Internutional Journal of Ccrrdiologv. 13 (1986) 219-229

Elsevier

219

IJC 00450

Perhexiline maleate treatment for severe angina pectoris - correlations with pharmacokinetics J.D. Horowitz, S.T.B. Sia, P.S. Macdonald, A.J. Goble, W.J. Louis

Department.! of Cardiology and Clinical Pharmacologb: Austirr Hospiral, Heidelberg, L’ictona, 3084. Australia

(Received 19 August 1985; revision accepted 14 May 1986)

Horowitz JD, Sia STB, Macdonald PS, Goble AJ, Louis WJ. Perhexiline maleate treatment for severe angina pectoris - correlations with pharmacokinetics. Int J Cardiol 1986;13:219-229.

Perhexiline maleate, which causes inhibition of myocardial fatty acid catabolism with a concomitant increase in glucose utilization, is particularly useful in the management of patients with severe angina pectoris. While perhexiline exerts no significant negative inotropic or dromotropic effects, its short- and long-term use has hitherto been restricted because of complex pharmacokinetics and the eventual development, in many patients, of hepatitis and peripberal neuropathy.

Correlations between perhexiline dose, plasma drug concentrations, efficacy and development of toxicity were examined prospectively in 3 groups of patients. The first group (n = 29) were patients in whom perhexiline was added to previously prescribed anti-angina1 medication for short-term (pre-surgical or post-myocardial infarction) control of angina pectoris. Over a mean treatment period of 18 f 2 (SEM) days, 13 patients experienced a marked reduction in frequency and severity of attacks. No adverse effects occurred. A second group of patients (n = 19) were treated chronically with 50-400 mg/day of perhexiline, dosage being adjusted to minimize symptoms. Over a mean treatment period of 8.8 f 1.7 months, 5 patients became asymptomatic, while 9 developed evidence of hepatitis or neurotoxicity, with concomitant plasma perhexiline concentrations of 720-2680 ng/ml. Subsequently, a further group of similar patients (n = 22) were treated for 12.4 f 2.6 months, perhexiline dosage being adjusted to maintain plasma perhexiline concentrations below 600 ng/ml. Nine patients became asymptomatic, while none developed adverse effects.

It is concluded that perhexiline is useful both as a short-term adjunct to anti-angi- nal therapy and in the long-term management of patients unsuitable for coronary

Correspondence and reprint requests to: Dr. J.D. Horowitz. Department of Cardiology, Austin

Hospital, Heidelberg, Victoria. 3084. Australia.

0167-5273/86/$03.50 c 1986 Elsevier Science Publishers B.V. (Biomedical Division)

220

artery bypass grafting. The risk of long-term toxicity can be reduced markedly by maintenance of plasma drug concentrations below 600 ng/ml without significantly compromising anti-angina1 efficacy.

(Key words: Ischemic heart disease: Drug trials: Pharmacology)

Introduction

The prophylactic antianginal agent perhexiline maleate is often regarded [l] as a particularly toxic calcium antagonist, which therefore has little place in cardiological

practice. However, recent studies [2-41 suggest that the relatively weak effects of perhexiline on slow channel activity do not contribute significantly to the anti-angi- nal or anti-arrhythmic effects of the drug. Rather, perhexiline acts via inhibition of

myocardial fatty acid catabolism, with a concomitant increase in glucose utilization and consequent oxygen-sparing effect. This mechanism of action is more consistent with the observed lack of negative inotropic or peripheral vasomotor effects of

perhexiline. The drug’s advantages include its superiority to beta-adrenoceptor blocking drugs

151, its incremental effects in combination with other anti-angina1 agents [6,7] and the minimal risk of adverse haemodynamic effects. Perhexiline can therefore be

added to the pre-operative treatment regimen of patients with severe angina pectoris [7] or used for the management of patients with angina pectoris and severely

impaired left ventricular function. We report here a series of investigations of the short- and long-term use of

perhexiline, correlating efficacy and toxicity with plasma drug concentrations. The data suggest that monitoring of plasma perhexiline concentrations may significantly reduce the risk of long-term toxicity while maintaining clinical efficacy.

Patients and Methods

Short-Term Treatment Group

Patients were considered prospectively for short-term (less than 3 months)

treatment with perhexiline, on the basis of unstable angina pectoris not responding adequately to usual doses of other anti-angina1 medication, or persisting angina in the immediate period following extensive acute transmural myocardial infarction. It

was anticipated that most of these patients would come to coronary artery bypass surgery. In all cases perhexiline was added to previously prescribed anti-angina1

medication, including nitrates, beta-adrenoceptor antagonists and calcium

antagonists, without subsequent adjustment of dosage of the other medications.

Long-Term Treatment: Drug Dose Adjustment on Basis of Clinical Response only

Patients were considered prospectively for long-term (more than three months) treatment with perhexiline, on the basis of severe angina pectoris either unrespon-

221

sive to or unsuitable for other forms of treatment. All of these patients were

considered unsuitable for coronary artery bypass grafting on the basis of distal

coronary artery stenosis, poor left ventricular function and/or advanced age. Except

for patients with severely impaired left ventricular function, perhexiline was added

to the treatment regimen only after an inadequate therapeutic response had resulted

from the use of beta-adrenoceptor and/or calcium antagonists. Patients were assessed clinically prior to initiation of perhexiline therapy and at two-weekly

intervals for six weeks thereafter. Subsequently, patients were seen every three

months. Perhexiline dosage was adjusted in order to minimize angina1 symptoms,

with reductions in dosage if patients became asymptomatic for prolonged periods.

Liver function tests and plasma perhexiline concentrations were measured at each visit. Perhexiline was ceased in any patient in whom clinical or biochemical evidence

of drug toxicity developed. At no stage was plasma perhexiline concentration used

as a guide to dosage.

Long-Term Treatment: Dosage Adjustment on Basis of Plasma Drug Concentrations

Indications for treatment and the treatment protocol were as for other patients

receiving long-term treatment except that adjustments in perhexiline dosage regimen were made primarily with the objective of achieving steady-state plasma perhexiline

concentrations of between 150 and 600 ng/ml, irrespective of residual angina1

severity. In all patients, the anti-angina1 effects of perhexiline were assessed relative to the

mean frequency of angina pectoris during the perhexiline treatment period im- mediately prior to initiation of therapy. Responses were graded as either complete suppression of symptoms, reduction in angina1 severity (to less than one third of

initial frequency of attacks) or equivocal responses to perhexiline. No patients experienced an increase in angina1 frequency.

Perhexiline dosage regimen was: for short-term treatment 200 mg twice daily for

three days, followed by 100 mg twice daily thereafter. For long-term treatment, dosage adjustment was within the range of 50 to 400 mg/day as dictated by the protocol, initial dose being 100 mg twice daily in most cases.

Blood samples for plasma perhexiline concentrations were taken four hours after

the last drug dose. Perhexiline concentrations were determined utilizing a previously described high performance liquid chromatographic assay [8].

Results

Short-Term Perhexiline Therapy

Twenty-nine patients were studied, 19 with unstable angina pectoris and 10 with ongoing angina pectoris immediately following acute transmural myocardial infarc-

tion (Table 1). Mean duration of treatment was 18 i 1.9 (SEM) days; the post-in- farct patients were treated for 9 to 70 days. Four patients had severe left ventricular failure. Twenty five received concomitant treatment with long-acting nitrate pre-

222

TABLE I

Patients treated with perhexiline as “short-term” measure. M = metoprolol: N = cutaneous nitro-

glycerine; Nif = nifedipine; P = propranolol; V = verapamil; # = severe left ventricular failure; * =

angina persisting after transmural myocardial infarction: + + = complete suppression of angina1 symp-

toms: + = reduction in angina1 symptoms; ? = equivocal response as regards angina1 symptoms,

Patient

no.

Sex Age Other

(yr) treatment

Duration of

treatment

(days)

Response

1

2

3

4

5

6#

7

8

9

10 #

11

12

13

14

15 #

16

17

18

19

20 * #

21 * #

22 *

23 *

24 *

25 *

26 *

27 *

28 *

29 *

Mean

SEM

Range

F

M

M

M

F

M

M

F

M

F

M

M

M

M

F

M

M

M

M

M

F

M

M

M

M

M

M

M

M

67 N. V 6

52 V 8

58 V 28

62 N. V 2

46 N. V 3

49 N 7

52 M. N, V 6

51 N. V 9

48 N. V 7

61 N 14

76 N, V 6

68

50

62 68

62

41

58

64

53

76

50

48

50

61

76

73

50

42

57.7

3.4

42-16

P. V

N, V N. P, Nif

N

N, Nif

N, V

N. V N. V N N

M. N. V N. V N. V V

N. V

N. V

N. P, V N

9

8

10

10

12

7

56

56

9

50

70

42

21

4

20

14

22

18.0

1.9

2-56

++ + ++ + + ++ + ? + + ? (subendocardial

infarct)

++

+

+

++

+

++

++

? ?

++

++ ?

+

ii

?

++

++

++

parations, 23 with calcium antagonists and 5 with beta-adrenoceptor antagonists. During the treatment period 13 patients became asymptomatic while a further 11

experienced a reduction in angina1 frequency. One patient developed a small subendocardial infarction three days after starting perhexiline while one post-infarc- tion patient died suddenly in electromechanical dissociation nine days after starting treatment. Permission for post-mortem examination was refused. No patient devel-

223

101 I , 4

1 2 3 L 5

Durotion of treatment (Cloy51

Fig. 1. Mean plasma perhexiline concentrations in short-term therapy patients (n = 29) over the first 5

days of treatment.

oped abnormal liver function tests, paraesthesiae or peripheral neuropathy during

this short treatment period. Plasma perhexiline concentrations were measured in 15 of the 29 patients during

the first 5 days of therapy. These revealed marked inter-individual variability (Fig.

1) although mean plasma drug concentrations remained at approximately 350 ng/ml after the second day of treatment.

Long-Term Perhexiline Therapy

Nineteen patients were treated long term with dosage adjustment on the basis of

the clinical response for periods of 8.8 & 1.7 months (range l-27 months) with a mean maximal daily perhexiline dosage of 200 + 24 mg (range 50-400 mg/day) as summarised in Table 2. Five patients became asymptomatic, while a further 9

experienced a reduction in frequency of angina1 attacks; in the remaining 5 patients the response to perhexiline was equivocal. Two patients died as a result of worsen- ing severe left ventricular failure after 4 weeks of perhexiline therapy. Two further patients underwent coronary artery bypass grafting after 6 and 9 months of perhexiline therapy respectively because of persistent severe angina pectoris. One

patient also developed a small subendocardial myocardial infarction during the

perhexiline treatment period. In 9 patients (Table 3) perhexiline therapy was stopped after 1 to 22 months

because of the occurrence of toxic adverse effects. These included biochemical or

clinical hepatotoxicity in 4 patients, paraesthesiae with or without clinical evidence of peripheral neuropathy in five. and blurring of vision in one patient. Liver biopsy was performed in one patient (no. 2) confirming the presence of hepatitic changes,

224

TABLE 2

Patients treated chronically with perhexiline in whom drug dosage was adjusted on the basis of clinical

response, irrespective of plasma perhexiline concentration. I = isosorbide dinitrate: M = metoprolol;

N = cutaneous nitroglycerine; 0 = oxprenolol; P = propranolol; V = verapamil: # = severe left ventricu-

lar failure; + + = complete suppression of angina1 symptoms; + = reduction in angina1 symptoms:

? = equivocal response as regards angina1 symptoms; * = adverse effects.

Patient Sex Age Other Perhexiline Max. perhexiline Duration Response

no. (Y’) treatment dose concentration of

( mg/day) (ng/ml) treatment

(months)

1 M 71 P 100-150 280 27 +

2 M 46 M.V 100-200 890 * 22 +

3 F 13 N,V 100 443 19 +

4# M 83 50 225 12 +

5 F 75 P 50-200 595 12 +

6 F 68 P 100-150 910 12 +

7 M 68 v 150-300 720 * 10 +

8 M 53 P 150-300 1500 * 9 ?

9 M 56 M 100-300 1390 * 9 +

10 M 52 N, 0. V 50-100 2 854 6 ? 11 M 62 N, V 200-400 1725 * 6 ?

12 M 65 I, M. V 100 1994 * 5 ++

13 F 67 V 100-200 600 4 ++

14 # F 72 1. N 150-200 751 * 4 ++

15 M 58 M,N 100-200 1157 * 4 ++ 16 M 49 N.V 200 1131 3 ?

17 M 75 v 200 2680 * 1 ++ 18 # M 48 - 50 85 1 ? 79 # F 80 N, V 200-400 2300 1 7 Mean 60.0 200 (max) 1170 8.8

SEM 3.9 23.6 188 1.7

Range 46-83 50-400 85-2854 1-27

TABLE 3

Adverse effects of perhexiline in patients treated chronically with dosage adjustment on the basis of

clinical response only. Plasma perhexiline concentrations are those corresponding with emergence of

toxic effect.

Patient

no.

Duration of Plasma perhexiline

treatment concentration

(months) (ng/ml)

Adverse effect(s)

2 22 890

7 10 720

8 9 1500

9 9 1390

11 6 1725

12 5 1994

14 4 751

15 4 1757

17 1 2 680

Mean: 1281+251

Hepatotoxicity/nausea

Peripheral neuropathy

Hepatotoxicity

Paraesthesiae

Peripheral neuropathy

Hepatotoxicity

Paraesthesiae

Paraesthesiae/

hepatotoxicity

Blurring of vision

225

TABLE 4

Patients treated chronically with perhexiline in whom drug dosage was adjusted to keep steady-state

perhexiline concentration less than 600 ng/ml. I = isosorbide dinitrate; M = metoprolol; N = cutaneous

nitroglycerine: P = propranolol: V = verapamil: * = severe left ventricular failure; + + = complete

suppression of angina1 symptoms; + = reduction in angina1 severity.

Patient

no.

1

2

3

4*

5

6

7

s*

9

10

11

12 *

13 *

14

15

16 *

17

18

19

20

21

22

Mean

SEM

Range

Sex

-

Age Other

W) treatment

48

69

14

56

57

61

72

60

56

59

38

13

61

76

69

69

71

15

75

15

63

43

63.9

2.3

38-76

M. V 100-150

P

P, V N

N, V

M. V

N. V N

M

N, V

M, N

I. N N

V

N. V

L N

N, V

M, V

N. V

I. V N

N. V

Perhexiline

dose range

(mg/day)

100

loo-150

200

200

200-300

150-200

50-100

100-150

100

100-200

50-150

150

50-100

200

100

100-200

150-200

50

100-200

200

200

161 (max.)

12.3

50-300

-

Max. Duration Response

perhexiline of

concentration treatment

(rig/m))) (months)

660 42 +

26X 40 +

436 34 +

560 21 ++

208 19 ++

417 18 +

440 12 +

630 11 ++

600 11 +

512 9 ++

125 8 +

126 I ++

180 7 +

464 7 +

370 6 +

270 4 ++

614 4 +

164 4 +

110 3 ++

35 3 ++

313 3 +

339 3 ++

389 12.4

44 2.6

35-164 3-42

while nerve conduction studies revealed impaired conduction in patients 7 and 12.

In all cases, symptoms and abnormal clinical findings resolved within 6 months of cessation of perhexiline therapy.

Maximal plasma perhexiline concentrations were 1170 f 188 ng/ml in this group of patients overall and 1281 f 251 ng/ml in patients developing adverse effects. No patient developed adverse effects with corresponding plasma perhexiline concentra- tions below 700 ng/ml, the range being 720 to 2680 ng/ml. Four patients had

maximal levels above 700 ng/ml without developing adverse effects during the period of therapy.

In the 22 patients treated long-term with dosage adjustment on the basis of plasma drug concentrations (Table 4) we tested the hypothesis that adverse effects of perhexiline might be prevented by maintaining steady-state plasma drug levels below the point at which toxic effects had been noted in other patients on long-term

226

treatment. Patients selected were similar to the previously studied long-term patients

in age, duration of therapy, concomitant anti-angina] treatment and frequency of severely impaired left ventricular function. Mean maximal perhexiline dosage was

161 $- 12 mg/day, although the duration of maximal dosage was shorter than that of

other long-term treatment patients by virtue of the provisions for dosage adjust-

ment. Maximal plasma perhexiline concentrations were 389 _t 44 ng/ml (P < 0.001 vs. the other long-term treatment group) with a range of 35 to 764 ng/ml. Nine patients became asymptomatic and reduced angina1 frequency occurred in the

remaining 13. No patient developed clinical or biochemical evidence of toxicity.

Discussion

The results of the currently reported investigations indicate that perhexiline maleate can be utilized in the short- and long-term prophylaxis of severe angina

pectoris without appreciable risk of the development of clinical or biochemical toxicity. These findings are of dinical significance because of the unique actions and therapeutic efficacy of perhexiline. For approximately ten years after its initial

development, no adequate explanation was available for the anti-angina1 (and anti-arrhythmic) effects of perhexiline. although it was observed to be a weak coronary vasodilator and to improve myocardial lactate extraction in patients with

ischaemic heart disease. It was then observed that perhexiline was a weak calcium antagonist [9], and it was thereafter assumed for several years that this property explained its therapeutic effects. Usual plasma perhexiline concentrations in pa-

tients on chronic treatment, however, were unlikely to induce significant antagonism of slow channel activity [2]. In one study, perhexiline was reported to be far less

effective than other calcium antagonists in the management of vasospastic angina

pectoris [lo]. The review of Vaughan Williams [2] summarised evidence of unique effects of

perhexiline on myocardial metabolism, consisting largely of a shift from fatty acid

to carbohydrate utilization by ischaemic myocardium, with a concomitant sparing of myocardial oxygen utilization. Such an effect, suggested by a number of biochem- ical, clinical and tissue culture studies, would accord with the clinical efficacy of perhexiline in patients with classical, rather than vasospastic, angina pectoris, its lack of negative inotropic effects in normal therapeutic doses (indeed a weak

positive inotropic effect may occur [II]) and even its potential for eventual develop- ment of toxicity, via tissue deposition of non-metabolized lipids [12]. Other drugs may exert, inter alia, similar anti-angina1 effects to those of perhexiline - these include 4-hydroxyphenylglycine [13] and amiodarone [14]. Similarities between the

patterns of toxicity of perhexiline and amiodarone have also been observed [15]. The clinical efficacy of perhexiline includes significant anti-angina1 effects,

incremental over those of beta-adrenoceptor antagonists, nitrates and conventional

calcium antagonists. in patients with otherwise intractable angina pectoris (5-71. Major impairment of left ventricular function is not a contraindication to the use of the drug. There is therefore considerable incentive to investigate methods of limiting

the development of major perhexiline toxicity.

227

Singlas et al. [16] demonstrated that plasma perhexiline levels were usually elevated above 2000 ng/ml in patients with drug-induced peripheral neuropathy and significant hepatotoxicity. Further studies at St. Mary’s Hospital identified that

“slow hydroxylators” of debrisoquine and phenformin also had an increased risk for

the development of perhexiline-induced peripheral neuropathy [17]. The proportion

of patients at risk as regards perhexiline toxicity, however, is higher than can be

expected from the prevalence of “slow hydroxylators” [18]. This is confirmed by the

high incidence in the initial group of long-term treatment patients of the current

series. Moreover, peripheral neuropathy has been documented in the presence of

“normal” hydroxylator status [19]. Our previous finding [8] that perhexiline metabolism is readily saturable identi-

fies a further difficulty in predicting steady-state plasma drug concentrations from

daily drug dosage, and emphasizes the risk of increasing daily dosage above 200 mg in most patients. Even at this dose, prospective evaluation in patients treated long

term with adjustment of drug dosage on the basis of clinical response only indicated a significant risk of toxicity. The occurrence of toxicity at plasma perhexiline concentrations below those reported by Singlas et al. probably relates to differences

in study design; our study detected cases of early drug toxicity, which were readily reversible on cessation of perhexiline therapy. Nevertheless, it was observed that elevation of plasma perhexiline concentrations above 700 ng/ml antedated the

development of toxicity in all cases. The recent observations of Pilcher et al. [20] also indicated that long-term adverse effects of perhexiline developed at plasma

drug concentrations of less than the 2000 ng/ml suggested by Singlas et al. [16]. In patients treated long term with perhexiline dosage adjustment on the basis of

plasma drug concentrations, steady state plasma perhexiline concentrations were largely below 600 ng/ml and significant drug toxicity did not occur. We emphasise that this was not a controlled study and that there are therefore difficulties in

assessing the extent of a possible placebo component of the symptomatic response to perhexiline, although overall, the efficacy of the drug has been established by other controlled studies. However, 9 of 22 patients in this group became

asymptomatic, suggesting that efficacy was not markedly impaired. On the basis of correlations between plasma drug concentrations and subjective improvement in angina1 frequency, we would suggest 150 ng/ml as the lower limit of the therapeutic

range for plasma perhexiline concentrations. This corresponds with the observations of other investigators [20]. There is little information available as to possible anti-angina1 activity of the various hydroxylated metabolites of perhexiline, al-

though these are unlikely to contribute significantly to toxicity [16,19] and available evidence suggests that the major metabolite (M,) is an even weaker calcium antagonist than is perhexiline [21]. It is therefore relatively unlikely that concom-

itant assay of metabolite concentrations would markedly improve the predictive relationship between plasma drug concentrations and efficacy [20].

The short-term use of perhexiline maleate has previously been shown to help reduce frequency and severity of angina1 attacks. The results in the short-term treatment patients in the current series are in accordance with this finding, and confirm marked inter-individual variability in drug handling. It would appear

228

appropriate to utilize an initial loading dose of perhexiline in such patients.

Furthermore, although drug toxicity is not a significant risk in the short term,

monitoring of plasma drug concentrations may permit optimization of dosage.

It has been a general finding that other cardio-active drugs with long durations of

action such as amiodarone, digoxin and diphenylhydantoin often present significant

risks of long-term toxicity. Monitoring of plasma drug concentrations for such

agents tends to be of value in optimizing drug use and preventing toxicity. While the clinical role of perhexiline should remain a secondary one in the prophylaxis of

angina pectoris, we feel that with routine monitoring of plasma drug concentrations the drug offers important therapeutic advantages for a select group of patients.

Acknowledgements

We wish to acknowledge the expert technical assistance of Mrs. P. Morris, Mrs. M. Syrjanen and Miss M. Mirceta, who performed the plasma perhexiline assays.

The support of the nursing staff of the Coronary Care Unit and general medical wards of the Austin Hospital is also acknowledged. This study was supported in part by a grant from the National Health and Medical Research Council of

Australia.

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