

• Css in μg/mL = mg/L

• Q// NJ is a 67-year-old, 72-kg (height = 6 ft 1 in) male
with chronic bronchitis who requires therapy with oral
theophylline. He currently smokes three packs of
cigarettes daily and has normal liver and cardiac
function.
• Suggest an initial oral theophylline dosage regimen
designed to achieve a steady-state theophylline
concentration equal to 10 μg/mL.
1. Estimate the half-life and elimination rate constant
half-life (t1/2) is 5 hours.
k = 0.693/t1/2 = 0.693/5 h = 0.139 h–1.

2. Estimate volume of distribution and clearance.

V = 0.5 L/kg • 72 kg = 36 L.
Cl = kV = 0.139 h–1 • 36 L = 5.0 L/h.

3. Compute dosage regimen.

D = (Css • Cl • τ)/(F • S) = (10 mg/L• 5.0 L/h • 8h)/(1 • 1) = 400 mg
every 8 hours.
 Literature-Based Recommended Dosing
• In general, the expected theophylline steady-state
serum concentration used to compute these doses was
10 μg/mL
If theophylline is to be given orally, the dose equal:
D = (theophylline dose • Wt • τ)/S
If theophylline is to be given as a continuous intravenous infusion the
following equation is used :
k0 = (theophylline dose • Wt)/S

If an intravenous 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).
 Q// LK is a 50-year-old, 75-kg (height = 5 ft 10 in)
male with chronic bronchitis who requires therapy with
oral theophylline. He currently smokes two packs of
cigarettes daily, and has normal liver and cardiac
function. Suggest an initial theophylline dosage regimen
for this patient.

• A theophylline dose of 0.7 mg/kg/h is suggested by the table for an

adult cigarette smoker.
• D = (theophylline dose • Wt • τ)/S
= (0.7 mg/kg/h • 75 kg • 8 h)/1 = 420 mg, rounded to 400 mg every
8 hours.
 USE OF THEOPHYLLINE SERUM
CONCENTRATIONS TO ALTER DOSES

1-Linear pharmacokinetics

2-Pharmacokinetic parameters
 Linear Pharmacokinetics Method

• Because theophylline follows linear, dose-proportional

pharmacokinetics in most patients with concentrations within and
below the therapeutic range, steady-state serum concentrations change
in proportion to dose according to the following equation:

D new = (Css new/Css old) D old

 Q// LG is a 53-year-old, 69-kg (height = 5 ft 10 in) male with
chronic bronchitis who requires therapy with intravenous
theophylline. He currently smokes two packs of cigarettes
daily, and has normal liver and cardiac function. LG was
prescribed intravenous aminophylline 50 mg/h. A theophylline
serum concentration was obtained after 24 h of this regimen
and equalled 7.4 μg/mL. Compute a new intravenous
aminophylline infusion dose that will provide a steady-state
concentration of 11 μg/mL.
• D new = (11 µg/mL /7.4 µg/mL ) 50 mg/h
=74.3 mg/h
The new suggested infusion rate would be 75 mg/h of aminophylline.
 Pharmacokinetic Parameter Method
1- Actual clearance for patient

Route of administration Equation

Oral Cl = [F • S (D/τ)]/Css
Continuous intravenous infusion Cl = [S • k0]/Css
2-Actual Vd
V = (S • D)/(C postdose – C predose)
D :is the dose of theophylline salt in mg
C : post dose is the post loading dose concentration in mg/L
C: Predose is the concentration before the loading dose was
administered in mg/L.
3- The half-life and elimination rate constant can be computed.
• ke = Cl/V
• t1/2 = (0.693 • V)/Cl
• 4- Calculate dose

Route of administration Equation

Oral D = (Css • Cl • τ)/(F • S)

Continuous infusion k0 = (Css • Cl)/S
Intravenous loading dose LD = (Css • V)/ S
Q// ZQ is a 7-year-old, 20-kg (height = 4 ft 7 in) female with
asthma who requires therapy with oral theophylline. She has
normal liver and cardiac function. ZQ was prescribed
theophylline sustained-release tablets 100 mg orally every 8
hours. A theophylline serum concentration was obtained after 3
days of this regimen and equaled 4 μg/mL just before the
seventh dose was administered. Suggest a new oral
theophylline dose that will provide a steady-state concentration
of 6 μg/mL.
 1. Compute pharmacokinetic parameters.
• Theophylline clearance
Cl = [F • S (D/τ)]/Css = [1 • 1 (100 mg/8 h)]/(4 mg/L) = 3.13 L/h.
2. Compute theophylline dose.
• D = (Css • Cl • τ)/(F • S)
= (6 mg/L • 3.13 L/h • 8 h)/(1 • 1) = 150 mg every 8 hours.

• Since the patient is expected to have a half-life equal to

3.5 hours, the theophylline steady-state concentration
could be obtained any time after the first day of dosing
(5 t1/2 = 5 • 3.5 h = 17.5 h).
 USE OF THEOPHYLLINE BOOSTER DOSES TO
IMMEDIATELY INCREASE SERUM CONCENTRATIONS
• If a patient has a subtherapeutic theophylline serum concentration in
an acute situation, it may be desirable to increase the theophylline
concentration as quickly as possible. In this setting, it would not be
acceptable to simply increase the maintenance dose and wait 3-5 half-
lives for therapeutic serum concentrations to be established in the
patient.
• A rational way to increase the serum concentrations rapidly is to
administer a booster dose of theophylline.

BD = [(C desired – C actual)V]/S

Q// BN is a 22-year-old, 50-kg (height = 5 ft 2 in) female with asthma
who is receiving therapy with intravenous theophylline. She does not
smoke cigarettes and has normal liver and cardiac function. After
receiving an initial loading dose of aminophylline (300 mg) and a
maintenance infusion of aminophylline dihydrate equal to 20 mg/h for
16 hours, her theophylline concentration is measured at 5.6 μg/mL and
her pulmonary function tests are worsening. Compute a booster dose of
aminophylline to achieve a theophylline concentration equal to 10
μg/mL.
• 1. Estimate volume of distribution
V = 0.5 L/kg • 50 kg = 25 L.
• 2. Compute booster dose.
BD = [(C desired – C actual)V]/S
= [(10 mg/L – 5.6 mg/L)25 L]/0.8 = 137.5 mg, rounded to 150 mg of
aminophylline infused over 20-30 minutes.
 Lithium is an alkali metal that is administered as a monovalent
cation (Li+) for the treatment of:

Bipolar disorder
Depression
Mania.
THERAPEUTIC AND TOXIC CONCENTRATIONS
• The general therapeutic range for lithium is 0.6-1.5 mmol/L.

• Because lithium is a monovalent cation, the therapeutic range

expressed in mEq/L is identical to these values (0.6-1.5 mEq/L).

• For individuals with acute mania, a minimum lithium concentration

of 0.8 mmol/L is usually recommended. The usual desired range for
these individuals is 0.8-1 mmol/L.
 BASIC CLINICAL PHARMACOKINETIC
PARAMETERS
• Lithium is eliminated almost completely (>95%) unchanged in the
urine.

• Lithium eliminated in the saliva, sweat, and feces accounts for less
than 5% of the administered dose.

• On average, lithium clearance is approximately 20% of the patient’s

creatinine clearance
Dosage form
Lithium carbonate capsules (150, 300, 600 mg) and tablets (rapid
release: 300 mg; sustained release: 300, 450 mg) are available.
There are 8.12 mmol (or 8.12 mEq) of lithium in 300 mg of lithium
carbonate.
Lithium citrate syrup (8 mmol or mEq/5 mL).

• Oral bioavailability is good for all lithium salts and dosage forms and
equals 100%.
The typical dose of lithium carbonate is 900-2400 mg/d in adult
patients with normal renal function.
EFFECTS OF DISEASE STATES AND CONDITIONS ON
LITHIUM PHARMACOKINETICS
Disease state and T 1/2 CL Vd
conditions
Adults with normal renal 24 hours 20 mL/min
function (CrCl >80 mL/min)
During an acute manic phase ½ the normal increase by
0.9 L/kg
value 50%

children 9-12 years of age 18 hours 40 mL/min

elderly patients 36 hours decrease
INITIAL DOSAGE DETERMINATION METHODS

1- Pharmacokinetic Dosing method

2-Literature-based recommended dosing

 Pharmacokinetic Dosing Method

1- Creatinine Clearance Estimate

2- Lithium clearance Estimate
Cl = 0.288(CrCl) [For normal patients]
Cl = 0.432(CrCl) [For patients with acute mania]
• where Cl is lithium clearance in L/d and CrCl is creatinine clearance
in mL/min.
 3- Calculate dose
D/τ = (Css • Cl )/F
Where:
F=1 for oral lithium
D: dose in millimoles
Cl: lithium clearance in L/d
Css: steady state in mmol/L
τ : dosage interval in days
Note: The ratio of (300 mg lithium carbonate/8.12 mmol Li+)
should be used to convert the result from this equation into a lithium
carbonate dose & this dose should be given in 2 or 3 times daily.
Q// DU is a 21-year-old, 70-kg (height = 5 ft 9 in,
serum creatinine = 0.8 mg/dL) female with bipolar
disease who requires therapy with lithium. She is
currently experiencing an episode of acute mania.
Suggest an initial lithium carbonate dosage
regimen designed to achieve a steady-state lithium
concentration equal to 0.8 mmol/L.
1- CrCl est={[(140-age)BW]/(72*Scr)}*0.85
={[(140-21y)*70]/(72*0.8)}*0.85
=123 mL /min
2-Cl = 0.432 (CrCl)
= 0.432 *123 = 53.1L/d
3- Calculate dose
D/τ = (Css • Cl )/F
D/τ = (0.8 mmol/L* 53.1 L/d)/1
= 42.5 mmol/d
D/τ = (300 mg lithium carbonate/8.12 mmol Li+) 42.5 mmol/d =
1570 mg/d, rounded to 1500 mg/d of lithium carbonate. This dose
would be given as 600 mg of lithium carbonate at 0800 H and
2000 H and 300 mg of lithium carbonate at 1400 H.
 Literature-Based Recommended Dosing

• For the treatment of acute mania, initial doses are usually 900-1200
mg/d of lithium carbonate.
• If the drug is being used for bipolar disease prophylaxis, an initial
dose of 600 mg/d lithium carbonate is recommended. In both cases,
the total daily dose is given in 2-3 divided daily doses.
• Recommended doses for children and adolescents with normal renal
function are 15-60 mg/kg/d and 600-1800 mg/d, respectively, with
doses administered 3-4 times daily.
• To avoid adverse side effects, lithium doses are slowly increased
by 300-600 mg/d every 2-3 days according to clinical response
and lithium serum concentrations.
• Renal dysfunction is the major condition that alters lithium
pharmacokinetics and dosage.
If creatinine clearance is 10-50 mL/min, the prescribed initial
dose is 50%-75% of that recommended for patients with normal
renal function.
For creatinine clearance values below 10 mL/min, the prescribed
dose should be 25%-50% of the usual dose in patients with good
renal function.
Q // MJ is a 50-year-old, 70-kg (height = 5 ft
10 in) male with bipolar disease. He is not
currently experiencing an episode of acute
mania. His serum creatinine is 0.9 mg/dL.
Recommend an oral lithium dose for this
patient for maintenance therapy.
1. CrCl est={[(140-age)BW]/(72*Scr)}
={[(140-50y)*70kg]/(72*0.9mg/dL)}
=97 mL /min

2. Chose lithium dose

• A lithium carbonate dose of 600 mg/d, given as 300 mg
every 12 hours, is recommended as the initial amount.
• The dosage rate will be increased 300-600 mg/d every 2-3
days as needed to provide adequate therapeutic effect, avoid
adverse effects, and produce therapeutic lithium steady-state
concentrations.
 Q // MJ is a 50-year-old, 70-kg (height = 5 ft
10 in) male with bipolar disease. He is not
currently experiencing an episode of acute
mania. His serum creatinine is 3.5 mg/dL.
Recommend an oral lithium dose for this
patient for maintenance therapy.
 1. Estimate creatinine clearance
• CrCl est={[(140-age)BW]/(72*Scr)}
={[(140-50y)*70kg]/(72*3.5mg/dL)}
=25 mL /min
2. Chose lithium dose
• With an estimated creatinine clearance of 25 mL/min, lithium
carbonate doses should be 50%-75% of the usual amount. A lithium
carbonate dose of 300 mg/d, given as 150 mg every 12 hours, is
recommended as the initial amount.
 USE OF LITHIUM SERUM CONCENTRATIONS TO
ALTER DOSAGES

Linear Pharmacokinetics Method

D new = (Css new/Css old)D old

 Q //YC is a 37-year-old, 55-kg (height = 5 ft 1 in)
female with bipolar disease. She is currently not
experiencing an episode of acute mania and requires
prophylactic treatment with lithium. Her serum
creatinine is 0.6 mg/dL. The patient is receiving 900 mg
of lithium carbonate at 0800 H, 1400 H, and 2000 H,
and her 12-hour postdose steady-state lithium serum
concentration equals 1.1 mmol/L.
• Compute a new lithium dose to achieve a steady-state
concentration of 0.6 mmol/L
 D new = (Css, new/Css, old)D old
= (0.6 mmol/L / 1.1 mmol/L) 2700 mg/d
= 1473 mg/d, round to 1500 mg/d

• The patient would be administered 600 mg of

lithium carbonate at 0800 H and 2000 H, and
300 mg of lithium carbonate at 1400 H.