Antiepileptic Drugs, 5th Edition

Primidone

65

Primidone

Richard W. Fincham MD*

Dorothy D. Schottelius PhD**

* Deceased, November 11, 2000.

** Research Scientist, Department of Neurology, University of Iowa, Iowa City, Iowa

Primidone (PRM) can provide effective treatment for partial or tonic-clonic seizures, singly or as adjunctive therapy. Its clinical use began in 1952 (1), although controlled testing for efficacy waited more than a decade (2, 3, 4, 5). Clinical efficacy and toxicity were most extensively evaluated in a double-blind, controlled study published in 1985, with comparison made among phenytoin (PHT), carbamazepine (CBZ), valproic acid (VPA), and PRM in treatment of secondarily generalized seizures (6). PRM was identified as less effective for partial seizures compared with CBZ and possessed the greatest potential for poor tolerability at initiation. It has since been regarded as a drug of second choice in the treatment of epilepsy.

Extensive testing in animal models of epilepsy, such as are required today, did not precede the first use of PRM in treatment of epilepsy in humans (7). Excellent reviews of these studies of PRM are available in Chapters 33 and 34 of the fourth edition of this text, Antiepileptic Drugs (8,9). A variant of the standard maximal electroshock seizures (MES) model established pharmacologic and toxic properties of PRM (10). The drug was found to lack potency in chemoconvulsant models of epilepsy such as determined by pentylenetetrazole. This dichotomy in response to two standard animal models of epilepsy indicated a pharmacodynamic effect of PRM leading to inhibition of the spread of seizures, rather than one raising the threshold for their development.

CHEMISTRY AND METABOLISM

PRM (5-ethyldihydro-5 phenyl-4,6-(1H, 5H)-pyrimidedione) was first synthesized and used as an anticonvulsant in 1952 (11). It is a desoxyphenobarbital differing from phenobarbital (PB) by the absence of the carbonyl group in position 2 of the pyrimidine ring (Figure 65.1). Because it contains only two carbonyl groups and not three, PRM is not, per se, a barbiturate but is considered clinically in that group.

PRM (molecular weight, 218.25) is an odorless crystalline white powder with a slightly bitter taste and a melting point of 279° to 282°C. Pharmacokinetic properties of PRM are influenced by its physicochemical characteristics, namely, its low solubility in water (600 µg/mL), weak acidity (negative log of dissociation constant, 13), and low lipophilic partition coefficients compared with PB. Quantitative discussions of serum concentrations may involve either micrograms per milliliter or micromoles per liter; therefore, a conversion factor of 4.58 may be used (µg/mL × 4.58 = µmol/L; µmol/L ÷ 4.58 = µg/mL).

The clinical use of PRM requires an understanding of its pharmacokinetics, which is complicated by the presence of two active metabolites: PB and phenylethylmalonamide (PEMA).Figure 65.1 illustrates the primary and most relevant metabolic pathways of PRM. The transformation of PRM to PEMA and PB was not recognized until after the clinical introduction of PRM. Bogue and Carrington (12) identified PEMA as a metabolite in rats, and Butler and Waddell (13) found PB as well as p-hydoxyphenobarbital in urine and in the plasma of a dog and a patient receiving PRM. Later, both PEMA and PB were shown to have anticonvulsant properties. Minor metabolites identified include α-phenylbutyramide (14), p-hydoxyprimidone (15,16), and α-phenyl-γ-butyrolactone (17), but no evidence indicates that these metabolites have any importance during therapy with PRM. The biotransformation of PRM has been shown to take place in all animals tested, although with variable rates and extent. It is necessary to consider the pharmacokinetics of the two active metabolites along with PRM. PB is discussed in Chapter 51 and is considered only with regard to its influence on PRM; PEMA is considered concurrently.

The rate and extent of absorption of PRM have been studied indirectly in humans because only oral preparations (tablets and syrup) are available. Such studies have indicated

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average peak absorption time between 2.7 and 4.2 hours after single-dose administration in adult patients (18,19). In one case, we gave a single 125-mg dose to a woman and found that 60% of the dose was absorbed in 0.5 hour, and the patient complained of minor side effects. A study of 14C-labeled PRM in 10 patients receiving combination therapy indicated that almost 100% of PRM is rapidly absorbed (20). Kauffman et al. (21) studied absorption of PRM in children; an average of 92% of dose was absorbed, with a peak plasma concentration at 4 to 6 hours. All these studies suggest a great deal of variability in the rate and extent of absorption of PRM. Toxicity symptoms associated with the initial dose of PRM are discussed later, in relation to determining dosage schedules for treatment with this drug.

 

FIGURE 65.1. The main biotransformation pathways of primidone consist of formation of phenylethylmalonamide by ring scission and oxidation to phenobarbital, which is then parahydroxylated.

Differences in formulation of PRM may have an influence on rate and extent of absorption, as observed in two instances (22,23). Few studies have been reported on the influence of age, pregnancy, and other diseases or conditions on the rate and extent of absorption of PRM. The bioavailability and peak absorption time for PEMA determined in adult volunteers averaged 91% and 3 hours (24).

The distribution of PRM throughout body tissues and fluids is apparently similar to that of PB (25). Several animal studies (10,26,27) have indicated that PRM enters the brain rapidly, with the brain:plasma ratio remaining constant for ≤2 hours. The distribution of PEMA and PB involves the rate of biotransformation from PRM as well as their physiochemical properties, with both reaching maximum plasma and brain concentrations 6 to 8 hours after orally administered PRM (27, 28, 29). Houghton et al. (30) reported an average brain: serum ratio of 0.87 in humans. PRM was present in muscle, skin, and bone, but this distribution correlated poorly with concentration in plasma.

PRM does not bind significantly to plasma proteins, and several studies using either equilibrium dialysis or ultrafiltration show a range of 9% to 20%. (18,23,27,31, 32, 33, 34, 35, 36,37, 38, 39, 40, 41, 42). Saliva values equal 70% to 80% of total plasma concentrations (21,42, 43, 44). PRM concentration in the cerebrospinal fluid (CSF) averages 70% to 100% of that in plasma (31,32,36, 37, 38, 39, 40, 41,45); the variance may result from time required for PRM to equilibrate between these fluids. Our data indicated a CSF:serum ratio of 0.6 at a dose-sample interval of 2.6 hours when patients were taking PRM alone or PRM plus PHT (46). When samples were obtained approximately 7.2 hours after administration, the ratio was approximately 0.997. The relatively low penetration of PRM across lipid membranes could account for the timeand flow-related differences in CSF or saliva and plasma ratios. Distribution volumes of PRM have been characterized in patients with means of 0.72 L/kg (20) and 0.65 kg/L (47). The distribution volume for PEMA is similar to that of PRM (37).

Elimination of PRM is highly variable (half-life range, 3.3 to 22.4 hours) because of factors such as age and concomitant therapy (18,19,21,24,47,48). Studies indicate

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that PRM half-life after a single dose is independent of dose or plasma concentration, a finding consistent with a first-order, linear pharmacokinetic model. Long-term PRM therapy could decrease its half-life for various, such as microsomal enzyme induction, structural similarity of PB and PRM, and the presence of other antiepileptic drugs (AEDs) (18,20,21,40,47,48). When PEMA is administered directly to humans, its half-life ranges from 10 to 25 hours (22,37).

Correlation between PRM daily dose and steady-state concentrations results in large measure from a wide range of clearance found in patients. Clearance is not affected by the size of dose but is altered by concomitant AED therapy with an increase of approximately 50% (28,47). Changes in clearances may also be time dependent, with increases of 30% to 200%, which may be a result of PB-mediated enzyme induction.

The liver appears to be responsible for most of the biotransformation of PRM, although the kidney may also play a role (27,49, 50, 51, 52). PRM and its metabolites are primarily eliminated by renal excretion (20), with 75% to 77% of a dose recovered during a 5-day collection period. Patients receiving monotherapy excreted 64% as PRM, whereas those receiving concomitant AED therapy excreted 40% of PRM. Advanced age, pregnancy, lactation, and liver disease may all have an influence on PRM pharmacokinetics, and care must be taken in clinical situations when PRM is used in anticonvulsant therapy.

Biotransformation of PRM to two active metabolites (PB and PEMA; Figure 65.1) illustrates the complexities involved when a drug with pharmacologic activity of its own is converted into active metabolites. The attempts to ascertain the basis of mechanisms of action of PRM were complicated by the uncertainty regarding whether it has independent antiepileptic activity. In long-term therapy with PRM in humans, in all but a few instances (5), PB is present.

In a clinical study of epileptic patients, PRM was found to be more effective than PB against generalized tonic-clonic seizures. Several experiments in animals have shown independent anticonvulsant activity of PRM; dogs were found to be protected against chemically induced seizures at a lower concentration of PB when PRM was also present (53). Rats were protected against induced seizures after a single dose of PRM before the active metabolites were detectable (10); similar seizure protection was achieved in mice and fowl when pretreatment of a liver enzyme inhibitor SKF 52A was used (27,51,52). Some evidence suggests that the anticonvulsant spectra of PRM and PB differ, that is, PRM and PB are equally potent against seizures induced by MES, but against seizures produced chemically, PB is effective but PRM is totally ineffective. Therefore, the two compounds may have different mechanisms of action. PRM has an anticonvulsant spectrum similar to that of CBZ and PHT. A relatively weak anticonvulsant activity was found for PEMA in rats (48) as well as in mice (27,51). These experimental results, together with blood levels in patients receiving long-term therapy with PRM, suggest that PEMA contributes little or not at all to the antiepileptic effect or clinical toxicity of PRM in patients.

The question of the relative amounts of PRM converted to its metabolites after single or multiple doses has been the subject of several studies. Rabbits were given single or multiple oral doses of PRM (50), and the amount of PRM excreted unchanged in urine was calculated to be about 20% of a single dose, whereas 48% was excreted as PEMA and 10% as PB and p-hydroxyphenobarbital. The conversion to PEMA occurred earlier and more rapidly than conversion to PB. In another study (35) in which PRM was given intravenously, 20% of the dose was excreted as unchanged PRM, 40% was metabolized to PEMA, and 40% was metabolized to PB. PHT pretreatment increased the total body clearance of PRM, PEMA, and PB and accelerated the rate of formation of the metabolites.

Studies of quantitative aspects of PRM transformation in humans have been assessed. One study (2) concluded that 24.5% of PRM was converted to PB. Another study (55a) found that, to achieve the same PB levels, the PRM dose had to be five times higher than a corresponding dose of PB.

Two groups of patients with epilepsy (group I with no previous exposure to anticonvulsants and group II taking over anticonvulsants) were studied using an intravenous infusion of 14C PRM (20). The mean plasma half-life was 50% shorter in group I, although the total amount of PRM was approximately equal. The relative amounts of the compounds excreted were different in the two groups: PRM, 42% unchanged, 2% PEMA, 1.2% PB, and 1.5% unidentified products in group I; in group II, 31% unchanged PRM, 10% PEMA, 1.3% PB, and 1.5% unidentified products (considered to be free and conjugated p-hydroxyphe-nobarbital). The profile of PRM and the rate of production of its two main metabolites were studied in a group of 12 children (21), with a pronounced interpatient variability.

The quantitative assessment of PRM biotransformation has also been evaluated using steady-state blood concentrations between PRM and its two main metabolites. The levels of PRM fluctuate more than the levels of the metabolites because of the drug's short half-life, and the concentration ratios are therefore not constant. If comparisons are made between the PB:PRM ratio in patients receiving monotherapy and that in patients receiving combination therapy, there is a threefold increase in this ratio. The :PRM ratio approximately doubles (5,40,47,55b).

Several factors can cause change in these ratios, such as age (49,56), pregnancy (57), and disease, that is, viral hepatitis (28). From all the current information, PRM is both a drug in itself and a PB prodrug that has implications for the clinical use of this drug.

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DRUG INTERACTIONS

The many interactions reported between PRM and other drugs can be beneficial as well as potentially damaging. PRM biotransformation creates a kind of polypharmacy in a setting of monotherapy, and the use of other drugs enhances the complexity of these biotransformations. Because PRM and PB appear to induce enzyme activity, their influence on other drugs is important (58).

Drugs that can affect the gastrointestinal tract and can produce changes such as alteration in pH, motility of the tract, and possible formation of insoluble complexes can delay or prevent absorption of PRM. Conversely, PRM may affect the transport system of the brush border of the enterocyte (59). Acetazolamide may impair the absorption of PRM (60). PRM has been shown to impair biotransport in human intestine in a concentration-dependent manner (59). Folate metabolism or absorption has been shown to be affected by anticonvulsants including PRM (61). Distribution, including protein binding of either PRM or its main metabolites, does not seem to be altered by biotransformation.

Because PRM is a weak organic acid, excretion may be altered by changes in the pH of the urine. Patients receiving only PRM eliminated it more slowly than those patients taking PRM in combination with other AEDs, particularly PHT (47,62), and CBZ (63).

The main pharmacokinetic interactions concern the biotransformation or metabolism of PRM and its metabolites. The biotransformation of PRM to PB and PEMA can be both markedly induced and markedly inhibited by other drugs, and this inducibility is influenced by various factors, including genetics, age, and disease processes. The effect of induction was studied extensively in adults and children, and findings clearly indicated that the presence of other drugs decreased the amount of unchanged PRM approximately 20% (5,10,20,64).

Clinical studies also indicate the possibility of substance interaction. The delayed appearance of PEMA and PB in plasma (18,47,48) and the influence of repeated administration on that delay (5,10,64) suggest that the enzyme systems responsible for the biotransformation of PRM may be altered by interactions among all three of these compounds (40,58).

The combination of PHT and PRM results in a pronounced acceleration of the enzymatic transformation (5, 32,47,65) and in a marked increase in the PB:PRM ratio (5,32,66; Table 65.1). Determining the exact mechanism responsible for this enzyme induction and/or inhibition of hydroxylation of PB (47,67) is not critical before one decides that this is a clinically significant finding.

CBZ also increases the metabolism of PRM to its metabolites in both animals (47) and humans (20,63, 68, 69, 70). An apparent opposite effect was found in one study (71). It has been reported that PRM lowers the serum level of CBZ (70, 71, 72, 73) and decreases the CBZ:CBZ-epoxide ratio (69).

TABLE 65.1. EFFECT OF PHENYTOIN ON PRIMIDONE BIOTRANSFORMATIONa

 

Primidone Only (n = 80)

Primidone and Phenytoin (n = 127)

PRM dose (mg/kg)

9.7 ± 0.2

10.6 ± 0.4

PHT dose (mg/kg)

4.8 ± 0.1

Serum PHT level (µg/mL)

12.1 ± 0.1

Serum PRM level (µg/mL)

11.3 ± 0.2

8.1 ± 0.4

Serum PB level (µg/mL)

15.0 ± 0.4

27.2 ± 1.4

PB/PRM

1.45 ± 0.10

3.82 ± 0.24

PRM, primidone; PHT, phenytoin; PB, placebo.

aValues are expressed as mean ± standard error.

VPA has been reported to alter the serum levels of PRM (74, 75, 76, 77) and to change the PRM:PB ratio. Our results, in 16 patients, did not show an average change when VPA was added to the regimen, although there was marked interindividual variability (58).

Clonazepam apparently causes a significant increase in PRM concentration (78), in contrast to other AEDs. Two drugs, isoniazid and nicotinamide (51,79, 80, 81), decrease the conversion of PRM to PB, and it has been postulated that this action results from inhibition of the cytochrome P450 enzyme system. Interaction of PRM with several other drugs has been investigated (66,82, 83, 84, 85).

Table 65.1 summarizes most of the reported interactions of PRM and its metabolites. As with all drug interactions, individual variability is of marked concern and points out the necessity and benefits of using serum drug levels to gain maximum therapeutic effect of all drugs.

PRIMIDONE AS AN ANTICONVULSANT

Animal Studies

Initial support for an independent anticonvulsant effect of PRM was provided by Frey and Hahn (53), with their demonstration of protection against pentylenetetrazole-induced seizures in dogs with lower concentrations of PB in the presence of PRM. Studies in rats by Baumel et al. (10) indicated an independent anticonvulsant effect for PRM, with protection of 50% of the rats from MES in the first 6 hours after administration and before the appearance of its metabolites PB and PEMA in the brain. This was accomplished with 3.9 mg/kg compared with a median effective dose of 5 mg/kg for PB and of 62.5 mg/kg for PEMA. PRM did not show protection against pentylenetetrazole- or hexafluorodiethyl ether-induced seizures at this low concentration. Protection against these two systemic chemoconvulsants required time for PRM's biotransformations to

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PB and PEMA. Thus, different pharmacodynamic effects for PRM and PB were indicated by this study.

PRM was shown to have an independent anticonvulsant effect in seizures induced in epileptic fowl by intermittent photic stimulation (52). The metabolic inhibitor SKF 525A prevented PRM's conversion to PEMA and PB in this study. Leal et al. (27), using SKF 525A, showed similar independent effectiveness of PRM against MES in mice. Further comparison of protection against seizures, by using brain concentrations of PRM, PB, and PEMA after single doses of PRM without SKF 525A, led these investigators to conclude that PB probably gave the greatest anticonvulsant effect in that circumstance.

Another study of PRM and its two major metabolites PB and PEMA in mice, showed PRM to raise the electroconvulsant threshold, but with 1.7 times less potency than PB (33). Eighty percent of the anticonvulsant effect in this study was attributed to PRM when brain concentrations of PRM, PB, and PEMA were measured at the time of the test. Seizures were produced in gerbils using a blast of compressed air, and PRM was responsible for the main anticonvulsant effect in the first hours after administration using measures of serum and brain concentrations (86). In a longterm, study only one of 15 dogs was shown to have improved control of seizures when PRM was substituted for PB at comparable serum concentrations of PB (87).

Bourgeois et al. (51,80) performed a series of experiments in mice to assess neurotoxicity of PRM and its metabolites and to view the pharmacodynamic interactions of PRM, PB, and PEMA with regard to their anticonvulsant potency and neurotoxicity. Seizure protection was quantitated as median effective brain concentration (EC50) against MES and pentylenetetrazole-induced seizures. Neurotoxicity was measured as median toxic brain concentration (TC50) with employment of the rotorod test. Therapeutic indices (TI = TC50/EC50) were also individually assessed for PRM, PB, and PEMA. Brain concentrations were used to eliminate any possible pharmacokinetic interactions from the test. The median neurotoxic concentration for PRM was much higher than that for PB, a finding indicating PRM to be 2.5 times less neurotoxic in this model than PB. PRM was as potent as PB in controlling MES seizures, with a resultant higher therapeutic index because of its lesser neurotoxicity. PRM showed no effectiveness against the chemoconvulsant models employing pentylenetetrazole (with brain concentrations of 81.7 µg/mL) and bicuculline (with brain concentrations of 103.3 µg/mL). PB, however, showed similar potency against MES and chemoconvulsant seizures. PEMA showed an anticonvulsant spectrum similar to that of PB for both the MES and chemoconvulsant models, but it was 16 times less potent for each.

PRM's differential effectiveness against MES seizures and its inability to influence chemoconvulsant seizures reconfirmed the finding of Baumel et al. (10). As indicated earlier, PB and PRM are different anticonvulsants with two different mechanisms of action; PRM has a spectrum of effectiveness similar to that of CBZ and PHT (88).

Bourgois et al., acknowledging the eventual obligatory presence of PB and PEMA with use of PRM, addressed the potential for toxicity as well as effectiveness in this mouse model (89). Bourgeois et al. hypothesized that if neurotoxicity is lower for PRM than PB, as in this mouse model, then an upper therapeutic limit for serum PRM concentrations is meaningless in naturally occurring PB:PRM ratios. Animal studies have provided a preponderance of evidence that PRM has antiepileptic effects independent of metabolically derived PB.

Results of clinical studies have demonstrated arguments both for and against the independence of PRM as an AED. Most early studies were not prospective or controlled and used PRM as add-on therapy. Early double-blind studies, such as that of White et al. (90), found no significant difference in the anticonvulsant efficacy of PRM, PB, or PHT, and toxicity was comparable among the three drugs. Booker et al. (18) studied 30 patients taking only PRM and showed effectiveness with a PB:PRM ratio of 3:1. Several comparative clinical studies of PRM have been performed since the 1960s (91, 92, 93, 94, 95), and only one showed that PRM was superior in efficacy (96). Other clinical studies (58,91,95) have demonstrated seizure control with PRM when PB was not within therapeutic range.

Clinical Observations

PRM was first used in the treatment of patients before its metabolic transformations were understood and before any controlled trials had been undertaken. Initial enthusiasm for treatment of epilepsy in humans with PRM (1,50, 90,98, 99, 100, 101, 102, 103) was tempered by the discovery that PB was a major metabolite. Clear evidence for the effectiveness of PRM beyond that provided by PB was not established in numerous clinical investigations (6,19,92,104, 105, 106, 107).

An add-on study by Rodin et al. (94) is of interest with regard to seizure control with and side effects of PRM in comparison with those of CBZ when both drugs were used as adjunctive therapy. Forty-five patients with partial or tonic-clonic seizures occurring at least twice monthly completed a 6-month study, with each patient serving as his or her own control. Either PRM or CBZ was added to a stable regimen of PHT after all other drugs had been withdrawn. One adjunctive drug (either CBZ or PRM) was given for 3 months, after which the other was substituted for the next 3 months. Single-blind observations by the treating neurologist and double-blind observations by the electroencephalographer and psychologists indicated no difference between the two drugs in their effectiveness in controlling seizures and noted “somewhat more side effects—nonserious—with CBZ than with PRM.” However, they did find more severe impairment on a repeatable neuropsychological

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test battery and an increase on the psychopathic deviation scale of the Minnesota Multiphasic Personality Inventory with use of PRM. They also reported that CBZ led to lessened depressive feelings, if that mood change was present, in contrast to PRM. These investigators speculated that an intellectually and emotionally intact patient could do better with PRM, but they favored CBZ for patients with a history of emotional or intellectual deficits.

The double-blind prospective study of treatment of patients with partial or secondarily generalized seizures in the nationwide Veterans Administration (VA) Cooperative Study was completed in 1985 and provides the most definitive clinical insights available regarding therapy with the four studied anticonvulsant drugs: PB, PRM, PHT, and CBZ (6,107). Patients were randomized to therapy with one of the four drugs. CBZ and PHT showed the best success with treatment, followed by PB and, finally, by PRM. The length of time that the patient received treatment (patient retention time) constituted one of the end point measures of efficacy. This retention rate was poorest for PRM despite limiting initial dosing to 125 mg. The common appearance of acute side effects of nausea, vomiting, dizziness, and sedation led to early discontinuation of PRM in this study. When this problem was not encountered or was manageable, the patients usually completed the study. Similar side effects have been observed during induction of PRM when it is used in treating essential tremor (108).

Another end point in a later VA study (96) compared the percentage of patients who were free of tonic-clonic seizures while taking each of the drugs. No significant differences were found in this measure, with 63% of patients receiving PRM, 58% receiving PB, 55% receiving CBZ, and 48% receiving PHT being free of tonic-clonic seizures at the end of 1 year, but CBZ was more effective than PB and PRM for partial seizures. PRM showed fewer adverse behavioral effects as measured by the total behavioral toxicity battery than either PHT or PB (95). PRM showed a definitely different behavioral profile on the subtests of the behavioral toxicity battery and on the total behavioral toxicity battery score than was shown by PB. This difference in toxicity between PRM and PB pointed to PRM's effects being independent of those related to PB. These behavioral differences as measured by this psychological test battery are of interest to consider in relation to the differential action and inaction of PB and PRM in the chemoconvulsant animal models of epilepsy. Relatively subtle structural differences in chemical makeup appear capable of bringing about noteworthy differences in anticonvulsant and behavioral changes.

PB's obligatory appearance with biotransformation of PRM led Bourgeois et al. (80) to look for an optimal PB:PRM ratio for treating seizures in their experiments with mice. These researchers found brain concentrations of PB and PRM to be optimal at 1:1, with resultant effect of potentiation of both drugs against electroshock seizures. Leal et al. (27) showed that brain penetration is better for PB than for PRM and that PB concentrations in the brain were twice that of PRM with equal plasma concentrations in the mouse model. The plasma PB:PRM ratio would, in this way, underestimate the cerebral ratio. Data from the VA study (95) indicated minimal plasma levels of PB in the first week of therapy that climbed to a higher and relatively stable concentration in 1 month. Additional data indicated a poor correlation between dose and serum concentration of PRM and between serum PRM and serum PB concentrations, except for a tendency of higher serum PB concentrations to correlate with higher serum PRM levels. The mean serum PB:PRM ratio for the first year was 1.2:1, close to the ratio favored by Bourgeois et al. (80), although their ratio used brain and not serum concentrations. Our conclusions that PRM itself was an effective antiseizure drug were based on our study of 80 patients who had received only PRM for at least 12 months (5). Twenty-nine patients with excellent control of seizures had plasma PB concentrations of <15 µg/mL (mean derived PB concentrations at 12 months, 13.4 µg/mL; range, 12.1 to 15.4 µg/mL at 12 months) and led us to the conclusion that PRM, per se, possessed anticonvulsive potency. If brain concentrations had been measured, PB could have been present at much higher concentration, and this, with a consideration of PRM's half-life, would lessen the strength of our conclusion. Bourgeois et al. noted that the mouse model (80), which showed lesser neurotoxicity for PRM than PB (rotorod test) and higher brain concentrations of PB than PRM, would render an upper therapeutic limit for serum PRM concentrations without meaning.

Oxley et al. (109) provided clinical evidence that PRM was superior to PB in treating certain seizures. Twenty-one residents of the Chalfont Centre for Epilepsy who were taking either PRM or PB for at least 1 year along with several other AEDs were included in this study. Doses of the concomitant AEDs were held constant, whereas doses of PRM and PB were adjusted to obtain comparable levels of PB for those receiving PRM and those receiving PB. One year of observation was followed by interchanging PRM and PB and readjusting plasma PB to similar levels for each group and another year of observation. Mean serum PB during treatment was 30.1 + 12.8 µg/mL with concurrent PRM values of 29.9 + 11.6 µg/mL. Fourteen of 21 patients experienced better control of generalized tonic-clonic seizures when they were taking PRM, and four had more frequent seizures. Patients with complex partial and generalized absence seizures did not show a difference in response to the two drugs.

A study using 24-hour video electroencephalographic (EEG) monitoring correlating EEG paroxysms, seizure frequency, and plasma PRM and PB levels demonstrated that peak plasma levels were associated with periods of decreased clinical seizures and fewer EEG paroxysms. Dosing intervals of PRM were closer (8 hours), and there was little fluctuation in drug level in a patient receiving PRM monotherapy.

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These data indicated a better correlation with EEG and clinical changes with PRM levels than PB (110)

These clinical observations present strong but not conclusive evidence for the independent antiepileptic activity of PRM. Before discussing the clinical use of this drug, we should discuss the adverse effects associated with its use.

ADVERSE EFFECTS

Assessment of PRM for adverse effects necessarily includes attention to its metabolic derivative PB (13), except for a singular initial interval after its first dosage, before conversion to PB has taken place. Booker et al. (18) showed that this interval may last up to 48 hours in testing serum of normal volunteers given their first dose of PRM. Two of these six volunteers experienced this noteworthy acute initial toxicity of PRM defined by marked dizziness, slurred speech, giddiness, and altered mental status (difficulty with concentration) when only PRM is present. PB is almost always present with PRM, thus rendering it impossible to separate its adverse effects from those of PRM.

Clinicians must consider potential adverse events as well as therapeutic efficacy in their choice of available AEDs. Classification systems for adverse events have been designed to help recognize, prevent, and treat potential adverse events of AEDs (111). PRM's clinical usage since 1952 must have allowed for recognition of most of its adverse events. This discussion employs an approach using involvement of organ systems with some consideration of mechanistic processes (teratogenicity and hypersensitivity reaction). Attention is focused on adverse effects involving the central nervous system (CNS) with recognition that those undesired effects that can be unequivocally attributed to PRM can only be identified in one interval, not exceeding 48 hours, after its initial dosage. Long-term use of PRM, with its obligatory metabolite PB, is necessarily associated with adverse events relatable to PB (Chapter 55).

Adverse Events Viewed in Organ Systems

It is not surprising that therapeutic intervention with AEDs designed to prevent clinical seizures may affect these other neuronal activities. Lennox expressed concern about this ability of AEDs to impair other neurologic functions in 1942 (112) with the observation that “many physicians in attempting to extinguish seizures only succeed in drowning the finer intellectual processes of their patients.”

Consistent interest in and studies of possible cognitive side effects of AEDs appeared in the 1970s (113,114). All established AEDs were recognized to possess cognitive side effects (115), with PB, the obligate metabolite of PRM, showing the least favorable cognitive profile of all (116).

Acute initial toxicity appears as PRM's unique contribution to CNS toxicity, apart from those engendered by its usual companion, PB. Goldin (117) and Timberlake et al. (102) commented about this in early reports of clinical use of PRM. Other reports of toxicity followed (92,106). Mattson et al. (91) listed clinical identifiers for this state of acute CNS toxicity similar to those noted by Booker et al. (18): drowsiness, dizziness, ataxia, nausea, and vomiting, with observation that these untoward effects of PRM often resulted in its therapeutic discontinuation. Although intensely disabling, these acutely altered mental states usually end within hours of discontinuation of PRM. The appearance of this state of toxicity follows ingestion of PRM by an hour or so and before the appearance of serum PB, a finding thereby indicating PRM to have causal importance for this state of toxicity. PEMA serum levels may equal those of PRM, but PEMA has been believed to play a small role if any, in the appearance of this toxicity on the basis of animal studies (51).

This acute state of toxicity may appear with even a limited first dose of 50 mg of PRM, although it is much more likely to develop after higher doses. Serum concentrations of PRM near 10 µg/mL after 500-mg doses were found in normal volunteers (18). Other investigators noted this acute state of toxicity with lower serum concentrations (118). Some patients decide at this point to discontinue trial use of PRM, whereas others, perhaps with less severe acute toxicity, persevere and are able to tolerate the drug and eventually live comfortably with much larger doses in long-term therapy. Leppik et al. (118) explored this development of tolerance to PRM, which can occur in hours or days, by comparing clinical toxicity scores with serum concentrations of PRM. Toxicity scores were seen to decline with time, despite identical and even higher serum concentrations of PRM. The possibility that PB could produce a cross-tolerance to acute PRM toxicity had been suggested after noting that patients receiving long-term PB therapy were less likely to experience this severe toxicity on their first exposure to PRM (106).

Bourgeois et al. (80), noting the obligatory appearance of both PB and PEMA with ingestion of PRM, studied the potential of these metabolites with regard to neurotoxicity and efficacy in controlling electroshock and chemoconvulsant seizures in a mouse model. Combined brain concentrations of PRM and PB near a ratio of 1:1 provided maximal protection against MES with minimal neurotoxicity (rotorod test). Brain concentrations of PB were found to be twice those of PRM (80,119), a finding confirming that of Leal et al. (27) that brain penetration is better for PB than for PRM. Observation of variable PB:PRM ratios in clinical settings indicate that the 1:1 ratio is approached in settings of monotherapy with PRM, with enhancement of PB concentrations by a factor of more than 3 in the presence of enzyme-inducing comedications such as CBZ and PHT (120). Bourgeois (9) believed that these data indicated that it would be meaningless to set an upper therapeutic limit for serum PRM concentrations with naturally occurring PB:PRM ratios.

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Symptoms of CNS toxicity beyond those of acute initial toxicity include personality changes (99,121). Rodin et al. (94) stabilized 45 patients with partial and tonic-clonic seizures on PHT therapy. CBZ was added to this regimen for half of the group, with the others given PRM for 3 months. These comedications were then interchanged for the next 3 months. Patients receiving PRM showed a significantly higher psychopathic deviate scale on testing with the Minnesota Multiphasic Inventory in comparison with those receiving CBZ. Depressive feelings, when present, lessened when CBZ was substituted for PRM in this study.

PB, PRM's companion in long-term therapy, has been associated with behavioral changes and depression in adults (122,123) and in adults and children (124). Dodrill's review of 90 studies (125) emphasized negative behavioral changes, including depression, with the use of PB in comparison with PHT, CBZ, and VPA in the treatment of epilepsy.

Cognitive impairments in memory functions and psychological development have been related to use of PB, without dosage data, in comparison with no treatment (126, 127, 128,129). Psychotic symptoms have been observed with PRM in combination with PHT (130).

The best documentation of the role of PRM in the development of sexual impotence comes from Mattson et al. (6). Three patients intoxicated with PRM and PHT were reported with partial or complete external ophthalmoplegia (131).

Integumentary System

Rare benign maculopapular rash may appear within 2 months of starting PRM. The role of derived PB in this setting is not clear. Disappearance of the rash is anticipated within 2 weeks of PRM's discontinuation. Association of rashes with systemic reactions is even more uncommon, but those rashes are much more serious.

Hematologic and Lymphatic Systems

Several instances of megaloblastic anemia have been reported (132). Severe megaloblastic anemia was reported to follow PRM's substitution for PHT in a regimen of PHT and PB that had been given for the 4 years preceding the anemia (133). PRM's substitution for PB was followed in 4 months by megaloblastic anemia in one patient and appeared after 2 years of monotherapy with PRM in another (134). The macrocytic anemias associated with use of PRM have been reported to respond to folic acid in some patients and to vitamin B12 in others (135,136).

An instance of a neonatal coagulation defect was related to maternal use of PRM and was suspected in others (137). Prophylactic use of vitamin K is indicated in the treatment of women receiving PRM during pregnancy.

Thrombocytopenia appeared in one patient who was given PRM to replace PHT after the latter had caused bone marrow depression (138). Another instance of thrombocytopenia was also reported with PRM therapy (139). Unusually transient leukopenias (140) have also been noted. Lymphadenopathy has been observed in association with folate-deficient anemias in patients taking PRM (141).

Hepatic Toxicity

Induction of liver enzymes with asymptomatic slight elevations of liver enzymes has been noted as with other AEDs (142). There is no report linking PRM to the appearance of hepatitis (143). PRM's derived metabolite, PB, could be of causal import in serious hepatotoxicity in the very rare AED hypersensitivity syndrome (144). Granick (145) hypothesized that drugs such as PB could interact with heme and so could diminish inhibition of enzymes controlling γ-aminolevulinic acid synthetase production, thereby allowing the appearance of hereditary acute porphyria. Potential metabolic effects of PB's potent ability to induce hepatic microsomal enzymes are worthy of consideration (142).

Renal Effects

Crystalluria has been recognized as a sign of PRM intoxication in humans (119,131,146,147). The identified urinary crystals have been found to be mostly PRM (148). Renal problems, however, such as hematuria and acute or chronic renal failure have not appeared even after massive overdoses (146).

Skeletal Disorders

Enzyme-inducing AEDs may affect bone metabolism by increased conversion of active metabolites of vitamin D to inactive forms (149). Studies have shown reduced bone mineral density and impaired calcium metabolism in patients being treated with enzyme-inducing AEDs, and this list would include metabolically derived PB as well as PRM. Clinical incidence of osteomalacia is rare (150), and it is perhaps most reflective of the patient's diet and exposure to the sun (151). Calcium and vitamin D supplementation can be helpful in high-risk patients (152).

Connective Tissue Disorders

Dupuytren's contractures, various nodules, and other connective tissue changes may be included in this grouping of possible side effects. The VA study data (153) indicated statistically significant associations between use of PB and PRM for at least 6 months and the development of 10 instances of connective tissue disorders. PB had previously been identified as having causal importance in the development of contractures (154). PRM had been associated with appearance of the frozen shoulder syndrome (155). The frozen shoulder syndrome was reported to be reversible

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with continued therapy, although Mattson et al. (153) reported clearing of these changes when PHT, CBZ, and VPA were substituted for PRM.

Teratogenicity

A significant increase in cleft palates was demonstrated in mice given 100 to 250 mg/kg during 6 to 16 days of their pregnancies, with peak PRM concentrations of 43 µg/mL in comparison with untreated controls (156,157). Sprague-Dawley rats were given PRM (0 or 120 mg/kg) by gavage on gestational days 8 to 20, with PRM proving to be embryolethal for 57% of the dams (100% of the pregnant controls produced offspring) and with evidence of a specific learning deficit in the PRM-treated offspring (158).

A human syndrome of hirsute forehead, thick nasal root, anteverted nostrils, long philtra, and thin upper lips with distal digital hypoplasia and increased risks of heart defects and psychomotor retardation has been reported (159). These features have also been reported with many other AEDs. Aqueductal stenosis and enteroencephalocele have been observed with the use of PRM in pregnancy (119,134,158,160). The linkage of PRM to human malformations was complicated by the rarity of use of PRM as the sole agent (160). A survey of 983 births to epileptic mothers treated with AEDs in Japan, Italy, and Canada indicated PRM to be associated with the highest incidence of congenital malformations related to use of a single drug (161). A complex study of antiepileptic therapy during pregnancy suggested long-term effects on intellectual performance of children into adolescence in those instances of treatment with PRM (162).

Antiepileptic Drug Hypersensitive Syndrome

Various types of skin reactions can occur with the use of PRM and PB; the incidence is low (1% to 3%) (163) and usually occurs at the onset of therapy. A fatal case of dermatitis bullosa was reported (164). A patient taking PRM developed eosinophilia, edema, and a rash during the first month of pregnancy, and the rash cleared when PH was substituted (165). Systemic lupus erythematosus was associated with PRM in one case that cleared when PHT was substituted (166). It has been suggested that AEDs elicit the production of antinuclear antibodies by altering nuclear components that may unmask systemic lupus erythematosus in predisposed persons (167). This AED hypersensitivity syndrome has been reviewed (168).

CLINICAL USE

The choice of PRM as a single drug for treatment of partial or secondarily generalized seizures is valid during its first usage and for up to the next 48 hours, but the appearance of its metabolic derivative PB thereafter creates a more complex state of polypharmacy. This situation has led some investigators to view PRM as only a prodrug for PB, with PB regarded as providing the major or perhaps only antiepileptic effect (169). Eadie recognized antiepileptic effectiveness with both PRM and PB but believed that PB probably provided the major anticonvulsant effect (170). PRM's other major metabolic derivative, PEMA, has not been believed to contribute notably to either therapy or toxicity in humans. Our observation that 29 of 80 patients receiving PRM monotherapy for 12 months had excellent control of their seizures with derived serum concentrations of <15 µg/mL provided evidence of the efficacy of this drug (5). Wylie et al. (23) presented evidence in a case report that indicated that PRM possesses antiepileptic potency and pointed out an instance in which its generic substitution was followed by low serum concentrations of PRM. A 16-year-old girl with two tonic-clonic and atonic seizures weekly suddenly experienced a dramatic rise in frequency of seizures after generic substitution of PRM. Reinstitution of treatment with the brand name Mysoline was followed by return of her seizures to their baseline frequency. Generic PRM was again administered 3 months later during hospitalization, and, again, there was an increase in seizures. At this time, plasma PRM concentration had decreased by 53%, and plasma PB concentration had decreased by 16%. It was viewed as unlikely that the relatively small decline in plasma PB from 19.1 to 15.9 µg/mL was of importance in the patient's increasingly frequent seizures. Return to the brand name drug resulted in decreasing frequency of seizures to baseline values and return of plasma PRM levels.

Initiation of Therapy

Administration of large initial doses of PRM followed by rapid escalation to a desired final regimen is not possible without high likelihood of a very unpleasant experience in drug toxicity for the patient. This will almost certainly lead to discontinuation of its use. First-time users of AEDs are at the greatest risk. This potential ordeal for the patient has been noted for some time (18,171), and it has been correlated with the appearance of PRM in serum and presumably brain (48) before the appearance of either of its metabolites PB or PEMA. Discontinuation of PRM is followed by clearance of this state of toxicity in hours or sometimes days, but it will leave the patient with a distressing recollection. Patients who have been receiving AEDs, particularly drugs that induce activity of the cytochrome P450 system, usually tolerate the addition of PRM to their drug regimen with less difficulty, and that allows a higher initial dose and a more rapid upward titration of PRM. It is reasonable to recall here that experimentally shown cross-tolerance to neurotoxic effects of PRM by pretreatment with

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PB in mice (118) and rats (172) supports the clinical observations that individuals previously treated with PB have fewer side effects on first exposure to PRM (19,106).

How should PRM be started? It should begin with a discussion with the patient about potential acute side effects (dizziness, nausea, unsteadiness, sedation), followed by noting possible long-term effects. If a decision to use PRM is made, and the patient has not previously taken AEDs, an initial dose of 25 or 50 mg at bedtime may be given for several days. This should be followed by an increase to 50 mg twice daily (b.i.d.) for several more days, followed by an increase to 125 mg b.i.d. for 4 days, with a final increase to 250 mg b.i.d. as the initial goal. Some patients who have tolerated other AEDs, including those that induce hepatic cytochrome enzyme systems, may also benefit from this conservative approach, whereas others may tolerate an initial dose of 125 mg daily with a more rapid increase to a 125- and 250-mg b.i.d. schedule. At this point, a trough PRM value of ≥6 µg/mL is often achieved. It may be necessary to increase the dose to 250 mg three times daily or more to achieve satisfactory seizure control. If satisfactory control of seizures has not been achieved with serum PRM levels in the 15 µg/mL range, success is not likely with this drug in monotherapy, and other therapeutic regimens will need to be considered, although clinically unacceptable side effects are the ultimate measure of AED failure.

Serum Concentrations and Control of Seizures

A poor correlation has been noted between dose of PRM and plasma PB and plasma PRM concentrations in several studies (5,95), as is true for other AEDs. Plasma PRM concentrations do correlate with brain concentrations, and therefore dosing decisions in each patient can be guided by plasma PRM values. Plasma PB levels do not predict plasma PRM concentrations, but they do give information about the PRM:PB ratio, which may be the most important factor in determining clinical success; it is important to adjust the dose of PRM on the basis of both levels. The cooperative VA study suggests that the optimal mean plasma PRM level is 12 µg/mL, with an associated mean derived PB level of 15 µg/mL, resulting in a PRM:PB ratio of 0.8. There is great interpatient variability. Toxicity in long-term PRM therapy appears to be associated with low ratios, such as found when PRM is coadministered with PHT. Investigators have suggested that autoinduction on monotherapy with PRM does not occur to any clinically significant degree (173), and in rare patients it does not occur at all (5).

The half-life of PRM in humans ranges from 3 to >20 hours (18,19,47,174), and this range makes the assessment of PRM levels alone difficult. Without a detailed pharmacokinetic study in each patient, the timing of a trough level is complex and leads to inaccuracies (58).

Drug interactions have a significant effect on plasma PRM levels, as previously noted, and the variability in the PRM:PB ratio may be markedly altered. Measurement of plasma levels is necessary whenever PRM is used in conjunction with other drugs and especially other AEDs. Any instance of abrupt change in seizure control should alert one to the possibility of drug interaction, and one should treat the patient and not the plasma drug level.

The effect of age, both young and old, with concomitant changes in metabolism may influence the clinical effectiveness of PRM, and the variability of the PRM:PB ratio may be enhanced. Steady-state PRM concentrations are even more variable in children than in adults (175). In elderly patients, the half-life of PRM may be somewhat prolonged, but PB still accumulates (176). This population may be more sensitive to the hypnotic effects of PB and may not tolerate the usual doses of PRM. It would seem wise to monitor the plasma PRM and PB levels in children, adolescents, and the elderly more frequently, probably as often as every 3 months.

The usefulness of PRM in patients with psychiatric problems has been the subject of few investigations. One investigation demonstrated a persistent positive therapeutic effect of PRM as an adjunctive therapy in 31% of patients with refractory bipolar disorders (177).

Treatment of the developmentally delayed patient is one of the most challenging problems presented to the physician. The use of barbiturates in these patients has fallen into disfavor, but one study indicates the usefulness of PRM in retarded patients with mixed seizure types (178, 179, 180).

The metabolism of most AEDs changes during pregnancy, and PRM is no exception. The levels of PB and PEMA tend to decrease during the first trimester, although the plasma levels of PRM tend to remain fairly stable (181) or may even increase (57,182). The large decrease in PB during pregnancy is often followed by a rapid increase after delivery. Increased seizure activity is not associated with these changes. Transplacental passage of PRM is well documented (157,183,184) and has been associated with a syndrome of tremulousness, jitteriness, disturbance of sleep rhythm, and unmotivated crying in neonates. No PRM levels are detectable, although PEMA and PB concentrations are still considerable (185,186), thus providing evidence of PRM withdrawal as the significant feature. The possibility of specific PRM teratogenicity has been raised in several reports (157,159,186, 187, 188), but the data are still insufficient to allow meaningful assessment of PRM teratogenicity independent of its derived PB.

Discontinuing PRM therapy, unless there is a specific reason to proceed more quickly, should be tapered in a linear fashion during 3 to 6 months, with dosage reductions at monthly intervals. Withdrawal of barbiturates seems to be associated with a higher overall risk of withdrawal seizures, and, therefore, because of its metabolite PB, PRM should be gradually tapered.

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Other Uses

Although the use of PRM for epilepsy therapy has decreased, especially with the introduction of newer AEDs, a major role has evolved in the treatment of essential postural tremor. Eight double-blind, placebo-controlled trials were reviewed by Koller et al. (189) and indicated consistent evidence of efficacy comparable to results from β-adrenergic blockers. Doses ranged from 50 to 1000 mg/day. Adverse effects were often experienced at initiation of treatment unless low doses (25 to 50 mg) were used and were titrated slowly. Koller and Veter-Olderfiled (108) showed that the effect on tremor was the result of PRM rather than metabolically derived PB. Tremor subsided acutely after PRM initiation before clinically significant blood levels of PB had appeared, and substitution of PB for PRM resulted in recurrence of the tremor.

SUMMARY

PRM has been demonstrated to be an effective drug in the treatment of partial and secondarily generalized epilepsy and is still widely used in the treatment of epilepsy. It has also become a drug of choice for treatment of essential tremor. It is an intriguing drug because of the unique quantitative and qualitative aspects of its metabolism. PRM is both a drug in itself and, under certain circumstances, a prodrug for PB.

The liver metabolism of PRM results in the production of two metabolites with antiepileptic activity, and this has led to the confusion about whether its activity is a result of the parent compound or its PB metabolite. The other metabolites of PRM have little clinical efficacy. Numerous clinical investigations have not provided a completely clear answer to this question, although various animal studies have demonstrated the independent activity of PRM. PRM is infrequently used as a drug of first choice because of the unpleasant side effects occurring on initiation of therapy. When PRM is used as adjunctive therapy, especially with PHT, there is increased metabolism to PB that can lead to adverse effects. The clinical use of PRM represents an obligatory combination between a drug with a short elimination half-life and a drug with a long elimination half-life. The PRM:PB serum concentration ratio should be maintained as high as possible. Thus, the combination of PRM with enzyme-inducing drugs should be avoided, and it makes no sense to prescribe PB in combination with PRM. Side effects, except those appearing on initiation of therapy, are relatively uncommon, and, aside from connective tissue changes, they disappear readily on discontinuing use of PRM. Despite the introduction of several newer drugs for the treatment of epilepsy, PRM is still a drug that should be considered in certain patients.

ACKNOWLEDGMENTS

Richard Fincham died unexpectedly on November 11, 2000 without completing those sections he was writing, and I, Dorothy Schottelius, assume full responsibility for the entire chapter. Completion of this chapter would not have been possible without the assistance of Carol Devore.

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