Drug Development Research 11:131-143 (1987)

Human Safety Profile of Tolrestat: An Aldose Reductase Inhibitor Steven Ryder, Brenda Sarokhan, David G. Shand, and John F. Mullane

Ayerst Laboratories, New York

ABSTRACT

Ryder, S., B. Sarokhan, D.G. Shand, and J.F. Mullane: Human safety profile of tol- restat: An aldose reductase inhibitor. Drug Dev. Res. 11:131-143, 1987.

The safety of tolrestat use in the diabetic patient was demonstrated by data from 14 double-blind and open-label studies conducted in 1,300 patients with diabetic neuropathy; the results were supported by data from earlier bioavailability, pharmacokinetic, and clinical pharmacology trials. There was a generally comparable frequency of complaints in the tolrestat dose groups and placebo groups. In a year-long double-blind study, the only complaint considered to be “possibly” drug-related that occurred with a significantly greater incidence in patients treated with tolrestat than in those on placebo was dizziness. Laboratory test values recorded during the trials supported the positive safety findings of tolrestat. A review of blood urea nitrogen and serum creatinine values did not suggest any potential for tolrestat-induced renal dysfunction. Infrequently, significant elevations in serum hepatic enzyme (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) levels occurred, accounting for 27 of 42 possibly drug-related patient withdrawals following tolrestat administration. On review of these cases, it was concluded that tolrestat may cause hepatocellular damage with coincident elevations in AST and ALT in approximately 2% of patients. Importantly, the abnormalities were reversible after discontinuing the drug, commonly within 8-16 weeks. There was no evidence of a hypersensitivity syndrome in any patient in any study. These results support a favorable safety profile for tolrestat.

Key words: aldose reductase, diabetes, neuropathy

INTRODUCTION

Tolrestat is a novel compound of a new therapeutic class of drugs, the aldose reductase inhibitors (Fig. 1) [Dvornik et al., 19831. There is increasing evidence supporting the involve-

Received final version March 11, 1987; accepted March 12, 1987.

Address reprint requests to John Mullane, Ayerst Laboratories, 685 Third Avenue, New York, NY 1oO17-4071.

0 1987 Alan R. Liss, Inc.

132 Ryder et al

Fig. 1. Molecular structure of tolrestat, an orally active aldose reductase inhibitor. Tolrestat is a stable, yellowish crystalline compound with a molecular weight of 357.36 and an empirical formula of C ,6H 14F3NO3S2. Chemical name: N-[[5-(trifluoromethyl)-6-methoxy- 1-naphthenyll-thioxomethyll-N- methylglycine.

ment of aldose reductase in the pathogenesis of chronic diabetic complications, including diabetic neuropathy [Culebras et al., 1981; Fagius and Jameson, 1981; Handelsman and Turtle, 1981; Jaspan et al., 1983; Judzewitsch et al., 1983; Koglin et al., 1985; Young et al., 19831 and, possibly, diabetic retinopathy and nephropathy [Cogan et al., 1984; Johnson and Bressler, 19841. Aldose reductase (AR) is the first enzyme of the polyol pathway, an alternate route of glucose metabolism principally active under hyperglycemic conditions [Johnson and Bressler, 19841.

In established animal models of acute and chronic diabetes, orally administered tolrestat effectively prevents polyol accumulation in a variety of AR-containing tissues, including the sciatic nerve [Simard-Duquesne et al., 1985al. Tolrestat-induced prevention of polyol accu- mulation in AR-containing tissues of experimentally diabetic or galactosemic rats also prevents the development of subsequent biochemical, functional, and morphological changes [Dvornik et al., 1986; Kemper et al., 1985; Notvest et al., 1986; Robison et al., 1986; Shard-Duquesne et al . , 3985b; Sredy et al., 19861. Thus, tolrestat prevented neural myoinositol depletion in rats with experimentally induced diabetes and galactosemia [Dvornik et al., 1986; Kemper et al., 19851, prevented the hyperglycemia-induced impairment of auditory-evoked brainstem responses in diabetic rats [Notvest et al., 19861, and, in chronic, severe galactosemia, pre- vented both the thickening of basement membranes of retinal capillaries [Robison et al., 19861 and the appearance of any relevant lenticular changes detectable by slit-lamp microscopy [Simard-Duquesne et al., 1985bI.

In diabetic patients, tolrestat dosages of 200-400 mg per day produce prompt and sustained normalization of elevated red blood cell (RBC) sorbitol levels without affecting glucose control [Raskin et al., 1985; Weidler et al., 19861. Administration of tolrestat is also associated with both significant objective (motor nerve conduction velocity) and subjective (painful and paresthetic symptom severity) neuropathic improvement [Boulton and The Tolres- tat in Neuropathy Study Group, 1986; Ryder and The Tolrestat in Painful Neuropathy Study Group, 19861. Tolrestat is currently being further investigated in the treatment and prevention of diabetic neuropathy as well as retinopathy and nephropathy.

A substantial body of data on the safety of tolrestat has been collected from 14 double- blind and open-label neuropathy studies in which 1,300 patients were exposed to tolrestat for periods of up to 2 years. Assessments of premature discontinuations, patient complaints/ adverse experiences, laboratory tests, physical examinations including vital signs and electro- cardiograms, and intercurrent illnesses were performed. In addition, extensive analyses of liver and kidney function were conducted as well as an evaluation of the drug’s safety in elderly patients. Safety data were also analyzed from 12 single- and multiple-dose bioavailabil- ity, pharmacokinetic, and clinical pharmacology trials conducted in normal subjects and in diabetic subjects without neuropathy.

Human Safety Profde of Tolrestat 133

MATERIALS AND METHODS General Safety Analyses

The safety of tolrestat was monitored by regularly scheduled visits as well as by interim visits if necessitated by a patient’s clinical condition. In the neuropathy trials, regularly scheduled visits occurred at 2- to 12-week intervals. Any and all patient complaintsladverse experiences as well as any intercurrent illnesses were recorded at each visit. The complaints/ adverse experiences were either volunteered by the patient or elicited by the investigator. The occurrence of a patient complaint/adverse experience was recorded as a new complaint if it was not present at the screening and baseline visits (“normal during pretreatment”), regardless of whether or not the patient had a past history of the complaint. If an investigator assessed the complaintladverse experience to have even a possible relationship to the trial medication, the complaint was considered drug-related. In the neuropathy trials, an extensive printed list of complaints, organized by body system, was provided in every case report form for every visit, specifying 75 potential complaints and allowing for any nonspecified complaint (using the preferred terminology of the World Health Organization Terminology for Adverse Reaction to Drugs).

At every visit, a physical examination was performed, including measurement of vital signs and an electrocardiogram, and specific laboratory data were obtained in order to monitor the hematologic, hepatic, renal, and other biochemical parameters before and after exposure to the study drug. In addition to these standard laboratory tests, supplementary tests of diabetic control (fasting plasma glucose and glycosylated hemoglobin) and renal function (creatinine clearance determinations and 24-hour urinary protein excretion) were performed regularly during each study.

Each premature discontinuation was recorded, and the event necessitating withdrawal was described by the investigator. The possible reasons for discontinuation of a patient from a study were categorized as follows: intercurrent illness; adverse reaction or laboratory abnor- mality, whether drug-related or not; withdrawal of consent by the patient; administrative request; and other, such as protocol violation or failure of a patient to meet entrance criteria. All premature discontinuations were reviewed for any possible relationship to drug administration.

Special Safety Analyses

As liver and kidney changes had occurred in some animals exposed to doses of tolrestat ranging from 100 to 500 mglkg during toxicology studies, separate specific and rigorous reviews of the hepatic and renal function test results were conducted. Another review was conducted of the patient complaintsladverse experiences and laboratory test abnormalities that occurred specifically in the elderly patient population.

Study Populations

Three study populations form the bases for the various safety analyses. 1) A premature discontinuation analysis includes all 1,300 patients from the neuropathy trials (Table 1). 2) An overall safety analysis covers data from the 1,121 neuropathy patients enrolled in two com- pleted double-blind, placebo-controlled trials, one of 52 weeks and the other of 8 weeks duration, and in three ongoing open-label trials that include all of the above-mentioned general and special analyses. 3) A separate patient complaint/adverse experience analysis covers the 12 single- and multiple-dose studies conducted in 180 normal subjects and 63 diabetic subjects without neuropathy. It should be noted that in some instances the numbers of patients in the different tolrestat treatment groups do not equal the total number that was analyzed because some of the patients who received placebo or unknown blinded drug during the double-blind trials received tolrestat during a subsequent open-label extension study.

Because of the markedly different durations of the two double-blind tolrestat trials, a step-wise review of potential patient complaints and laboratory abnormalities was undertaken.

134 Ryder et a1

TABLE 1. Summary of Clinical Diabetic Neuropathy Studies

Study location Study Treatmenta Dose (mg) and length (No. of studies) design group of treatment (wk) Nb

Double-blindc

34 centers parallel group,

Open-label extensions of double-blind studies,

27 centers Open-label, 13 centers Open-label

extension of open-label study,

12 centers

Double-blind

21 centers Open-label

parallel group,

extensions of double-blind studies,

P

T

T 50 q.d.d X 52 100q.d. x 52 200 q.d. x 52 400 q.d. x 8 100 b.i.d.e x 52 200 b i d . X 8

X 52 X 8

200q.d. x 48+ 400 q.d. X 40-48 t

T

T

200q.d. X 52 400 q.d. x 52 200 q.d. x 4 8 t

T 200-400q.d. X 12-24

P x 12-24 T 200-400 q.d. X 28-40

116 110 112 86

105 85

107 89

138 254

69 242

11

1 79f

96

21 centers

dT, tolrestat; P, placebo. bN, No. of patients enrolled. ‘Data from completed trials only; all other trials are ongoing. dQuaque die, once a day. eBis in die, twice a day. fNo. of patients enrolled in an ongoing double-blind trial whose randomization code has not been broken.

First, the greatest reliance was placed on the data from the 1-year double-blind trial, which was used to identify those complaints and laboratory abnormalities that occurred significantly more often on drug than placebo [Boulton and The Tolrestat in Neuropathy Study Group, 19861. Second, confirmation was then sought from the results of the 8-week double-blind trial [Ryder and The Tolrestat in Painful Neuropathy Study Group, 19861. Third, an indication of general incidence rates for laboratory abnormalities and drug-related patient complaints/ adverse experiences was developed on the basis of pooled data from open-label and double- blind trials for the patients receiving tolrestat 200 and 400 mg quaque die (q.d.) dosages. Finally, data from the open-label investigations were used to supplement the parametric safety analyses of renal and hepatic function, diabetic control indices, lipid levels, and vital signs.

RESULTS Demographics

In the 14 studies involving 1,300 patients with diabetic neuropathy (Table l), the total patient exposure to tolrestat was approximately 650 patient-years. The U. S./Canadian trials

Human Safety Profile of Tolrestat 135

were geographically dispersed with four Canadian centers participating in one double-blind study and its open-label extension. The European trials involved the United Kingdom, the Benelux countries, France, and Italy, with separate double-blind and open-label extension trials in each of these regions. The majority of these patients were between the ages of 41 and 64 years old. Of the total patients entered, 209 were age 65 years or older. For the U.S./Canadian trials, the baseline demographic data included the following: mean patient age of 55.1 years, 74% male and 26% female, 37% type I (insulin-dependent) and 63% type I1 (non-insulin- dependent) diabetes mellitus, and mean duration of diabetes of 13.9 years. Preliminary analysis reveals a similar demographic profile for patients in the European studies.

Premature Discontinuations in Neuropathy Trials

The data base for review of patients prematurely discontinued from the neuropathy trials included all 1,300 patients; 1,067 had received tolrestat (Table 2). Of these, 323 received tolrestat at a dose of 200 mg q.d., with 255 receiving this dose for at least 22-26 weeks and 126 receiving it for at least 47-58 weeks. Five hundred seven patients received tolrestat at a dose of 400 mg q.d., 124 of these for at least 22-26 weeks and 12 of these for at least 47-58 weeks. Since the initial 52-week double-blind trial included a dose range of 50-200 mg/day, most of the patients completing 47-58 weeks of therapy by the cut-off date for this analysis received doses of up to 200 mg/day.

Table 3 presents the number of premature discontinuations in the treatment groups of the tolrestat neuropathy trials according to the reason given at termination. Of the 54 tolrestat- treated patients discontinued owing to an adverse reaction or laboratory abnormality, 42 (4 %) were considered to be at least “possibly” related to the administration of tolrestat. Of these, 27 dropped from a study owing to elevated hepatic enzymes. None of the adverse reactions or laboratory abnormalities causing discontinuation were life-threatening or caused permanent disability. (The results of a separate review of hepatic function are given below.) With the exception of these abnormalities, all other events leading to discontinuation for possibly drug- related reasons did not cluster significantly into a particular body system. It is important to note that only 3 of the 1,067 patients exposed to tolrestat therapy withdrew participation because of a skin and appendages system adverse reaction that was considered to be possibly related to tolrestat, and in none was there evidence of a hypersensitivity syndrome.

TABLE 2. Number of Patients and Duration of Drug Administration Included in the Safety Analysis of Premature Discontinuations From the Neuropathy Trials

Completed Completed Initiated at least at least

Treatmenddosage therapy 22-26 wk 47-58 wk

- Ongoing 179 87 double-blind

Placebo 196 98 73 Tolrestat

50 mg q.d.a 116 100 65

200 mg q.d. 323 255 126 100 mg b.i.d.b 105 81 65

100 mg q.d. 110 91 75

400 mg q.d. 507 124 12 200 mg b i d . 85 - -

Total tolrestat‘ 1,067

‘Quaque die, once a day %is in die, twice a day. ‘The total No. of patients is less than the sum of the dose groups because the patients who received tolrestat in both double-blind and subsequent open-label extension studies were counted once, at their highest prcscribed daily dose.

136 Ryderet al

TABLE 3. Tolrestat Neuropathy Trials: Premature Discontinuations by Treatment Group According to Reason Given at Termination

Treatment proup

Tolrcstat (n = 1,067)

Placebo (n = 196)

Double- blindb (n = 179)

No. of patients

discontinuing Inter- Adverse SponsoP Other prematurely current reaction/ Withdrawal admin (protocol

251 (24) 42 (4) 54 ( 5 ) 39 (4) 59 (6) 57 ( 5 )

39 (20) 6 (3) 6 (3) 6 (3) 13 (7) 8 (4)

(%) illness (%) lab abn (%) of consent request (%) dev; etc.) (%)

aSponsor’s administrative request refers to those who had not yet completed 52 weeks of treatment when the long-term trial was terminated. hPatients discontinued from ongoing double-blind trials in which the randomization code has not been broken.

Thirteen patients died during, or immediately subsequent to, participation in a neuropa- thy trial. All died of intercurrent illnesses unrelated to study drug: 9 patients died of cardiovas- cular disease; 1 patient died of stroke; 1 of cancer; 1 of septic shock caused by an infected foot ulcer; and I of postoperative complications following surgery for a bleeding ulcer 1 month after discontinuing the study drug. In addition, one patient died of a myocardial infarction more than 2 months after discontinuing study participation owing to withdrawal of consent. The frequency and reasons for these mortalities do not appear exceptional when compared with those in a population matched for demographic statistics, concomitant medication use, and concurrent medical illness. A report of the morbidity and mortality noted during the Diabetic Retinopathy Study (DRS) states that in the DRS overall mortality averaged 4.7 % per year [Knatterud, 19831. Among the tolrestat-treated patients reviewed here, mortality averaged 1.8% per year.

Patient Complaints

Neuropathy Trials. For the overall safety analysis, 976 of the 1,121 patients evaluated received tolrestat (Table 4). Of these, 289 received a dose of 200 mg q.d., with 236 receiving this dose for at least 22-26 weeks and 126 receiving it for at least 47-58 weeks. Further, 450 patients received tolrestat at a dose of 400 mg q.d., with 124 receiving this dose for at least 22-26 weeks and 12 receiving it for at least 47-58 weeks. Following the administration of tolrestat, there were no alarming events, and the incidences of patient complaints/adverse experiences were not remarkably different from that expected in a patient group analogous to the study population with respect to age and medical history.

In the 19-center, 52-week double-blind trial in patients with symptomatic diabetic sensorimotor polyneuropathy, only 4 patient complaints-dizziness, weight gain, palpitations, and dyspnea-occurred with statistically significantly different incidences in the tolrestat 200 mg q.d. group compared with the placebo group. Of these, the tolrestat group had a reduced incidence of weight gain and palpitations. Only dizziness was considered drug-related by the investigators. Table 5 lists the patient complaints/adverse experiences considered to be drug- related by investigators that occurred with a 3 % or greater incidence in either the tolrestat 200 mg 9.d. or placebo group and that were not present at screening or baseline. Dizziness occurred in a dose-related fashion with a drug-related incidence of 11 % in patients on the 200 mg once daily regimen compared with 3% in those on placebo. Although not statistically significant, the incidence of dizziness was also higher in the shorter 8-week trial when

Human Safety Profile of Tolrestat 137

TABLE 4. Number of Patients and Duration of Drug Administration Included in the Overall Safety Analysis of the Neuropathy Trials

Completed Completed Initiated at least at least

Treatmentidosage therapy 22-26 wk 47-58 wk

Placebo 196 98 73 Tolrestat

50 mg q.d.a 116 100 65 100 mg q.d. 110 91 75 200 mg q.d. 289 236 126 100 mg b i d b 105 81 65 400 rng q.d. 450 124 12 200 mg b i d 85

Total tolrestat’ 976

aQuaque die, once a day. %is in die, twice a day. ‘The total No. of patients is less than the sum of the dose groups because the patients who received tolrestat in both double-blind and subsequent open-label extension studies were counted once, at their highest prescribed daily dose.

- -

TABLE 5. Patient ComplaintslAdverse Experiences Considered Drug-Related by Investigators in the 52-Week Double-Blind Study

Body system: patient complaints/ Percentage of incidences adverse experiences (incidence Tolrestat of 3 % or greater in any group)

Skin and appendages

Musculoskeletal system

200 mg q.d. (n=112) Placebo (n = 107)

Rash 3 4

Arthralgia 3 3 Myalgia 3 3

Central and peripheral nervous system Dizziness l la 3 Headache 8 11

Insomnia 1 3 Somnolence 6 1

Abdominal pain 8 5 Diarrhea 5 5 Dyspepsia 4 4 Flatulence 8 3 Nausea 11 16 Vomiting 1 3

Enzyme abnormality 4 5

Cramps, legs 5 2 Edema, peripheral 4 3 Fatigue 4 1

Psychiatric

Gastrointestinal system

Metabolic and nutritional

Body as a whole

aSignificantly greater than placebo.

138 Ryder et al

compared with placebo. This side effect appeared to be real, and a possible mechanism was investigated.

That tolrestat lowered both systolic and diastolic blood pressures in the long-term double- blind study and diastolic blood pressure in the shorter study led us to investigate the relationship of dizziness to blood pressure. We found that 37 % of the patients who complained of dizziness did so at a time when their lowest systolic blood pressure was recorded, but the values could not be considered hypotensive. Blood pressure was recorded in the sitting position, so data on orthostatic hypotension were not available. However, there was no increase in complaints of orthostatic hypotension or syncope in either of the double-blind studies. Despite the long-term nature of one of the studies, the majority of patients complained of dizziness once or twice, and the symptoms tended to occur early in the course of therapy (Table 6). Further, dizziness did not limit treatment as none of the 1,067 tolrestat-treated patients discontinued therapy as a result of this complaint.

Combining the data from both the open-label and double-blind trials, the following complaints occurred with an incidence of 3 % or greater for those complaints/adverse experi- ences considered at least possibly drug-related by the investigators in patients receiving tolrestat 200 or 400 mg once daily: skin rash, dizziness, headache, decreased libido, somnolence, abdominal pain, increased appetite, diarrhea, flatulence, nausea, glycosuria, hypoglycemic reaction, thirst, weight decrease, weight increase, enzyme abnormality, and polyuria. Most of these complaints are common diabetic-related symptoms and thus are unlikely to be related to drug. The overall incidence of dizziness was 18% at 200 mg q.d., of which 6% was considered drug-related. Among the few remaining complaints, the low occurrence (5 %) of premature discontinuations owing to an adverse reaction strongly supports the modest nature of these complaints.

An interesting finding in the long-term trial was a reduced incidence of complaints of weight gain on tolrestat 200 mg q.d. compared with placebo. This was confirmed in the shorter-term double-blind trial in patients receiving the 400 mg q.d. dosage. An analysis of body weight changes in the longer trial generally showed a lower body weight gain in the 200 mg q.d. group compared with the placebo group with the difference achieving statistical significance at 42 weeks. There was no difference between the groups in the incidence of weight loss. Thus, the difference in change from baseline of body weight between the tolrestat 200 mg q.d. and the placebo groups appears to be due to a failure to gain weight in the tolrestat group rather than to weight loss.

There was no notable difference in the complaints that occurred with a drug-related frequency exceeding 3% in the elderly participants of the combined double-blind and open- label tolrestat trials compared with those that occurred in the young or total population.

Bioavailability, Phannacokinetic, and Clinical Pharmacology Studies. The positive safety results in the neuropathy trials are supported by the 12 studies in which tolrestat was administered in single and multiple doses to 180 normal and 63 diabetic male subjects in order to evaluate their tolerance to tolrestat, the bioavailability and pharmacokinetics of tolrestat, and the effect of tolrestat on RBC sorbitol levels. In all of these trials, the patient complaints/

TABLE 6. The Frequency Distribution of Patients Normal at Screening and Baseline Who Reaorted Drue-Related Dizziness in the 52-Week Double-Blind Trial

No. of patients with complaintiNo. entered (%) No. of occurrences: 1 2 3 4 f

Placebo 2173 (3) 2 (3) 0 (0) 0 (0) 0 (0)

Tolrestat 200 rng q.d. lOi88 (11) 7 ( 8 ) 2 (2) 1 (1) 0 (0)

No. of patients (76 )

Human Safety Profie of Tolrestat 139

adverse experiences were relatively infrequent and were of a minor nature. None led to the premature discontinuation of study medication.

Laboratory Tests

In the long-term double-blind trial, patients receiving tolrestat 200 mg q.d. showed an increased incidence of low hemoglobin, which was not associated with a difference in hema- tocrit or RBC count. The patients involved were reviewed, and the abnormality was found to be generally sporadic and not of clinical significance. An increased incidence in low hemoglo- bin was not found in any other tolrestat group in either the 52-week or 8-week double-blind trial.

In the same study, statistically significant changes from baseline of total cholesterol and triglyceride and differences in the changes from baseline between the tolrestat and placebo groups were sporadic and without pattern except for small increases both in cholesterol, ranging from 11.7 to 21.0 mg/dl, and in triglyceride, ranging from 12.8 to 55.2 mg/dl, at weeks 24, 32,42, and 52 in the tolrestat 100 mg b.i.d. (bis in die, twice a day) group. These changes were accompanied by a concomitant rise in glycosylated hemoglobin in this group- consistent with the hyperlipidemia occurring with worsened glycemic control. Changes from baseline of total cholesterol and triglyceride occurred sporadically and without a progressive trend in the open-label tolrestat trials. Considering the experience of all drug groups, the incidence of abnormalities in lipid level tests in patients normal during pretreatment and the results of the analysis of variance of total cholesterol and total triglyceride demonstrate no pattern of drug relationship.

Physical ExaminatiodECG

Although significant increases from baseline of body weight were occasionally found in the tolrestat treatment groups, the changes found in the double-blind trials were generally similar to or slightly less than those noted in the placebo groups. Significant changes were not seen in heart rate in either a drug or placebo group during the trials. Significant changes from baseline of systolic and diastolic blood pressure did not occur in placebo groups. However, statistically significant declines ranging from 4.3 to 6.6 mm of mercury in systolic blood pressure and from 2.2 to 3.4 mm of mercury in diastolic blood pressure were seen in the tolrestat treatment groups in the 52-week trial, and declines ranging from 3.8 to 4.4 mm of mercury in systolic blood pressure and of 2.6 mm of mercury in diastolic blood pressure were seen in the 8-week trial. Similar reductions in both systolic and diastolic blood pressure occurred during the open-label trials. No dose relationship for these occurrences was apparent.

The pattern of occurrence of the electrocardiogram (ECG) findings developing after study entry, including those considered clinically significant by the investigators, was sporadic, and no consistent relationship to tolrestat administration was apparent.

Glycemic Control

In the 52-week double-blind trial, significant differences between the changes from baseline of glycosylated hemoglobin and fasting plasma glucose between the tolrestat and placebo groups were limited to a worsening of glycemic control indices in the tolrestat 100 mg b.i.d. group only. There were no changes in these indices in the 8-week double-blind trial, and the abnormalities in the open-label trials were sporadic and mild. Considering the experience of all tolrestat groups in all trials, the changes in fasting plasma glucose and glycosylated hemoglobin seen during the studies do not indicate any effect of tolrestat on diabetic control.

Special Safety Analyses

Renal Function. Separate analysis of renal function supported the absence of an adverse effect of tolrestat on renal function. Only four patients dropped from a study because of abnormal renal function. One received placebo, and one was on double-blind medication in a

140 Ryderet al

trial in which the randomization code has not yet been broken. In the two patients known to be receiving tolrestat, another cause appeared to be present, namely, concomitant treatment with a nonsteroidal anti-inflammatory drug in one and natural disease progression in the other.

In the 52-week double-blind study, serum creatinine, BUN, creatinine clearance, and 24-hour urinary protein excretion were evaluated. In only one instance was an abnormality noted, with an increased BUN at week 42 in the tolrestat 50 mg q.d. group. Interestingly, proteinuria decreased in the tolrestat 200 mg q.d. group, but the higher baseline value in this group made it impossible to decide if this was a real effect or not. Renal function was also not adversely affected in the 8-week trial of 400 mg daily. The changes in serum creatinine and BUN occurring during the open-label trials were small and without apparent relationship to tolrestat administration.

In addition, there were no significant differences from placebo found on analysis of the elderly patient subpopulation.

Hepatic Function. Analysis of the results of four liver function tests revealed that tolrestat was associated with an infrequent occurrence of liver function abnormality. A total of 34 patients dropped from a study because of elevations in serum hepatic enzyme levels (serum AST [aspartate aminotransferase] and ALT [alanine aminotransferase]), usually occurring 3-6 months following initiation of therapy. Of these, 21196 (1 %) patients received placebo, 2/116 (2%) patients received tolrestat 50 mg q.d., 4/110 (4%) patients received 100 mg q.d., 9/323 (3 %) patients received 200 mg q.d., 5/105 (5%) patients received 100 mg b.i.d., 4/507 (1 %) patients received 400 mg q.d., and 3/85 (3%) patients received 200 mg b.i.d. In addition, 51 179 (3 %) patients received double-blind study drug in trials in which the randomization code has not yet been broken. Compared with the total study population, there was a higher incidence of females (15/34 or 44%) among the patients who discontinued because of elevated hepatic enzymes. Noncholestatic and generally centrilobular hepatocellular damage was notec' in the three liver biopsies that were obtained.

An analysis of 10 visits for the five treatment groups in the 52-week double-blind trial revealed significant differences from placebo in AST at week 16 on 100 mg q.d., at week 42 on 200 mg q.d., and at week 12 on 100 mg b i d . In the case of ALT, significant differences were seen at week 16 on 100 mg q.d., at weeks 20 and 32 on 200 mg q.d., and at weeks 12, 20, and 52 on 100 mg b i d . Thus, from a total of 40 visits on drug, there were mild changes in liver function seen at 9 visits. No changes were seen in alkaline phosphatase or bilirubin. In the 8-week trial only one difference from placebo was noted in ALT after 8 weeks of therapy with the tolrestat 200 mg b.i.d. dosage.

Similar to the total population, liver function analysis performed on the elderly subgroup indicated that tolrestat therapy was not commonly associated with significant liver function test abnormalities.

The occurrence of infrequent hepatotoxicity in man following tolrestat doses of up to 400 mg/day is consistent with the observations from preclinical canine toxicological investiga- tions. In both the 4-week and 6-month canine studies, hepatotoxicity was observed at doses of 100 mg/kg and higher. Similar to man, female dogs appeared more sensitive to toxic damage than male dogs. Histopathologically, centrilobular necrosis was observed in animals, and centrilobular changes were observed in two human biopsies. No canine hepatotoxicity was evident at a dose of 65 mg/kg administered for 6 months.

Overall, it was concluded that tolrestat administration may be associated with usually mild, reversible elevations in serum AST and ALT, and, in dosages of 200-400 mg daily, it appears to be associated with approximately a 2 % incidence of noncholestatic, generally centrilobular, hepatocellular damage. This lesion usually occurred in the first 3-6 months of therapy and was accompanied by significant elevations in serum AST and ALT, with ALT generally higher. The patients were usually asymptomatic, although some complained of abdominal discomfort or pain, and occasionally mild hepatomegaly was noted. Importantly, the abnormalities were reversible after discontinuation of drug, usually within 8- 16 weeks.

Human Safety Profde of Tolrestat 141

DISCUSSION

The safety of tolrestat use in the diabetic patient was demonstrated by the data from both double-blind and open-label neuropathy studies and was further supported by pharmacokinetic, bioavailability, and clinical pharmacology studies. Of 1,067 tolrestat-treated patients, 42 (4 %) dropped from their study owing to adverse reactions/laboratory abnormalities possibly related to the administration of tolrestat. Of these, 27 dropped because of elevated hepatic enzymes. In the long-term clinical trials conducted in American, Canadian, and foreign centers, most adverse reactions were mild, not requiring discontinuation of therapy.

There was a generally comparable frequency of complaints in the tolrestat dose groups and placebo groups. Of the drug-related patient complaints/adverse experiences that occurred in the tolrestat 200 mg/day group in the 52-week double-blind trial, only dizziness was significantly different from placebo. Although not statistically significant, the incidence of dizziness was also higher compared with placebo in the shorter 8-week trial in which tolrestat 400 mg/day was administered. Its cause is unknown but may be related to the small decrease in blood pressure seen in patients in the double-blind studies. Of the other drug-related complaints, most were common diabetic-related symptoms, and the low Occurrence of prema- ture discontinuations owing to an adverse reaction strongly supports the modest nature of these complaints.

Only four patients dropped from a study because of abnormal renal function, and the two patients known to be on tolrestat apparently withdrew for causes unrelated to drug. Overall, review of the BUN and serum creatinine values from both the double-blind and open- label tolrestat trials did not suggest any potential for tolrestat-induced renal dysfunction.

On review of the 27 tolrestat-treated patients dropped from the study owing to elevations in serum hepatic enzyme levels (serum AST and ALT), it was concluded that tolrestat may cause hepatocellular damage with coincident significant elevations in AST and ALT in approx- imately 2% of patients. Ordinarily, serum ALT exceeded serum AST. The cases usually were asymptomatic and occurred in the first 3-6 months of therapy. Importantly, the abnormalities were reversible on discontinuation of the drug, generally within 8-16 weeks. In the long-term double-blind trial, there were mild changes in the mean values of AST and/or ALT seen at 9 of 40 visits. In the &week trial only one difference from placebo was noted in ALT after 8 weeks of therapy on the tolrestat 200 mg b i d . dose. The mean values remained within the normal limits and were nonprogressive. Tolrestat has not been investigated in patients with preexisting hepatic disease, and caution is advised unless the treatment benefit outweighs the potential risk.

The pattern and occurrence of hepatotoxicity in approximately 2% of a drug-treated population appears to identify tolrestat as a cause of infrequent, idiosyncratic hepatocellular toxicity with an incidence apparently similar to isoniazid [Ocher, 19821. The difference in individual susceptibility to tolrestat-related hepatotoxicity remains unexplained. There was no evidence of an immune reaction with associated skin rash, arthralgia, or lymphocytosis, and the plasma levels of unchanged tolrestat were not remarkably higher among patients with significant hepatic enzyme elevation (S. Ryder et al., data on file at Ayerst Laboratories). It is possible that differences in susceptibility may reflect individual changes in drug metabolism although these changes have not been identified.

Examination of the safety data from elderly tolrestat-treated patients indicates that although increased bioavailability of tolrestat was found in the elderly (D. Hicks et al., data on file at Ayerst Laboratories), no special precautions appear necessary in this population, and no alteration of tolrestat dosage is required in the elderly.

Although there did not appear to be any marked difference in the Occurrence of dizziness or elevated hepatic enzymes between patients receiving tolrestat at doses of 200 or 400 mg/ day, there was no direct comparison of these doses within a single trial. Direct comparative data are expected from ongoing additional trials.

142 Ryder eta l

Results from the two completed double-blind, placebo-controlled trials showed both objective and subjective neuropathic improvement following administration of tolrestat 200- 400 mg q.d. [Boulton and The Tolrestat in Neuropathy Study Group, 1986; Ryder and The Tolrestat in Painful Neuropathy Study Group, 19861. Approximately 30% of patients appeared to have a sustained long-term clinical response [Boulton and The Tolrestat in Neuropathy Study Group, 19861. Based on the results presented in this report, it can be concluded that the safety data gathered from these and other clinical neuropathy trials appear to define a favorable safety profile for tolrestat.

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