Tacrine-Induced Hepatotoxicity

PRACTICAL THERAPEUTICS eNS Drugs 4 (3), 168-181. 1995 1172-7047/95/0009-0168/$07.00/0

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Tacrine-Induced Hepatotoxicity Tolerability and Management

Ross BaZson,l Peter R. Gibson,1,2 David Ames3 and Prithi S. BhathaZ4

1 Department of Gastroenterology, The Royal Melbourne Hospital, Parkville, Victoria, Australia 2 University of Melbourne Department of Medicine, The Royal Melbourne Hospital, Parkville,

Victoria, Australia 3 University of Melbourne Department of Psychiatry, The Royal Melbourne Hospital, Parkville,

Victoria, Australia 4 Department of Anatomical Pathology, The Royal Melbourne Hospital, Parkville, Victoria, Australia

Contents Summary ............................ . 1. Clinical Role and Efficacy of Tacrine in Alzheimer's Disease 2. Mechanisms of Action of Tacrine in Alzheimer's Disease

2.1 Biochemical Abnormalities in Alzheimer's Disease. 2.2 Pharmacological Effects of Tacrine

3. Pharmacokinetics of Tacrine .. 4. Adverse Effects of Tacrine .... 5. Tacrine-Induced Hepatotoxicity

5.1 Frequency.......... 5.2 Effect on Participation in Clinical Trials . 5.3 Clinical Features and Laboratory Abnormalities 5.4 Histological Features . . . . . . . . . . . . . . . . 5.5 Time Course and the Effect of Drug Withdrawal and Rechallenge 5.6 Predictors of Tacrine-Induced Hepatotoxicity . 5.7 Mechanisms of Tacrine-Induced Liver Cell Injury

6. Clinical Approach to Tacrine and Hepatotoxicity . 6.1 Aims ........ . 6.2 Practical Guidelines

7. Conclusions ....... .

168 169 169 169 170 170 170 171 171 172 172 172 173 175 177 178 178 179 180

Summary Tacrine, a centrally acting, reversible acetylcholinesterase inhibitor, is effective in the treatment of Alzheimer's disease. However, a major adverse effect of the drug is hepatotoxicity, which affects about one-half of patients treated.

The pathogenic mechanisms of this hepatotoxicity are poorly understood, but probably involve reactive metabolites. The liver injury is predominantly that of hepatocellular necrosis, and manifests as an increase in serum alanine aminotransferase (ALT) levels; 25 and 2% of patients will experience ALT levels greater than 3 times and 20 times the upper limit of the normal range, respectively.

Although hepatotoxicity is generally asymptomatic and has not led to death, severe reactions have been reported, and careful monitoring of ALT levels is mandatory in all patients, especially during initiation of therapy and following

Tacrine-Induced Hepatotoxicity 169

dose escalation. An ALT level exceeding 3 times the upper limit of the normal range should prompt withdrawal of the drug.

Following cessation of tacrine, ALT levels generally decrease rapidly and usually normalise within 6 weeks. Rechallenge can be safely attempted once ALT levels are near normal, except in patients whose ALT levels were markedly increased or in whom a moderate increase of ALT levels was associated with features of hypersensitivity (e.g. rash, fever, eosinophilia). Approximately 90% of those patients rechallenged with tacrine will tolerate the drug and continue with therapy on a long term basis. Minimisation of morbidity and maximisation of the number of patients treated in the long term can be achieved by following sensible guidelines and by the early recognition of danger signs.

1. Clinical Role and Efficacy of Tacrine in Alzheimer's Disease

The first report of the therapeutic use of tacrine (1 ,2,3,4-tetrahydro-9-arninoacridine) in dementia was published in 198!.lll Modest improvement in memory was reported in this nonblinded trial. In 1986, Summers et alP] published the results of the first randomised, double-blind, placebo-controlled, crossover trial of tacrine in 17 patients with Alzheimer's disease, which noted significant improvements in cognitive functions and behavioural deficiencies. However, a multicentre trial of tacrine in Alzheimer's disease was temporarily halted in October 1987 after just 2 months because of increases in aminotransferase levels in 7 of the 50 enrolled patientsJ3] As a consequence, subsequent clinical trials of tacrine have included weekly measurement of liver function tests (LFTs) as part of the trial protocol.

At least 15 randomised, double-blind, placebocontrolled trials of tacrine in Alzheimer's disease have been conducted (see Wagstaff and McTavish[4] for a review). Results have been both 'positive'[2.5-14] and 'negative' .[7,9,15-18] The earlier trials were of a crossover design, and have been justly criticised on the basis of inadequate treatment and washout periods. Other short-comings that make interpretation of the early trial results difficult include: • inadequate tacrine dosage • inadequate patient numbers • concomitant administration of drugs such as leci

thin and benzodiazepines

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• the use of insensitive and nonvalidated psychometric tests. More recent trials have been of a parallel design,

and most of these have shown definite improvement in tacrine recipients compared with those receiving placebo.

The exact clinical role of tacrine in patients with Alzheimer's disease is yet to be established, but, in a relentlessly progressive disease where few if any drugs show efficacy, the modest improvements documented during tacrine therapy offer some hope of improving functional status. Any adverse effects of tacrine, such as hepatotoxicity, that potentially might limit the use of the drug need, therefore, to be carefully evaluated, and strategies must be defined to minimise their impact on the use of the drug.

2. Mechanisms of Action of Tacrine in Alzheimer's Disease

2.1 Biochemical Abnormalities in Alzheimer's Disease

The primary cerebral defect in Alzheimer's disease is the degeneration of presynaptic cholinergic and glutamatergic neurons in parietal and temporal lobes,l19] This, combined with depressed activity of the acetylcholine synthetic enzyme choline acetyl transferase,[20] results in a deficiency of acetylcholine. Acetylcholinesterase, the enzyme responsible for degrading acetylcholine, is reduced in end-stage plaques of patients with Alzheimer's disease and in

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normal neurons of patients with the disease.[21,22] In contrast, the activity of both acetylcholinesterase and butyrylcholinesterase are increased in immature and mature neuritic plaques and neurofibrillary tangles typical of Alzheimer's disease.[21,22] Although cortical cholinergic receptor concentrations differ in Alzheimer's disease compared with those in healthy individuals, muscarinic (Md receptor numbers appear to be preserved in Alzheimer's diseaseP3] This is in contrast to nicotinic receptors, which are reduced in number.[23] Other abnormalities found include reduced brain glucose metabolism[24] and a reduction in the activity of cerebral doparninergic, serotonergic and noradrenergic systems.[20]

2.2 Pharmacological Effects of Tacrine

Tacrine is a centrally acting, reversible acetylcholinesterase and butyrylcholinesterase irihibitor, which prevents the degradation of endogenously released acetylcholine and butyrylcholineP5] In addition, tacrine binds with high affinity to muscarinic (MI and M2) receptors and, less avidly, to nicotinic receptors. [26] Tacrine produces upregulation of nicotinic receptors in rat cortex,[27] and, thus, theoretically, may reverse the trend seen in Alzheimer's disease. In contrast, muscarinic· receptors are not downregulated by doses of tacrine used in clinical practiceP7] The net effect of the above actions is an increase in the central level of acetylcholine and improvement in the cholinergic deficiency typically seen in Alzheimer's disease. In addition, central levels of histamine are increased due to tacrine-mediated inhibition ofhistamineN-methyltransferase.[28] Centrallevels of noradrenaline (norepinephrine), serotonin (5-hydroxytryptamine; 5-HT) and dopamine are also increased, as reuptake of these neurotransmitters is inhibited by tacrine[29,30] and their degradation reduced by tacrine-mediated inhibition of monoamine oxidase.[31]

3. Pharmacokinetics of Tacrine

There is wide interindividual variation in the pharmacokinetics oftacrine.[32-34] Its oral bioavailability varies between 17 and 24%,[34] with higher plasma

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Balson et al.

tacrine concentrations in women. [33,34] It is approximately 75% protein bound,[35] has a somewhat variable volume of distribution, and is widely distributed within the body, with maximal concentrations found in liver, kidney and brainP6]

Tacrine is metabolised in the liver by the cytochrome P450IA2 enzyme (fig. 1).[37] This oxidative metabolism results in the production of stable metabolites, such as I-hydroxy-tacrine,[38] which in turn undergo phase II reactions (conjugation), with subsequent excretion into bile or urine.

In addition to the production of stable metabolites, reactive metabolites capable of causing cellular damage are produced by cytochrome P450IA2. The major reactive metabolite produced during tacrine metabolism is quinone methide; produced by oxidation of 7-hydroxy-tacrine,[39] quinone methide is detoxified in the hepatocytes by conjugation with glutathione in the presence of glutathione-S-transferase. However, this conjugation step is saturable and, when this occurs, quinone methide may bind to liver cell macromolecules, causing cell damage and deathP9] In addition, quinone methide may induce unproductive oxidation-reduction cycling within the hepatocytes. This depletes cellular glutathione levels[40] and produces free radicals which, through a process of lipid peroxidation, cause cell membrane damage and cell deathp9]

Theoretically, any agent that induces cytochrome P450IA2 may increase the risk of hepatocyte injury by producing larger than usual quantities of quinone methide. Conversely, inhibition of cytochrome P450IA2 may reduce the risk of hepatocyte injury. Such hypotheses, however, have not been tested.

4. Adverse Effects of Tacrine

The major adverse reactions of tacrine are hepatotoxicity (discussed in detail in section 5) and cholinergic effects.

Cholinergic effects are generally mild, occurring in up to 92% of patients.£5] These effects are predominantly gastrointestinal in nature, including anorexia, vomiting, dyspepsia, abdominal pain and



, .. Glutathione

Excretion

COvalent binding to liver macromolecules

Fig. 1. The hepatic metabolism of tacrine. Abbreviations and symbol: GST = glutathione-8-transferase; CytP450IA2 = cytochrome oxidase P4501A2; broken line indicates depletion.

diarrhoea. Other cholinergic adverse effects, including agitation, sweating, salivation, bradycardia and increased frequency of micturition, are reported in clinical trials much less frequently than gastrointestinal adverse effects.l61 Cholinergic adverse effects are directly related to serum concentrations of tacrine[411 and usually respond to a reduction in dosage. They may occur more frequently in women because of a gender-related increase in the oral bioavailability of tacrine.l411

It should be borne in mind, however, that adverse effects are commonly reported with placebo therapy. For instance, in a recently published controlled trial of tacrine therapy involving 663 patients with Alzheimer's disease, 90% of tacrinetreated patients and 82% of placebo-treated patients reported adverse effects)51 In the tacrine group, the most frequently reported adverse events were nausea/vomiting (35%), diarrhoea (18%), dizziness

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(14%), anorexia (12%) and headache (12%). In the placebo group, headache (16%), dizziness (13%), agitation (12%) and rhinitis (11 %) were most frequently reported. In this trial, 16% of the tacrinetreated group withdrew because of cholinergic adverse effects, accounting for 30% of total withdrawals in this group (n = 479).

5. Tacrine-Induced Hepatotoxicity

5,1 Frequency

Careful monitoring of LFfs has generally been done on a weekly basis as part of the protocol for clinical trials of tacrine in Alzheimer's disease. This has allowed accurate quantification of the frequency of tacrine-induced hepatotoxicity. Hepatotoxicity, as manifested by an increase in serum alanine aminotransferase (ALT) levels, is common in patients treated with tacrine. For example, among


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2446 patients treated with tacrine in several US and European trials, an increase of ALT levels to greater than the upper limit of the normal range on at least 1 occasion was observed in 1203 (49%), greater than 3 times the upper limit of the normal range in 621 (25%), and greater than 20 times the upper limit of the normal range in 40 (2%) patients)42]

5.2 Effect on Participation in Clinical Trials

Increases of ALT levels to greater than 3 times the upper limit of the normal range were regarded in most of the clinical trials as being 'clinically significant', and resulted in withdrawal of the patient from the trial.[5,6,21] This accounted for a high proportion of patients withdrawing from tacrine treatment. For example, one-half of the patients withdrawn from a 30-week trial of high-dose tacrine were removed from the trial due to ALT values exceeding 3 times the upper limit of the normal range. [5] In some of the trials, patients in this category were allowed to enter an open-label tacrine phase once their ALT levels had settled to within twice the upper limit of the normal range.[5]

5.3 Clinical Features and Laboratory Abnormalities

To date, there have been no reported deaths related to tacrine hepatotoxicity)43] Indeed, the majority of patients experiencing tacrine-induced hepatotoxicity are asymptomatic.[42] Symptoms consistent with hepatitis, such as fatigue, malaise, nausea and vomiting do occur, but they are actually experienced with reduced or equal frequency in tacrine-treated patients with increased ALT levels compared with those with normal levels. [42] This suggests that these symptoms are more likely to be cholinergic than hepatic in origin.

The only symptom significantly associated with abnormal LFTs is fever. This is uncommon, however, with only 5% of patients with an ALT level greater than 20 times the upper limit of the normal range experiencing fever, compared with 3% with ALT levels more than 10 times normal, and 1.8% of those with a normal ALT leveU42]

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Balson et al.

The most frequently observed biochemical abnormality in tacrine-induced hepatotoxicity is an increase of the ALT level. The aspartate aminotransferase (AST) level is also frequently increased, but to a lesser magnitude. A concurrent increase of alkaline phosphatase or y-glutamyl transferase activity is rare. Of the 2446 tacrine-treated patients reviewed by Watkins et al.,[42] no patient had a bilirubin value above the level at which jaundice would be detected clinically (52 ~mol/L), although this level has been reported in tacrine-treated patients)7,44]

Peripheral blood eosinophilia may be a feature of tacrine therapy, with or without an associated increase of liver enzyme levels, but its frequency increases in proportion to the degree of increase in aminotransferase levels. For instance, in 1 series,[42] eosinophilia occurred in 13% of tacrine-treated patients who had normal ALT levels compared with 23 % of those with an ALT level greater than 3 times the upper limit of the normal range and 44% of patients with ALT values greater than 20 times the upper limit of the normal range. The association of eosinophilia and fever with tacrine hepatotoxicity is suggestive of an immune or hypersensitivity mechanism underlying the lesion (see section 5.7).

5.4 Histological Features

Liver biopsy was not part of trial protocol in any of the studies oftacrine in Alzheimer's disease, nor does it form part of the routine management of patients with tacrine hepatotoxicity, except in exceptional circumstances. As a result, only a few biopsies have been undertaken on these patients, and the reported findings are shown in table I.

Consistent with the 'hepatitic' pattern of the LFTs, focal hepatocellular necrosis or lobular hepatitis, with or without mild steatosis, have been described in most biopsies (fig. 2a,b,c). The degree of hepatocellular necrosis has generally been reflected in the level of ALT increase. Cholestasis has not been a feature in any of the reports.

Three other findings with potential implications as to the pathogenesis of hepatic abnormalities have also been noted. First, as might be anticipated


Tacrine-Induced Hepatotoxicity

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in association with peripheral blood eosinophilia, hepatic infiltration by eosinophils was described in 2 patients (fig. 2d). Secondly, a different histological picture and one with presumed immune-mediated pathogenesis, that of granulomatous hepatitis, was found in patient 1 in the study of Ames et aU45) (fig. 2d). Thirdly, other causes of increased ALT levels may also be present, as shown in patient number 9 of table 1[42) who had steatosis with nonspecific hepatitis 6 weeks after cessation oftacrine. Further investigation of this patient revealed positive hepatitis C serology and the ingestion of another potentially hepatotoxic drug (exifone). Thus, information gleaned from the limited histopathological database of tacrine-induced hepatotoxicity suggests heterogeneity of pathological patterns, implying that more than one pathogenic mechanism may be at work.

5.5 Time Course and the Effect of Drug Withdrawal and Rechallenge

A relatively consistent pattern has emerged from clinical trials of the timing of the onset of tacrineinduced hepatotoxicity, as indicated by increasing serum ALT levels. Typically, there is a delay of several weeks after the initiation of therapy before ALT levels increase, with a mean time to onset of ALT levels of greater than 3 times the upper limit of the normal range of 39 days (fig. 3).£5) However, in the majority of patients, the increase occurs in the first 12 weeks of therapy.£5,6,42)

Upon cessation of tacrine in patients with ALT levels greater than 3 times the upper limit of the normal range, ALT levels generally begin to decrease within 1 week, reaching values less than 2 times the upper limit of the normal range in a mean of 28 days[42) and normalising in a mean of 39 days (range 8 to 190 days).[5) Thus, ALT levels would be expected to normalise in all patients with tacrine hepatotoxicity upon cessation of the drug, and long term hepatic problems are not expected and have not been reported.

In patients with increased ALT levels less than 3 times the upper limit of the normal range, continuation of tacrine therapy (as done in most trials)


174 Balson et al.

Fig. 2. Uver biopsies from patients receiving tacrine (patients are numbered according to table I). (a) Patient 2 - moderate centrilobular focal necrosis (arrows) characterised by collections of pigmented macrophages and lymphocytes. Haematoxyiinleosin stain. (b) Patient 4 - more widespread cellular injury with cell swelling, mild steatosis and moderate centrilobular focal necrosis stigmatised by collections of ceroid-filled m.acrophages and lymphocytes (arrows). Periodic acid/Schiff (PAS) stain after diastase digestion. (Legend contd)

is generally associated with normalisation of ALT levels. Such an effect of continued usage has also been described for other drugs, including phenytoin and methotrexate.

Re-exposure to a drug that has previously in· duced hepatic injury in the form of hepatocellular necrosis carries a risk of fatal liver necrosis. For this reason, no patients withdrawn from tacrine treatment who had ALT levels more than 20 times the normal value have been rechallenged. However, most patients in whom tacrine is ceased following more modest increases of ALT levels have tolerated the drug when rechallenged. Of 145 tacrinetreated patients withdrawn from 2 trlalS[5,6] because


of hepatotoxicity, rechallenge with the drug (at a reduced dosage) once the ALT level had decreased to less than twice the upper limit of the normal range was associated with ALT increases to greater than 3 times the upper limit of the normal range in only 48 patients (33%). The increases in ALT levels observed following rechallenge occurred earlier (mean 22 days) than on first treatment (mean 48 days), but were of smaller magnitudeJ5,6,42] In to

tal, 88% of patients rechallenged were able to continue with treatment, some for several months, and 90 (72%) of those eventually received doses higher than that which initially necessitated cessation of the drug.[42]



c

(c) Patient 3 - centrilobular zone with drug-induced adaptive or induction cell change of liver cell, characterised by ground glass cytoplasm (crossed arrows). There is also mild focal necrosis (arrow). PAS stain after diastase digestion. (d) Patient 1 - granulomatous hepatitis and mild steatosis of liver cells. The portal tract is expanded by an epitheloid granuloma containing mutlinucleated giant cells and a mixed infiltrate of lymphocytes and eosinophils. Haematoxylin/eosin stain. Abbreviation: C = central vein.

5.6 Predictors of Tacrine-Induced Hepatotoxicity

If patients who are more likely to experience toxic effects from a given drug can be identified according to risk factors, then more detailed surveillance can be undertaken, the dosage of the drug adjusted or an alternative drug selected. Unfortunately, useful predictors of susceptibility to tacrineinduced hepatotoxicity have not been identified. Nevertheless, possible risk factors have been identified, as outlined in sections 5.6.1 to 5.6.6.

5.6. 1 Dosage of Tacrine A survey of the clinical trials of tacrine in Alz

heimer's disease reveals the relationship between


tacrine dosage and the risk of hepatotoxicity to be somewhat blurred. This is because many trials incorporated 6-weekly dosage escalations and, given that hepatic reactions to tacrine are frequently delayed, it is not possible to assess the effect of dose. The design of 1 trial,(6) however, appears to address this problem. In this placebo-controlled trial in Alzheimer's disease, 2 of 6 treatment groups comprised 77 patients receiving tacrine 20 mg/day for 12 weeks and 78 patients receiving tacrine 40 mg/day for 12 weeks. The incidence of ALT levels being greater than 3 times the upper limit of the normal range was 23% (in the 20 mg/day group) and 18% (in the 40 mg/day group). Of interest, the sixth treatment group


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15

5

o

T (n = 628) P(n=340)

40 mglday

2 4 6

T (n = 325) P (n = 266)

8 10 12

T(n=179) P (n = 185)

120 mglday

14 16 18 20

T (n = 84) P(n = 130)

160 mglday

• Taerine o Placebo

22 24 26

Balsan et al.

28 30

Treatment week

Fig. 3. Conditional probability of developing a first increase in alanine aminotransferase level to greater than 3 times the upper limit of the normal range following the recommended dosage regimen of taerine (T) or placebo (P). These patients received continuous therapy with escalating dosages of tacrine, as noted along the top of the figure. The number of patients receiving tacrine continuously for 24 and 30 weeks was 76 and 67, respectively (reproduced from Watkins et al.,142J with permission).

(in which the dosage of tacrine was doubled at 7 weeks from 40mg to 80mg daily) had an incidence of ALT levels being greater than 3 times the upper limit of the normal range of 11 %.l61 This apparent negative correlation between dosage and risk of hepatotoxicity remains to be confirmed by further studies.

5.6.2 Circulating Concentrations of Tacrlne and its Metabolftes Maximal serum concentrations of tacrine and the

ratio of tacrine to its principal metabolite appear to be directly related to the incidence of cholinergic adverse effects.!411 While tacrine concentrations are not associated with hepatic dysfunction, significantly higher ratios of tacrine : metabolite were demonstrated in patients with abnormal ALT levels compared with those without.!411 However, the overlap between the populations with and without hepatic dysfunction was large. The measurement

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oftacrine: metabolite ratio, therefore, would be of little value in predicting adverse hepatic events in individual patients, and cannot be recommended in routine clinical practice for this purpose.

5.6.3 Gender Female patients receiving tacrine are more sus

ceptible to the development of hepatotoxicity than their male counterparts. Of 2446 patients who received tacrine in several clinical trials, 43% of men and 54% of women developed an ALT level that was outside the normal range (p < 0.0l).l421 Overall, 20% of men and 27% of women developed ALT levels greater than 3 times the upper limit of the normal range (p < 0.01). This statistically significant difference may possibly be related to the increased bioavailability oftacrine in females,!41 1 but is of such small magnitude to be of little practical relevance.



5.6.4 Factors Influencing Cytochrome P450 Enzymes Theoretically, tobacco smoking and paracetamol

(acetaminophen) consumption should increase the metabolism of tacrine and the production of toxic metabolites via the induction of the cytochrome P450IA2 enzyme. Conversely, alcohol (ethanol), which specifically induces cytochrome P450IIEl[46] but has no effect on cytochrome P4501A2, should not alter the metabolism of tacrine or the frequency of hepatic dysfunction. The influence of these agents on the effects of tacrine has been examined in only 1 trial of tacrine in Alzheimer's diseaseJ42] Among smokers, 34% developed hepatotoxicity compared with 29% of nonsmokers (p = 0.45). Among alcohol drinkers (mean of 4.7 drinks/week), the incidence of hepatotoxicity was 30% compared with 29% in nondrinkers (p = 0.76)}42] Other drugs known to inhibit cytochrome P450IA2, such as cimetidine, were ceased prior to trial entry or the patients taking these drugs were excluded, and, therefore, no information of their effects is available.

5.6.5 Pre-Existing Renal or Hepatic Disease All patients included in clinical trials of tacrine

in Alzheimer's disease were required to have normal serum creatinine levels and LFTs at baseline. As a result, there are no data available on the risk of hepatotoxicity in patients with underlying renal or hepatic disease who are treated with tacrine.

5.6.6 Other Factors Other potential predictors of tacrine hepatotox

icity, such as age, indices of body habitus and baseline ALT levels, were examined by Watkins et aU42] Multiple linear regression analysis revealed that age, bodyweight, height and body surface area were significant risk factors. However, the direction of these correlations was in a counterintuitive direction, with younger and taller/heavier patients at greater risk of hepatotoxicity, and the model could account for less than 3% of the variance in maximum ALT levels.

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5.7 Mechanisms of Tacrine-Induced Liver Cell Injury

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The majority of hepatotoxic drugs cause injury via reacti ve metabolites formed during metabolism of the drug by the hepatic microsomal cytochrome P450 enzyme system. As outlined in section 3, the major reactive metabolite of tacrine is quinone methide, but how this compound induces cellular injury remains uncertain. It may cause direct cellular injury and death by binding to vital cellular components, or may, after binding to cellular macromolecules, act as haptens that incite indirect injury by a hypersensitivity-type immune reactionJ44]

There is evidence for heterogeneity of mechanisms based upon clinical and histological observations. An immunological basis is supported by the delay in onset, the apparent lack of relationship with tacrine dose,[41] the association with eosinophilia and fever, [42] the presence of granulomata and eosinophilic infiltrates in the livers of some patients,[4S] and a rapid increase in ALT levels on rechallenging with tacrineJs,6] Data supporting a nonimmune basis are the low frequency with which rash, fever and arthritis occur in patients who have tacrine-induced hepatotoxicity,[42] the attenuated ALT response on rechallenging with tacrine,[S,6] qnd the apparent tolerance to the hepatic effects on continuation of tacrine therapy. Evidence suggests, therefore, that at least 2 possible pathogenic mechanisms may underlie tacrine hepatotoxicity.

Other factors potentially influence the risk of hepatotoxicity. Since quinone methide is normally detoxified within the hepatocyte by phase II reactions (in which it is conjugated with substances such as glutathione, sulphate and glucuronide)[39] the concentrations of these cofactors in the hepatocytes may influence reactive metabolite concentration and subsequent cell damage. Likewise, factors that might modulate the activity of cytochrome P450IA2 might also influence the hepatotoxicity of tacrine by changing the rate of production of reactive metabolites. As discussed in section 5.6.4, tobacco smoking was not associated with an increased frequency of adverse hepatic reactions to tacrine.


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Mechanisms involved in the apparent 'tolerance' to the hepatotoxic effects of tacrine are not known. It presumably reflects lower levels of reactive metabolites that induce injury, and this could occur via improved detoxification from induction of existing pathways, or from better supply of substances essential for conjugation. Alternatively, other pathways for the metabolism of the drug may develop or be induced. None of these issues has been investigated.

6. Clinical Approach to Tacrine and Hepatotoxicity

6.1 Aims

Although adverse hepatic reactions to tacrine are of concern, tacrine does appear to have some efficacy in Alzheimer's disease. Since there is a paucity of alternative therapies, and since hepatotoxicity has rarely caused serious morbidity and has not resulted in mortality, it is more appropriate to learn how to use the drug within the constraints of hepatotoxicity than to stop its use altogether. The optimal clinical approach (i.e. to treat the maximum number of patients with the minimum morbidity within sensible economic constraints) should satisfy a number of aims, as outlined in sections 6.1.1 to 6.1.4.

6. 1. 1 Idenftfication of High Risk Patients As discussed in section 5.6, no clinical or lab

oratory features that enable identifioation of patients at high risk of hepatic adverse reactions to tacrine have been recognised. An alternative approach is to identify patients at higher risk following commencement of therapy, especially since hepatic reactions are characteristically delayed.[5,61 The ratio of serum concentrations of tacrine : I-hydroxytacrine has some predictive value, but measurement is costly and subject to error depending on the time from last dose to sampling)411 Thus, patients chosen for treatment with tacrine should all be considered to have similar risk, and surveillance using a cheap and readily available marker of hepatotoxicity, namely ALT (and not AST, which is neither as sen-

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Balson et al.

sitive nor specific), appears to be the best practical approach.

6. 1.2 Identification of Signs that Necessitate Drug Withdrawal The protocol employed in clinical trials of with

drawing tacrine when the ALT level exceeded 3 times the upper limit of the normal range seems an arbitrary, but nonetheless, reasonable practice to adopt. To choose a higher cut-off value of ALT level may be safe, but, to date, there is no published clinical experience to support this. Thus, at present, an ALT level exceeding 3 times the upper limit of the normal range is the only criterion for withdrawal of tacrine on the grounds of hepatotoxicity.

6.1.3 Avoidance of Unnecessary Exclusion of Patients From Further Treatment with Tacrine 25% of patients are likely to develop an ALT

level that is greater than 3 times the upper limit of the normal range and, therefore, be withdrawn from treatment.[42] Since rechallenge has ahigh success rate because of tolerance to the effect of the drug,[5,61 it is inappropriate that these patients be excluded from further tacrine treatment.

6. 1.4 Rechallenge Patients with Satety Safe rechallenge is important since clinical ex

perience with other drugs has shown the possibility of severe morbidity, or even mortality, on rechallenge with a hepatotoxic drug. As a general principle, rechallenge should be performed with a small dose of tacrine, preferably once the ALT level has normalised or is within twice the upper limit of the normal range, and with frequent monitoring of ALT levels.

The criteria for excluding rechallenge are an ALT level more than 20 times the upper limit of the normal range (especially since the height of ALT increase seems to reflect the degree of hepatocyte necrosis) and the combination of increased ALT level greater than 3 times the normal range with fever, eosinophilia or rash. This is because these features suggest an immune-mediated basis ofhepatotoxicity, which is more likely to be associated with severe reactions on rechallenge. The danger sign following rechallenge is a rapid and exaggerated increase in ALT level. Experience from clini-



cal trials suggests that approximately 12% of patients will be excluded from or will fail rechallenge because of ALT levels exceeding 3 times the upper limit of the normal rangeJ42]

6.2 Practical Guidelines

The clinical approach to the use of tacrine requires a clearly and prospectively defined management plan. We recommend that the following principles should be obeyed:

Patients must be appropriately selected - on current information, patients with known liver disease, pretreatment abnormalities of LFfs or significant renal impairment should be excluded from treatment with tacrine, as the safety of the drug in these patients is not known.

A standard dosage regimen should be adhered to - most of the current information on the management of hepatotoxicity with tacrine is based upon a standard dosage plan, i.e. 40 mg/day (in divided doses) for 6 weeks, increasing every 6 weeks to a maximum dosage of 160 mg/day. More than minor variance from this regimen cannot be justified. Rechallenge must be performed at a low dosage, which should never be more than 40 mg/day.

Regular ALT level monitoring is mandatory -the frequency of monitoring should vary according to the clinical setting, and a suggested plan is outlined in table II. In clinical trials, ALT level has been measured weekly for 12 weeks following in-

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stitution of the drug and weekly for 6 weeks after a dosage change. However, in view of the relative slowness of onset of ALT level increases, except in rechallenged patients, and the generally benign nature of the hepatotoxicity, weekly tests are probably excessive and the inconvenience they cause the patient and caregiver is not justified. Therefore, intervals of 2 weeks are more appropriate. Such an approach has recently been approved by the US Food and Drug Administration. The exception to this is after rechallenge with tacrine, when ALT levels should be measured weekly. Patients treated long term with tacrine should have ALT levels checked every 3 months, although no data are currently available to support this recommendation. If the ALT level becomes abnormal, weekly tests are mandatory. Patients in whom the drug is stopped because of abnormal ALT levels should have weekly tests until the ALT level normalises (or until rechallenge).

Trigger points for action and the action taken should be clearly defined - an ALT level of greater than 3 times the upper limit of the normal range is the sole (hepatic) trigger for drug withdrawal (table II). Rechallenge is well tolerated in patients whose maximum ALT level was less than 10 times the upper limit of the normal range, although the presence of eosinophilia (>0.4 x 1091L), fever and/or rash with ALT level increases greater than 3 times normal may be associated with an increased risk during rechallenge and so rechallenge is not rec-

Table II. Management decisions during tacrine treatment based on serial measurement of serum alanine aminotransferase (ALT) levels

Action _A_l_T_le~v_el __________ ~~~ ________ ~~~~ ______________ ~ __ ~ ______________ __ normal <3x ULN 3-10x ULN 10-20 x ULN >20 x ULN

Administration 6-weekly dose Continue tacrine Cease tacrine Cease tacrine Cease tacrine schedule escalation (same dosage)

Frequency of Every 2 weeks for 12 Weekly for 12 Weekly until ALT level Weekly until ALT Weekly until ALT weeks; every 2 weeks weeks; weekly for 6 normalises or rechallenge level normalises ALT level measurement for 6 weeks after weeks after dosage normalises

dosage increases increase

Rechallenge Not applicable Not applicable Yes, when No, when Safety uncertain, No ALTlevel associated with if rechallenged decreases to eosinophilia use 10 mg/day <2 x ULN (>0.4 x 109/L),

fever (>37.8°C) or rash

Abbreviations: ALT = alanine aminotransferase; ULN = upper limit of the normal range.

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ommended (table II). ALT level increases to greater than 20 times the upper limit of the normal range excludes rechallenge. ALT levels between 10 and 20 times normal is a 'grey' zone where experience is insufficient to provide recommendations regarding the safety of rechallenge, although at least 20 patients in this category have been safely rechallenged.[42] Decisions about rechallenge in this situation must be made on an individual patient basis by weighing up potential risks against potential benefits, and, if the patient is rechallenged, the lowest dosage possible (10 mg/day) should be used. Following rechallenge, an increase of ALT levels to values similar to or greater than those observed during the initial challenge indicates permanent drug withdrawal.

Liver biopsy is rarely indicated - liver biopsy should be restricted to situations where a diagnostic dilemma regarding the cause of abnormal LFTs exists. These could include patients in whom increased ALT levels fail to return towards normal or increase, or those in whom other possible causes of liver disease, such as viral hepatitis, drugs or alcohol, are present.

7. Conclusions

One-half of patients treated with tacrine will develop evidence of an adverse hepatic reaction, manifesting nearly always as an asymptomatic increase in ALT level. Approximately 90% of those with an abnormal ALT level will be able to use tacrine in the long term because of hepatic tolerance to the drug. It is the dual responsibility of the prescribing physician to ensure that morbidity is minimised and the proportion of patients treated in the long term is maximised. This can be successfully achieved by following sensible guidelines and by the early recognition of danger signs.

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Correspondence and reprints: Associate Professor Peter R. Gibson, Department of Medicine, The Royal Melbourne Hospital, Victoria 3050, Australia.


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Tacrine-Induced Hepatotoxicity