Primidone (Fig. 1) corresponds chemically to 5-ethyldihydro-5-phenyl-4,6(1-H,5H)pyrimidine-dione with an empirical ­formula of C12H14N2O2 and a molecular weight of 218.25.

Figure 1
figure 1figure 1

Primidone

Full size image

Pharmacokinetic Characteristics

Absorption and Distribution

After oral ingestion, primidone is rapidly absorbed (T max  =  2–4 h, adults; 4–6 h children) with a bioavailability of >90 %. Its volume of distribution is 0.5–0.8 L/kg, and plasma protein binding is 10 %.

Biotransformation

Primidone is extensively metabolized in the liver by cleavage of the pyrimidine ring and oxidation of the methylene group to form, respectively, two primary metabolites, namely, phenylethylmalonamide (PEMA) and phenobarbital. Phenobarbital subsequently undergoes metabolism to two metabolites, p-hydroxyphenobarbital and 9-d-glucopyranosylphenobarbital. Both phenobarbital and PEMA are pharmacologically active. Primidone, via its metabolite phenobarbital, is an enzyme inducer, and additionally, phenobarbital undergoes autoinduction so that its clearance can increase and this may require an upward dosage adjustment of primidone.

Renal Excretion

Approximately 65 % of an administered dose is excreted as unchanged primidone in urine.

Elimination

In the absence of enzyme-inducing antiepileptic drugs, plasma elimination half-life values in adults are 7–22 h while in the presence of enzyme-inducing antiepileptic drugs, half-life values are 3–12 h. In newborns, half-life values are 8–80 h, and in children, they are 5–11 h.

Time to new steady-state blood levels consequent to an inhibition of metabolism interaction:

  • Primidone  =  2–4 days later

  • Phenobarbital (derived)  =  15–29 days later

Effects on Isoenzymes

No in vitro data on the induction or inhibition potential of primidone on human CYP or UGT isoenzymes have been published.

Therapeutic Drug Monitoring

Optimum seizure control in patients on primidone monotherapy is most likely to occur at primidone plasma levels of 5–10 mg/L (23–46 μmol/L) and phenobarbital plasma levels of 10–40 mg/L (43–172 μmol/L). The conversion factor from mg/L to μmol/L for primidone is 4.59 (1 mg/L  =  4.59 μmol/L), and for phenobarbital, it is 4.31 (i.e., 1 mg/L  =  4.31 μmol/L).

Propensity to Be Associated with Pharmacokinetic Interactions

  • Primidone affects the pharmacokinetics of other drugs – substantial.

  • Other drugs affect the pharmacokinetics of primidone – substantial.

Interactions with AEDs

Acetazolamide :

Decreases plasma primidone levels.

Consequence:

Acetazolamide decreases the absorption of primidone so that plasma primidone levels are low or not ­detectable [1].

Carbamazepine :

Enhances the metabolism of primidone.

Consequence:

Carbamazepine can decrease the mean plasma primidone level to dose ratio by 17 % and increase mean plasma phenobarbital to primidone ratio by 59 % [2].

Clobazam :

Inhibits the metabolism of primidone.

Consequence:

Clobazam decreases the plasma clearance of primidone so that plasma primidone levels are increased [3].

Clonazepam :

Does not affect the pharmacokinetics of primidone [4].

Eslicarbazepine acetate :

The interaction has not been investigated. Theoretically, a pharmacokinetic interaction would not be anticipated.

Ethosuximide :

Inhibits the metabolism of primidone.

Consequence:

Ethosuximide can increase the mean plasma primidone level to dose ratio by 7 % but does not affect the mean plasma phenobarbital to primidone ratio [2].

Felbamate :

The interaction has not been investigated. Theoretically, a pharmacokinetic interaction could occur.

Gabapentin :

The interaction has not been investigated. Theoretically, a pharmacokinetic interaction would not be anticipated.

Lacosamide :

The interaction has not been investigated. Theoretically, a pharmacokinetic interaction would not be anticipated.

Lamotrigine :

Does not affect the pharmacokinetics of primidone [5].

Levetiracetam :

Does not affect the pharmacokinetics of primidone [6].

Methsuximide :

The metabolism of primidone to phenobarbital is unaffected, but the subsequent metabolism of phenobarbital is inhibited.

Consequence:

Methsuximide may cause a 17 % increase in plasma phenobarbital levels. The interaction is considered to be the consequence of inhibition of phenobarbital metabolism through CYP2C9 [7].

Oxcarbazepine :

The interaction has not been investigated. Theoretically, a pharmacokinetic interaction could occur.

Phenobarbital :

Combination not commonly co-prescribed.

Phenytoin :

Enhances the metabolism of primidone.

Consequence:

Mean plasma primidone levels can decrease by 33 %, and mean plasma phenobarbital levels can increase by 112 % [8].

Piracetam :

The interaction has not been investigated. Theoretically, a pharmacokinetic interaction would not be anticipated.

Pregabalin :

The interaction has not been investigated. Theoretically, a pharmacokinetic interaction would not be anticipated.

Retigabine :

The interaction has not been investigated. Theoretically, a pharmacokinetic interaction would not be anticipated.

Rufinamide :

The interaction has not been investigated. Theoretically, a pharmacokinetic interaction would not be anticipated.

Stiripentol :

Inhibits the metabolism of primidone. The metabolism of the derived phenobarbital is also inhibited.

Consequence:

The plasma clearance of phenobarbital is decreased by >48 % so that plasma phenobarbital levels are increased. The interaction is the consequence of inhibition of CYP2C9 and CYP2C19 [9].

Sulthiame :

The metabolism of primidone to phenobarbital is unaffected, but the subsequent metabolism of phenobarbital is inhibited.

Consequence:

Sulthiame may increase plasma phenobarbital levels [10].

During combination therapy, sulthiame adverse effects such as dizziness, uncertain gate, and drowsiness may be enhanced. This is considered to be the consequence of a pharmacodynamic interaction [10].

Tiagabine :

The interaction has not been investigated. Theoretically, a pharmacokinetic interaction would not be anticipated.

Topiramate :

Does not affect the pharmacokinetics of primidone [11].

Valproic acid :

The metabolism of primidone to phenobarbital is unaffected, but the subsequent metabolism of phenobarbital is inhibited.

Consequence:

Mean plasma phenobarbital levels can increase by 51 %, probably via an action on CYP2C9 and/or CYP2C19, but plasma primidone levels are unaffected [12].

Vigabatrin :

Does not affect the pharmacokinetics of primidone [13].

Zonisamide :

Does not affect the pharmacokinetics of primidone [14].