Clinical Pharmacokinetics of
Primidone
Student’s name:Nadia Jazairli
I.D number: 9860165
Directed by: Dr. Rafiq Abou Shaaban
Back
Pharmacological actions :
generic name: Primidone
trade name: Mysoline
type of drug: Anticonvulsant, Antiepileptic drug.
 Used to treat: Seizure disorders (generalized and complex partial
seizures) as it’s very effective ,However , Primidone and
Phenobarbital are not the drugs of choice in the treatment of epilepsy
because of their sedating side effects.
 Dosage forms & doses of Primidone:
Primidone is available as 50 and 250 mg tablets ,as well as a 250 mg/5L
Suspension.
The daily recommended dose of Primidone for adults is approximately
10 to 20 mg /Kg and 15 to 30 mg/Kg for children .These doses are
approximately five times the usual dose of phenobarbital ;approximately
0.5 of Primidone is converted to Phenobarbital.
 Metabolism of Primidone :
Although Primidone has an anticonvulsant activity of its own ,much the
anticonvulsant activity stems from the conversion of Primidone to its
active metabolite Phenobarbital in the liver.
It’s also metabolized to phenylethylmalonamide (PEMA).
Plazma concentrations of PEMA usually are not monitored because its
activity is relatively minor .
So as Phenobarbital and primidone are metabolized by the liver.
Therefore, the amount of phenobarbital or primidone that you need to
take depends on how fast your liver metabolizes it. Anything that
adversely affects liver function, such as hepatitis or alcohol abuse, will
affect its ability to metabolize phenobarbital or primidone and in turn will
affect blood levels of the drug. Some medications, even
over the counter drugs, can affect how fast the liver metabolizes
phenobarbital or primidone.
 Contraindications: Hypersensitivity to primidone, phenobarbital, or
any component.
 Warnings: Do not abruptly withdraw therapy
 Precautions: Use with caution in patients with renal or hepatic
impairment, pulmonary insufficiency;monitor for hematologic effects
every 6 months; drowsiness may occur.
Caution when performing hazardous tasks.
 Adversed Reactions:
 Central nervous system: Drowsiness, vertigo, ataxia, lethargy,
behavior change (mood changes with
paranoia)
Dermatologic: Rash
Gastrointestinal: Nausea, vomiting
Genitourinary: Impotence
Hematologic: Leukopenia, malignant lymphoma-like syndrome,
megaloblastic anemia
Ocular: Diplopia, nystagmus
 Overdosage Symptoms :include unsteady gait, slurred speech,
confusion, jaundice,hypothermia, fever, hypotension.
Toxicology Repeated oral doses of activated charcoal significantly
reduces the half-life of primidone resulting from an enhancement of
nonrenal elimination.
 Drug Interactions
Primidone may decrease serum concentrations of ethosuximide,
lamotrigine, valproic acid,griseofulvin .
Succinimides may also decrease primidone and phenobarbital serum
concentrations.
Methylphenidate, nicotinamide, and isoniazid may increase primidone
serum concentrations .
Phenytoin (hydantoins) may increase primidone serum concentrations
Valproic acid may increase phenobarbital concentrations derived from
primidone .
Acetazolamide decrease primidone concentrations.
Primidone and carbamazepine concomitantly given together may
influence each others serum concentration (decrease or increased) .
 Stability: Protect from light
 Advantages of primidone:
History of safe use
Effective when other medications fail
 Disadvantages of primidone :
Requires frequent dosing
Excessive sedation

Advantages of phenobarbital
Once a day dosing
Long history of safe use
Effective
Very Inexpensive
 Disadvantages of phenobarbital:
Potential for liver damage
Excessive sedation
Memory lapses
Hyperactivity in children
Depression in the elderly
Pharmacokinetics
 Therapeutic and toxic plasma concentrations:
The range of therapeutic plazma concentrations for primidone is 5 to 12
mg/L . Side effects are common at concentrations exceeding 15 mg/L.
 Bioavailability (F):
Since parenteral formulations of Primidone are unavailable ,
bioavailability data for the drug are incomplete.
Nevertheless, Primidone appears to be rapidly absorbed(plazma
concentrations peak one to three hours following ingestion) and it
appears to be 100% bioavalable(F=1).
Primidone is labeled in terms of the milligrams of the acid compound;
therefore, it has a salt factor(S) of 1.
 Volume of Distribution(Vd):
Data on Primidone are limited and the specific characteristics of its
disposition are uncertain.An apparent volume of distribution of about
0.6L/Kg appears to be consistent with available data.
 Cleareance(Cl):
Is 0.06L/Kg/hr.
About 20%of Primidone is converted to Phenobarbital,which would
represent a clearance to Phenobarbital of 0.012L/Kg/hr.
Approximately 25% pf Primidone appears to be eliminated unchanged in
the urine , corresponding to a renal clearance of 0.015L/Kg/hr.
 Half-life (t0.5):
The apparent half-life for Primidone is approximately 8 hours ,with a
range of 4 to 15 hours. This relatively short half-life suggests that
Primidone as a parent compound may require relatively frequent dosing
at intervals of 6 to 12 hours.Primidone should accumulate relatively
rapidly ,with plateau concentrations being achieved within 24 hours.
 Time to Sample:
The sampling time of Primidone should be consistent within the dosing
interval because of its relatively short half-life .As with other
drugs,trough concentrations(i.e those obtained just before dose) of
Primidone are probably the most reproducible and most convenient .
Several weeks, however,must elapse before primidone anticonvulsant
effects are fully stabilized because of the long Phenobarbital half-life.
In addition,Phenobarbital serum concentrations should be monitored
because a significant amount of primidone is metabolized to
Phenobarbital.
Dosing must be altered with caution in patients who have been receiving
Primidone for less than three to four weeks because of the time needed
for Phenobarbital to reach a steady-state concentration.
Question #1:
A 65 Kg ,25-years-old male,has been taking 250 mg of Primidone t= 6 hr
for approximately 3 month .What would be the calculated trough
concentration of Primidone ?
To calculate the anticipated trough Primidone concentration one must
first estimat a cleatance and volume of distribution for D.M :
During the first few weeks after starting Primidone therapy , Primidone
and Phenobarbital plasma concentrations are simiar. As steady state is
approached , the Phenobarbital level is approximately two to four times
greater than the Primidone concentration.
Primidone Cl =(0.06 L/Kg/hr)(65Kg)
= 3.9L/hr
Primidone Vd=(0.6L/Kg)(65Kg)
= 39L
Kd=Cl
Vd
Kd =3.9L/hr = 0.1 hr-1
39L
t0.5=0.693
Kd
=0.693 =6.9hr
0.1hr-1
The elimination rate constant of 0.1hr-1 ,an assumed salt form (S) of 1.0
And a bioavailability (F) of 1.0
(S)(F)(Dose)
Vd
(e-Kdt)
Cpss min =
(1-e-kdt )
=
=
(1)(1)(250mg)
39L
(e-(0.1hr-1)(6hr))
(1-e-(0.1hr-1)(6hr))
[ 6.4mg/L]
[0.55] =[14.2mg/L][0.55]
0.45
= 7.8mg/L
This expected trough concentration of ~8mg/L is within the usual
therapeutic range . Also,as can be seen from the calculation above , the
expected peak concentration (cpss max) of 14.2mg/L does not appear to
be excessive.
Question #2:
Caculate the expected steady-state Phenobarbital concentration which
would be produced by D.M.’s Primidone regimen.
A number of approaches could be taken to calculate D.M’s Phenobarbital
concentration. One approach would be to first calculate the average
steady-state level of primidone by using appropriate values for the salt
form ,bioavailability, dosing interval,and clearance.
Cpss ave =(S)(F)(Dose/t)
Cl
=(1)(1)(250mg/6hr) = 41.7 mg/hr
3.9L/hr
3.9L/hr
=10.7 mg/L
This average steady-state plazma concentration of Primidone could the
be used along with the expected clearance of Primidone to Phenobarbital
of 0.78L/hr (0.012L/Kg/hr *65Kg) to calculate the rate at which
Primidone is being converted to Phenobarbital(RA).This is illustrated
below :
RA=(Cl)(Cpss ave)
=(0.78 L/hr)(10.7mg/L)
=8.3mg/hr
An administration rate of 8.3 mg/hr is equivalent to a daily Phenobarbital
dose of ~ 200mg (8.3mg/hr*24hr).This daily administration rate of
200mg would correspond to (S)(F)(Dose/t) equation. The expected
Phenobarbital clearance of 6.5L/day (0.1L/Kg/day * 65Kg) can then be
used in the following equation to predict the steady-state Phenobarbital
concentration as follows :
Cpss ave= (S)(F)(Dose/t)
Cl
=200mg/day
6.5L/day
=31 mg/L
This Phenobarbital concentration of 31 mg/L is approximately three
times the average expected Primidone level and approximately four times
the trough Primidone concentration . The actual ratio of Primidone to
Phenobarbital will ary depending upon the time of sampling within the
Primidone dosing interval. Alterations in the Primidone to Phenobarbital
Plazma ratio are usually due Primarly to changes in Primidone
concentrations within the 5 to 12 hour dosing interval. Within this time
interval, the serum concentration of Phenobarbital will not decrease
dramatically because Phenobarbital has an intrinsically long half-life
And Primidone is continually being converted to Phenobarbital.
An alternate approach to calculating the steady-state Phenobarbital level
is to recognize that approximately 20% of the Primidone dose will be
converted to Phenobarbital ; that is, ~ 200 mg/day (0.2*1000mg/day).
This value could be inserted in the previous equation to calculate the
expected steady-state Phenobarbital level of 31mg/L .This approach
avoids the necessity of calculating the expected average steady-state
Concentration of Primidone .
Question #3 :
R.O., a 12- year- old , 35 Kg female , is admitted to the hospital for
observation because of poor seizure control . Her current drug regimen
includes 200mg/day of Phenytoin and 750mg/day of Primidone.
The day after admission , R.O.’s serum drug concentrations were
reported to be 3mg/L for Phenytoin ,6mg/L for Primidone, and 8mg/L for
Phenobarbital.What are possible explanations for the unusual ratio of
Phenobarbital to Primidone?
Although only 0.5 of primidone is converted to Phenobarbital, one
generally observes an average steady-state Phenobarbital level that is
approximately two to four times greater than the average primidone level
because of the marked differences in the clearance for these two
compounds. Phenobarbital to primidone concentration ratios which are
lower than this may represent one of three possibilities.
First,R.O. may have only recently been started on Primidone and
insufficient time may have elapsed for Phenobarbital to accumulate to
steady-state concentrations (Phenobarbital t0.5 is 4 to 5 days).
Primidone plazma concentrations usually plateau within 24 hours, while
Phenobarbital levels rise slowly over several weeks (as in the previous
figure).A second Possibility is patient noncompliance with the Primidone
regimen .A third possibility is that the patient converts very small
amounts of Primidone to Phenobarbital or has an unusually high
Phenobarbital clearance.
In most cases, an unusually low Phenobarbital to Primidone ratio
represent noncompliance ;however ,the other two possibilities should be
explored.It would be difficult to evaluate unusual conversion or
elimination of Phenobarbital unless R.O. could be observed under a
controlled environment where compliance could be guaranteed.
Another option is to change R.O. from Primidone therapy to
Phenobarbital and observe her Phenobarbital disposition characteristics.
Therapeutic and toxic
plasmaconcentrations
5 to 12 mg/L
Bioavailability
100%
Volume of distribution (Vd)
0.6 L/Kg
Clearance (Cl)
0.06 L/Kg/hr
Half-life (t0.5)
8 hrs
S
1
Back