"Today, the U.S. Food and Drug Administration issued a proposal designed to assist companies developing new treatments for patients in the early stages of Alzheimer's disease, before the onset of noticeable (overt) dementia.
Although widespread degeneration of multiple CNS neuronal systems eventually occurs, early pathological changes in Alzheimer's Disease involve, in a relatively selective manner, cholinergic neuronal pathways that project from the basal forebrain to the cerebral cortex and hippocampus. The resulting deficiency of cortical acetylcholine is believed to account for some of the clinical manifestations of mild to moderate dementia. Tacrine, an orally bioavailable, centrally active, reversible cholinesterase inhibitor, presumably acts by elevating acetylcholine concentrations in the cerebral cortex by slowing the degradation of acetylcholine released by still intact cholinergic neurons. If this theoretical mechanism of action is correct, tacrine's effects may lessen as the disease process advances and fewer cholinergic neurons remain functionally intact. There is no evidence that tacrine alters the course of the underlying dementing process.
Clinical Trial Data
The conclusion that Cognex® (tacrine) isan effective treatment for Alzheimer's Disease derives from two adequate and well controlled clinical investigations that evaluated tacrine's effects in patients with probable Alzheimer's disease of mild to moderate severity (NINCDS criteria, Mini-Mental State Examination (MMSE) of Folstein, Folstein and McHugh scores of 10 to 26).
In each study, outcomes during treatment with tacrine and placebo were assessed on two primary measures: (1) the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS cog) of Rosen, Mohs, and Davis and (2) a clinician's rated clinical global impression of change.
The ADAS cog is a multi-item test battery administered by a psychometrician that examines aspects of memory, attention, praxis, reason, and language. The worst possible score is 70. Elderly, normal adults may score as low as 0 or 1 unit, but individuals judged not to be demented can score higher. The mean score of patients entering each study was approximately 28 units (range 7 to 62). The ADAS cog score is reported to deteriorate at a rate of about 6 to 10 units per year for untreated patients at this stage of dementia.
The clinician's global assessments used in the two studies relied on a clinician's judgment about the overall clinical change observed in patients over the course of the study. Although the conditions for obtaining the clinical assessment differed in each study, the global assessment was rated on a 7-point scale in both studies. A rating of four (4) represents no change; lower ratings indicate improvement from baseline and higher ratings deterioration.
In one study of 12 weeks duration, patients were randomized to sequences that provided a comparison between placebo, 20, 40, and 80 mg/day by study's end. Statistically significant drug-placebo differences were detected on both primary outcome measures for the group titrated to 80 mg/day. Estimates of the size of the treatment effect varied between 2 and 4 ADAS cog units. The imprecision in these estimates reflects the fact that different analyses, conducted in attempts to account for the effects of the failure of a substantial fraction of the patients randomized to complete the full 12 weeks of the study, yielded different results.
The placebo-80 mg/day comparison also achieved statistical significance on the clinician 's global impression of change (CGIC) with a 0.3 to 0.4 unit mean difference. The following diagram illustrates the percentages of patients falling into each global category at trial's end for the patients given placebo or 80 mg/day.
FIGURE 1. Percent of Patients in Each of the Seven Outcome Categories on the Clinician-Rated CGIC for Patients Completing 12 Weeks of Treatment (83% of patients randomized to placebo completed 12 weeks of treatment and are represented above; 56% of those randomized to the 80 mg/day Cognex® (tacrine) sequence completed 12 weeks)
The second study was 30 weeks long. Six hundred sixty-three patients were randomized to 4 treatment sequences (placebo and 3 drug groups) that called for the daily dose of tacrine to be increased at 6-week intervals, starting with a 40-mg/day dose. By study's end, a comparison between placebo, 80, 120, and 160 mg/day was possible. Patients in the 160 mg group received this dose for the final 12 weeks; the 120 mg group received that dose for 18 weeks.
The study showed statistically significant drug-placebo differences for the 80 and 120 mg/day groups at 18 weeks and for the 120 and 160 mg/day groups at 30 weeks on both a performance-based test of cognitive function (the ADAS cog) and a clinician's assessment of global change (Clinician Interview Based Impression: CIBI). Because many patients failed to complete 30 weeks on treatment, analyses that used each patient's last on-study value or retrieved patients' (see below) 30-week value, even if they were no longer in the study ("intent-to-treat" analysis) were also carried out. All analyses confirmed the effectiveness of tacrine, although the estimated mean treatment effect was different in each analysis.
Effects on ADAS Cog: The results for the ADAS cog are shown in Figure 2 for the subset of patients actually completing the full 30 weeks of the study. They show that individual patients, whether assigned to tacrine or to placebo, had a wide range of responses. This variability in response is illustrated in the display that follows (Figure 2).
FIGURE 2. Cumulative Percent of Patients Completing 30 Weeks of Treatment Who Attained a Change in ADAS Cog Score From Baseline at Least as Large as the Value on the X Axis.The display is based on scores obtained from a subset of patients (ie, 64% of the 184 randomized to placebo and 27% of the 239 randomized to the 160 mg/day treatment group).
Figure 2 presents the cumulative percentage (Y axis) of patients assigned to placebo or 160 mg/day who actually completed 30 weeks on treatment and who attained a change in ADAS cog score from baseline at least as large as the ADAS cog change score value given on the X axis. A negative change from baseline represents improvement; a positive change deterioration. Thus, in a display of this type, the curve for an effective treatment is shifted to the left of the curve for placebo. The frequency in each group of any response, e.g., an improvement of 7 ADAS cog units, can be found by plotting the change on the X axis, then reading upward along the Y axis. The variability of response is apparent from the fact that the distribution of responses under both treatment conditions range from large negative to large positive values. Nonetheless, the mean drug-placebo ADAS cog difference for the 30-week 160 mg/day completer patients is 4.8 units, a statistically significant difference.
Effects on CIBI: The results on the CIBI are shown in Figure 3.
FIGURE 3. Percent of Patients in Each of the Seven Outcome Categories of the CIBI Among Those Completing 30 Weeks. The display is based on scores obtained from the same subset of patients as Figure 2.
Figure 3 is a histogram of the frequency distribution of CIBI scores attained by patients assigned to placebo or to the 160 mg/day tacrine dose group who actually completed the full 30 weeks of the study. The mean tacrine-placebo difference for this group of patients on the CIBI was 0.5 units and was statistically significant.
Expected Responses in Newly Treated Patients: Although the results described clearly document tacrine's effectiveness, they are based on only a fraction of the patients nitially randomized to tacrine, those who could tolerate tacrine and remain on treatment uninterrupted for the full 30 weeks. In considering the expected outcome in a group of patients newly started on tacrine, account must be taken both of the likelihood of staying on therapy and the responses in patients who do so.
Table 1 provides 3 different estimates of the proportion of patients assigned to treatment with tacrine at 160 mg a day or with placebo who attained a particular measure of improvement (ie, a 7 point improvement from baseline in ADAS cog score). The criterion has been chosen entirely for illustrative purposes.
Table 1. Proportion of Patients Attaining 7 Unit Improvement
on the ADAS Cog at the Week 30 Assessment
N (%) of Those
N (%) of Those
Completing Week 30
N (%) of Those With
Week 30 Assessments
|Placebo (N = 184)||10/184 ( 5.4)||10/117 ( 8.5)||11/1431( 7.7)|
|160 mg/day (N = 239)||13/239 ( 5.4)||13/64 (20.3)||25/1722(14.5)|
|1: 13 of the 143 were receiving tacrine when evaluated.
2: 41 of the 172 were not receiving tacrine when evaluated.
The first column of the table is based on all patients participating in the study. The proportion provides an estimate of the likelihood that a patient entering the study will ( 1) still be on his or her assigned treatment at week 30 and 2) will improve 7 or more ADAS cognitive points over his or her baseline score. The estimate of response ( derived in this manner is conservative because the rules under which the 30-week study was conducted required the withdrawal of patients with relatively low ( > 3 X ULN), asymptomatic, transaminase elevations. In actual clinical practice under the conditions of treatment recommended in the Dosage and Administration Section, a larger fraction of these patients would be able to remain on tacrine and the proportion of those improving 7 or more points on tacrine would be expected, therefore, to be increased (the third column illustrates this).
The second column of the table presents the proportion of 7 unit responders based on the number of patients who (1) were able to complete the full 30 weeks of the study a nd (2) attained an ADAS cognitive score at week 30 that was 7 or more points better than their baseline score. This analysis provides an optimistic estimate of tacrine 's effects because it reflects experience gained only with the minority of patients who were able to remain on treatment to the study's end. The comparison between the proportions of placebo and 160 mg patients attaining a 7 or more point improvement is complicated further by the fact that a larger proportion of tacrine assigned patients withdrew prematurely.
The third column of the table presents the proportion of patients who had evaluations made at 30 weeks and had a 7-point or greater response. The analysis includes data from patients still on their assigned treatment at week 30 as well as patients who withdrew from the study prior to that time, but were retrieved for a week 30 evaluation. Because patients who withdrew prior to week 30 were permitted to receive tacrine under "open label" conditions, retrieved patients included in this analysis could be receiving either no treatment or treatment with tacrine. In this analysis, patients are considered under the treatment to which they were randomized, regardless of the treatment they were actually receiving at week 30. Thus, some placebo patients could have received tacrine and some tacrine patients could have been r eceiving no tacrine. Like the analysis based on percent randomized (column I), this analysis, therefore, tends to provide a conservative view of the expected effects of tacrine treatment.
Effects of Cognex® (tacrine) Over Time: Figure 4 shows for each dose group the time course of change from baseline in ADAS cog scores for patients completing 30 weeks of treatment. There appears to be a persistent difference between groups, but all groups, after initial improvement, deteriorate with time.
FIGURE 4. ADAS Cog Change From Baseline Over Time for the Subset of Patients Completing 30 Weeks of Treatment. In all tacrine treatment groups dosing was initiated at 40 mg/day and increased in increments of 40 mg every 6 weeks until the target dose was achieved.
Patient age, gender, and other baseline patient characteristics were not found to predict clinical outcome.
Clinical Pharmacokinetics (Absorption, Distribution, Metabolism, and Elimination)
Absorption: Cognex® (tacrine) is rapidly absorbed after oral administration; maximal plasma concentrations occur within 1 to 2 hours. The rate and extent of tacrine absorption ollowing administration of tacrine capsules and solution are virtually indistinguishable. Absolute bioavailability of tacrine is approximately 17 (SD±13) %. Food reduces f tacrine bioavailability by approximately 30-40%; however, there is no food effect if tacrine is administered at least an hour before meals. The effect of achlorhydria on the a bsorption of tacrine is unknown.
Distribution: Mean volume of distribution of tacrine is approximately 349 (SD ±193) L. Tacrine is about 55% bound to plasma proteins. The extent and degree of tacrine's distribution within various body compartments has not been systematically studied. However, 336 hours after the administration of a single radiolabeled dose, approximately 25% of the radiolabel was not recovered in a mass balance study, suggesting the possibility that tacrine and/or one or more of its metabolites may be retained.
Metabolism: Tacrine is extensively metabolized by the cytochrome P450 system to multiple metabolites, not all of which have been identified. The vast majority of radio-labeled species present in the plasma following a single dose of 14C radiolabeled tacrine are unidentified (ie, only 5% of radioactivity in plasma has been identified [tacrine a nd 3-hydroxylated metabolites; 1-, 2-, and 4-hydroxytacrine]).
Studies utilizing human liver preparations demonstrated that cytochrome P450 IA2 is the principal isozyme involved in tacrine metabolism. These findings are consistent with the observation that tacrine and/or one of its metabolites inhibits the metabolism of theophylline in humans (see PRECAUTIONS: Drug-Drug Interactions: theophylline). Results from a study utilizing quinidine to inhibit cytochrome P450 IID6 indicate that tacrine is not metabolized extensively by this enzyme system.
Special Populations: Age: Based on pooled pharmacokinetic studies (n = 192), there is no clinically relevant influence of age (50 to 84 years) on tacrine clearance. Gender: Average tacrine plasma concentrations are approximately 50% higher in females than in males. This is not explained by differences in body surface area or elimination half-life. The difference is probably due to higher systemic availability after oral dosing and may reflect the known lower activity of cytochrome P450 IA2 in women. Race: The effect of race on tacrine clearance has not been studied. Smoking: Mean plasma tacrine concentrations in current smokers are approximately one third the concenrations in nonsmokers. Cigarette smoking is known to induce cytochrome P450 IA2. Renal disease: Renal disease does not appear to affect the clearance of tacrine. Liver disease: Although studies in patients with liver disease have not been done, it is likely that functional hepatic impairment will reduce the clearance of tacrine and its metabolites.
Presystemic Clearance/Elimination/Excretion: Tacrine undergoes presystemic clearance (ie, first pass metabolism). The extent of this first pass metabolism depends upon he dose of tacrine administered. Because the enzyme system involved can be saturated at relatively low doses, a larger fraction of a high dose of tacrine will escape first t pass elimination than of a smaller dose. Thus, when a 40 mg daily dose is increased by 40 mg, the average plasma concentration will be increased by approximately 6 ng/mL. However, when a daily dose of 80 or 120 mg is increased by 40 mg, the increment in average plasma concentration is approximately 10 ng/mL.
Elimination of tacrine from the plasma, however, is not dose dependent (ie, the half-life is independent of dose or plasma concentration). The elimination half-life is approximately 2 to 4 hours. Following initiation of therapy or a change in daily dose, steady state tacrine plasma concentration should be attained within 24 to 36 hours.
Last reviewed on RxList: 6/24/2008
This monograph has been modified to include the generic and brand name in many instances.
Additional Cognex Information
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Get breaking medical news.