The Clinical Pharmacokinetics Single Doses of Estaiolam
of
LINDAE. GUSTAVSON, PH.D., PHILIP J. CARRIGAN, PH.D. mott Park, mois
stazolam is a triazolobenzodiazepine E for which hypnotic efficacy has been established in inpatient and outpatient sleep laboratory studies
The pharmacokinetics of estazolam were exaniined in 17 healthy male subjects. Plasma concentration-time profiles were compared following the oral administration of one 1-mg tablet, two 1-mg tablets, and one 2-mg tablet. No statistically significant differences were detected among the mean time of maximal plasma concentration (T,,,), maximal plasma concentration (C,,,), area under the plasma concentration-time curve from zero to 72 hours (AUC), or half-life values for the 2-mg doses. Mean C,,, was 97.7 and 98.6 rig/ml and mean T,,, was 1.9 and 1.6 hours for two 1-mg tablets and one 2-mg tablet, respectively. Proportionately decreased C,, and AUC were observed following the 1-mg dose. Mean max was 54.7 rig/ml for the 1-mg dose. Mean Tcmax and elimination half-life values were similar to those observed after the 2-mg doses. The overall harmonic mean half-life was 14.4 hours.
I
(Figure
1 From the Departments of Drug Metabolism and Development Services, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois. Requests for reprints should be addressed to Linda E. Gustavson,, Ph.D., D-463, AP9-1, Abbott Laboratories, One Abbott Park Road, Abbott Park, Illinois 60064-3500.
3A-2s
March 2, 1990
The American Journal of Medicine
1)
[l-4]. An early study of the pharmacokinetics of estazolam, performed in Japan, examined single 4-mg oral doses in six healthy male subjects [5]. The results of this study indicatkd that estazolam reached maximal blood concentrations at a mean of about five hours after dosing and that its elimination half-life was 24 hours. Allen et al [63 examined the pharmacokinetics of single doses of 2,4, 6, 8, 12, or 16 mg estazolam in a total of 21 healthy men (two to five subjects/dose group). When observed maximal plasma concentration (C,,) was adjusted for the dose administered, there were no differences between the six dose groups. The overall mean C,,, was 43 nglml per mg estazolam administered. The time of maximal plasma concentration (T,,) ranged from 0.5 to six hours. The elimination half-life had a harmonic mean of 15.2 hours. There was no evidence of dose-dependency for any of these parameters, suggesting that the pharmacokinetics of estazolam involved linear processes of absorption and elimination. These investigators also examined the pharmacokinetics of 2, 4, and 6 mg per day estazolam administered to six healthy male subjects over three consecutive weeks [6]. Mean predose estazolam concentrations appeared to increase proportionately with increasing dose. The harmonic mean half-life following the final 6-mg dose was 14.8 hours. The observed mean accumulation ratio of 1.84 was not significantly different from the predicted value of 1.53. These data provided additional evidence to suggest that the pharmacokinetics of estazolam are linear. Allen et al [6] also provided evidence that estazolam does not induce hepatic microsomal enzyme systems, showing that antipyrine pharmacokinetics were unaffected by a three-week multiple-dose regimen of estazolam. In a graded multiple-dose study examining estazolam doses over the range of 0.5 to 2 mg per day in five subjects, mean minimal and maximal plasma concentrations were linearly correl,ated with dose? supporting linear pharmacokinetic behavior (G. Richard Granneman, Ph.D., Abbott Laboratories, personal communication). In this study, the harmonic mean elimination half-life following the final 2-mg dose was 11.7 hours. Mancinelli et al [7] gave single 4-mg oral doses of estazolam to four healthy subjects. They reported that estazolam was rapidly absorbed, with a T,,, of one to three hours and a mean-C,,, of 194 ngiml(48.5 ng/ml/mg). The harmonic mean elimination half-life was 17.8 hours. Subsequently, these investigators gave 2-mg oral doses of estazolam daily for seven days to the same group of four subjects. Mean steady-state
Volume 88 (suppl 3A)
SYMPOSIUM
plasma concentration was 180 ngiml, and harmonic mean half-life was 16.5 hours. The disposition of a 2-mg oral dose of carbon-14labeled estazolam was evaluated in four healthy subjects by Machinist et al [8]. Plasma concentrations of estazolam declined with a harmonic mean half-life of 14.1 hours. Low concentrations of the 1-0x0 and 4-OH metabolites of estazolam were detected in plasma. Approximately 77 percent of the administered radioactivity was recovered in the zero to 72-hour urine collection. Metabolites formed through 4-OHestazolam comprised approximately 35 percent of the urinary radioactivity. Parent drug and the 1-0x0 and 4’-OH metabolites were associated with an additional 5, 6, and 15 percent of the dose, respectively. The studies reviewed earlier each used a relatively small number of subjects to estimate the pharmacokinetics of estazolam. They also used a variety of estazolam dosage forms and analytical methods. In general, mean half-lives ranged from 11.7 to 17.8 hours. However, the early Japanese study reported a longer mean half-life of 24 hours. This study examined the pharmacokinetics of recommended doses of estazolam in a larger number of subjects using a randomized crossover design. This type of study will provide an opportunity to firmly establish the pharmacokinetics of estazolam in healthy subjects. PATIENTS AND METHODS Subject Selection
Eighteen healthy adult men were selected to participate in this study. The subjects were judged to be in good health based on a medical history, a physical examination, and clinical laboratory testing performed within two weeks before the start of the study. The protocol and consent form were reviewed and approved by the Institutional Review Board of the University of Utah Medical Center, and each subject provided written informed consent to participate in the study. Potential subjects were excluded if they had physical or physiologic evidence of any active disease or of significant cardiovascular, pulmonary, renal, hepatic, or neurologic disease. Subjects with known hypersensitivity to benzodiazepines or a history of drug or alcohol dependence were also excluded. EXPERIMENTAL PROCEDURES Subjects were confined to the study area beginning the evening before dosing. A standardized dinner was served at approximately 8:00 P.M. Following dinner, an absolute fast except for water was maintained for a minimum of 10 hours before dosing. Water was available ad Zibitum. In the morning, subjects received one of three estazolam regimens according to a randomized schedule. The regimens included one 1-mg tablet, two 1-mg tablets, and one 2-mg tablet. Each estazolam regimen was ingested with 120 ml of water. Heparinized blood samples (10 ml) were collected before dosing and 0.33, 0.67, one, two, three, four, eight, 12,24,36,48, and 72 hours after dosing. Plasma was separated by centrifugation within one hour after sample collection. Plasma samples were transferred to labeled vials and stored frozen (less than or equal to -10%). Fasting was continued until the three-hour blood sample had been collected. Following collection of the three-hour blood sample, a standardized break-
ON INSOMNIA I GUSTAVSON and CARRIGAN
I
N r N’P
Cl 0 w
I
Figure 1. Structure of estazolam.
‘N
00
fast was served. A standardized lunch and dinner were served approximately six and 11 hours after dosing, respectively. There was a washout period of at least 14 days between the estazolam regimens. Analytical Procedures
Plasma concentrations of estazolam were determined by a high-performance liquid chromatographic assay [8] with minor modifications. Briefly, alkalinized aliquots of plasma were extracted with heptane-ethyl acetate (7:3, v:v) containing desmethyldiazepam as the internal standard. The extracts were evaporated to dryness and the residues reconstituted in mobile phase. Aliquots of the reconstituted extracts were injected into the high-performance liquid chromatographic system. Separation was achieved using a Cl8 reversedphase analytical column. The mobile phase consisted of 22 percent acetonitrile and 30 percent methanol in 0.05 M ammonium phosphate buffer (pH 4.6). Mobile phase was delivered to the column at 2 ml/minute. The column effluent was monitored using ultraviolet detection at a wavelength of 223 nm. The limit of quantification for estazolam was approximately 4 rig/ml. The mean coefficient of variation for interassay precision during the analysis of these samples was approximately 10 percent. Data Analysis
Pharmacokinetic parameters were calculated from the plasma concentration-time data using conventional noncompartmental analysis [9]. Analyses of variance were performed for the C,,,, the T,,,, and the area under the plasma concentration-time curve from zero to 72 hours (AUCj, using a model that included treatment, subject, and period effects as sources of variation. Ninety-five percent confidence intervals were determined for the ratios of the mean AUC [lO,ll]. Harmonic mean half-lives were calculated as the natural logarithm of 2 divided by the mean of the elimination rate constants. RESULTS Seventeen subjects completed all three phases of this study. Subject 2 was lost to follow-up after the first estazolam dose and his data have been excluded from all analyses. The remaining subjects ranged in age from 18 to 34 years and ranged in weight from 61 to 81 kg and in height from 173 to 193 cm. The mean plasma concentration-time profiles for
March 2, 1990
The American Journal of Medicine
Volume 88 (suppl 3A)
3A-3s
SYMPOSIUM
ON INSOMNIA / GUSTAVSON and CARRIGAN 1
w O--
TIME gure 2. Mean plasma concentration-time
Mean (SD) and Range of Pharmacokinetic Parameters Calculated for Estazolam in Healthy Male subjects Regime? One I-mg Tablet
Lx hours) ;a’n”g”e’Ss”’ AK (ng hour/ml) Mean[SD) Range Elimination rate constant (hours-‘) /;;;;SD) Half-life (hours) ;;$“I
Two 1-mgTablets
54.1(9.0)
97.7 j17.0)
42.0-70.4
72.2-148
1.9(1.3) 0.33-2.0
1.9(2.0) 0.33-8.0
1,050 (292) 555-1,440
One 2.mg Tablet
98.6(18.1) 74.7-131
1,930(501) l,llO-3,050
0.0464(0.0156) 0.0494 (0.0148) 0.0252-0.07520.032&0.0851 14.9* 9.2-27.5
14.0* 8.1-21.7
iarmonic mean.
the three estazolam regimens appear in Figure 2. Table I summarizes the mean pharmacokinetic parameters for each regimen. There were no significant differences between the mean T,,, or the harmonic mean half-lives for the three regimens. The overall harmonic mean for the three regimens together was 14.4 hours. For the 2-mg dose regimens, there were no significant differences between the mean C,,, or mean AUC. The ratio of mean AUC (two 1-mg tablets:one 2-mg tablet) was 0.94, with a 95 percent 3A-4S
March 2, 1990
One Two One
1 mg Tablet 1 rnb Tablets 2 mg Tablet
(hours)
profiles of estazolam following 1-mg and 2-mg oral doses of estazolam in 17 healthy subjects.
TABLE I
Parameter
- 4 0-a
The American Journal of Medicine
confidence interval of 0.85 to 1.04. The mean C,,, and AUC values for the 1-mg regimen were significantly lower than the values for either 2-mg regimen. The ratio of mean AUC (one 1-mg tablet:one 2-mg tablet) was 0.51, with a 95 percent confidence interval of 0.46 to 0.57. COMMENTS The data generated in this study have confirmed that estazolam is rapidly absorbed from orally administered tablets. Detectable estazolam concentrations generally appeared in plasma by the first sampling time, 20 minutes after dosing. The mean times of maximal plasma concentration were less than two hours for each dosing regimen examined in this study. The similarity of the values of T,,,, C,,,, and AUC for the two 2-mg dosage regimens indicated that the rate and extent of absorption of estazolam from two 1-mg tablets or one 2-mg tablet were virtually identical. The relationship between C,,, and AUC for the l- and 2-mg dosing regimens supported proportional absorption of l- and 2-mg doses of estazolam. The observed value for the AUC ratio (one 1-mg tablet:two 1-mg tablets) was 0.51, which agreed very well with the predicted ratio of 0.5. Elimination of estazolam appeared to be independent of the dose and dosage strength administered. The harmonic mean half-lives were very similar for the three estazolam regimens. The half-life values calculated from this study’s data were within the range previously reported in the literature. There was some tendency, however, for the current results to be toward the shorter end of the previously reported spec-
Volume 88 (suppl 3A)
SYMPOSIUM
trum. These pharmacokinetic characteristics are consistent with the clinical evidence that estazolam decreases sleep latency and/or increases sleep duration in patients with transient or chronic insomnia. ACKNOWLEDGMENT We wash to thank Drs. G. Richard Granneman, Joseph M. Machinist, and Mark W. Prerce of Abbott Laboratories for helpful discussrons.
REFERENCES 1. Roehrs T, Lorick F, Lord N, Koshorek GL, Roth T: Dose-related effects of estazolam on sleep of patients with insomnia. J Clin Psycho1 1983; 3: 152-156. 2. Lamphere J, Roehrs T, Zorrck F, Koshorek G, Roth T: Chronic hypnotic efficacy of estarolam, Drugs Exp Clan Res 1986; 12: 687-691. 3. Walsh JK, Targum SD, Pegram V, eta/: A multicenter clinical rnvestigatron of estazolam:
ON INSOMNIA / GUSTAVSON and CARRIGAN
short-term efficacy. Curr Ther Res 1984; 36: 866-874. 4. Domrnguez RA, Goldstein BT, Jacobson AF, Sternbrook RM: Comparatrve efficacy of estazolam, flurazepam and placebo in outpatients with insomnia. J Clin Psychiatry 1986; 47: 362-365. 5. Sekr T: Clknical pharmacology of D40TA. Rrnsho Yakun 1973; 4: 76-86. 6. Allen MD, Greenblatt DJ, Arnold JD: Single- and multiple-dose kinetics of estazolam, a triazolo benzodiazepine. Psychopharmacology 1979; 66: 267-274. 7. Mancinelli A, Guise G, Garattinr S, Urso R, Caccia S: Kinetic and pharmacological studies on estazolam in mice and man. Xenobiotica 1985; 15: 257-265. 8. Machrnist JM, Bopp BA, Anderson DJ, Granneman GR, Sonders RC: Metabolrsm of ‘%estazolam In dogs and humans. Xenobiotica 1986; 16: 11-20. 9. Rowland M, Tozer TN: Clinical pharmacokinetrcs: concepts and applrcations. Philadelphra: Lea & Febiger, 1980. 10. Miller RJ: Simultaneous statistical inference. New York: McGraw-Hill, 1964; 3770. 11. Flnney DJ: Statistical method in brological assay, 3rd ed. New York: MacMillan PublishIng Co., 1978; 80-82.
March 2, 1990
The American Journal of Medicine
Volume 88 (suppi 3A)
3A-5S
of
LINDAE. GUSTAVSON, PH.D., PHILIP J. CARRIGAN, PH.D. mott Park, mois
stazolam is a triazolobenzodiazepine E for which hypnotic efficacy has been established in inpatient and outpatient sleep laboratory studies
The pharmacokinetics of estazolam were exaniined in 17 healthy male subjects. Plasma concentration-time profiles were compared following the oral administration of one 1-mg tablet, two 1-mg tablets, and one 2-mg tablet. No statistically significant differences were detected among the mean time of maximal plasma concentration (T,,,), maximal plasma concentration (C,,,), area under the plasma concentration-time curve from zero to 72 hours (AUC), or half-life values for the 2-mg doses. Mean C,,, was 97.7 and 98.6 rig/ml and mean T,,, was 1.9 and 1.6 hours for two 1-mg tablets and one 2-mg tablet, respectively. Proportionately decreased C,, and AUC were observed following the 1-mg dose. Mean max was 54.7 rig/ml for the 1-mg dose. Mean Tcmax and elimination half-life values were similar to those observed after the 2-mg doses. The overall harmonic mean half-life was 14.4 hours.
I
(Figure
1 From the Departments of Drug Metabolism and Development Services, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois. Requests for reprints should be addressed to Linda E. Gustavson,, Ph.D., D-463, AP9-1, Abbott Laboratories, One Abbott Park Road, Abbott Park, Illinois 60064-3500.
3A-2s
March 2, 1990
The American Journal of Medicine
1)
[l-4]. An early study of the pharmacokinetics of estazolam, performed in Japan, examined single 4-mg oral doses in six healthy male subjects [5]. The results of this study indicatkd that estazolam reached maximal blood concentrations at a mean of about five hours after dosing and that its elimination half-life was 24 hours. Allen et al [63 examined the pharmacokinetics of single doses of 2,4, 6, 8, 12, or 16 mg estazolam in a total of 21 healthy men (two to five subjects/dose group). When observed maximal plasma concentration (C,,) was adjusted for the dose administered, there were no differences between the six dose groups. The overall mean C,,, was 43 nglml per mg estazolam administered. The time of maximal plasma concentration (T,,) ranged from 0.5 to six hours. The elimination half-life had a harmonic mean of 15.2 hours. There was no evidence of dose-dependency for any of these parameters, suggesting that the pharmacokinetics of estazolam involved linear processes of absorption and elimination. These investigators also examined the pharmacokinetics of 2, 4, and 6 mg per day estazolam administered to six healthy male subjects over three consecutive weeks [6]. Mean predose estazolam concentrations appeared to increase proportionately with increasing dose. The harmonic mean half-life following the final 6-mg dose was 14.8 hours. The observed mean accumulation ratio of 1.84 was not significantly different from the predicted value of 1.53. These data provided additional evidence to suggest that the pharmacokinetics of estazolam are linear. Allen et al [6] also provided evidence that estazolam does not induce hepatic microsomal enzyme systems, showing that antipyrine pharmacokinetics were unaffected by a three-week multiple-dose regimen of estazolam. In a graded multiple-dose study examining estazolam doses over the range of 0.5 to 2 mg per day in five subjects, mean minimal and maximal plasma concentrations were linearly correl,ated with dose? supporting linear pharmacokinetic behavior (G. Richard Granneman, Ph.D., Abbott Laboratories, personal communication). In this study, the harmonic mean elimination half-life following the final 2-mg dose was 11.7 hours. Mancinelli et al [7] gave single 4-mg oral doses of estazolam to four healthy subjects. They reported that estazolam was rapidly absorbed, with a T,,, of one to three hours and a mean-C,,, of 194 ngiml(48.5 ng/ml/mg). The harmonic mean elimination half-life was 17.8 hours. Subsequently, these investigators gave 2-mg oral doses of estazolam daily for seven days to the same group of four subjects. Mean steady-state
Volume 88 (suppl 3A)
SYMPOSIUM
plasma concentration was 180 ngiml, and harmonic mean half-life was 16.5 hours. The disposition of a 2-mg oral dose of carbon-14labeled estazolam was evaluated in four healthy subjects by Machinist et al [8]. Plasma concentrations of estazolam declined with a harmonic mean half-life of 14.1 hours. Low concentrations of the 1-0x0 and 4-OH metabolites of estazolam were detected in plasma. Approximately 77 percent of the administered radioactivity was recovered in the zero to 72-hour urine collection. Metabolites formed through 4-OHestazolam comprised approximately 35 percent of the urinary radioactivity. Parent drug and the 1-0x0 and 4’-OH metabolites were associated with an additional 5, 6, and 15 percent of the dose, respectively. The studies reviewed earlier each used a relatively small number of subjects to estimate the pharmacokinetics of estazolam. They also used a variety of estazolam dosage forms and analytical methods. In general, mean half-lives ranged from 11.7 to 17.8 hours. However, the early Japanese study reported a longer mean half-life of 24 hours. This study examined the pharmacokinetics of recommended doses of estazolam in a larger number of subjects using a randomized crossover design. This type of study will provide an opportunity to firmly establish the pharmacokinetics of estazolam in healthy subjects. PATIENTS AND METHODS Subject Selection
Eighteen healthy adult men were selected to participate in this study. The subjects were judged to be in good health based on a medical history, a physical examination, and clinical laboratory testing performed within two weeks before the start of the study. The protocol and consent form were reviewed and approved by the Institutional Review Board of the University of Utah Medical Center, and each subject provided written informed consent to participate in the study. Potential subjects were excluded if they had physical or physiologic evidence of any active disease or of significant cardiovascular, pulmonary, renal, hepatic, or neurologic disease. Subjects with known hypersensitivity to benzodiazepines or a history of drug or alcohol dependence were also excluded. EXPERIMENTAL PROCEDURES Subjects were confined to the study area beginning the evening before dosing. A standardized dinner was served at approximately 8:00 P.M. Following dinner, an absolute fast except for water was maintained for a minimum of 10 hours before dosing. Water was available ad Zibitum. In the morning, subjects received one of three estazolam regimens according to a randomized schedule. The regimens included one 1-mg tablet, two 1-mg tablets, and one 2-mg tablet. Each estazolam regimen was ingested with 120 ml of water. Heparinized blood samples (10 ml) were collected before dosing and 0.33, 0.67, one, two, three, four, eight, 12,24,36,48, and 72 hours after dosing. Plasma was separated by centrifugation within one hour after sample collection. Plasma samples were transferred to labeled vials and stored frozen (less than or equal to -10%). Fasting was continued until the three-hour blood sample had been collected. Following collection of the three-hour blood sample, a standardized break-
ON INSOMNIA I GUSTAVSON and CARRIGAN
I
N r N’P
Cl 0 w
I
Figure 1. Structure of estazolam.
‘N
00
fast was served. A standardized lunch and dinner were served approximately six and 11 hours after dosing, respectively. There was a washout period of at least 14 days between the estazolam regimens. Analytical Procedures
Plasma concentrations of estazolam were determined by a high-performance liquid chromatographic assay [8] with minor modifications. Briefly, alkalinized aliquots of plasma were extracted with heptane-ethyl acetate (7:3, v:v) containing desmethyldiazepam as the internal standard. The extracts were evaporated to dryness and the residues reconstituted in mobile phase. Aliquots of the reconstituted extracts were injected into the high-performance liquid chromatographic system. Separation was achieved using a Cl8 reversedphase analytical column. The mobile phase consisted of 22 percent acetonitrile and 30 percent methanol in 0.05 M ammonium phosphate buffer (pH 4.6). Mobile phase was delivered to the column at 2 ml/minute. The column effluent was monitored using ultraviolet detection at a wavelength of 223 nm. The limit of quantification for estazolam was approximately 4 rig/ml. The mean coefficient of variation for interassay precision during the analysis of these samples was approximately 10 percent. Data Analysis
Pharmacokinetic parameters were calculated from the plasma concentration-time data using conventional noncompartmental analysis [9]. Analyses of variance were performed for the C,,,, the T,,,, and the area under the plasma concentration-time curve from zero to 72 hours (AUCj, using a model that included treatment, subject, and period effects as sources of variation. Ninety-five percent confidence intervals were determined for the ratios of the mean AUC [lO,ll]. Harmonic mean half-lives were calculated as the natural logarithm of 2 divided by the mean of the elimination rate constants. RESULTS Seventeen subjects completed all three phases of this study. Subject 2 was lost to follow-up after the first estazolam dose and his data have been excluded from all analyses. The remaining subjects ranged in age from 18 to 34 years and ranged in weight from 61 to 81 kg and in height from 173 to 193 cm. The mean plasma concentration-time profiles for
March 2, 1990
The American Journal of Medicine
Volume 88 (suppl 3A)
3A-3s
SYMPOSIUM
ON INSOMNIA / GUSTAVSON and CARRIGAN 1
w O--
TIME gure 2. Mean plasma concentration-time
Mean (SD) and Range of Pharmacokinetic Parameters Calculated for Estazolam in Healthy Male subjects Regime? One I-mg Tablet
Lx hours) ;a’n”g”e’Ss”’ AK (ng hour/ml) Mean[SD) Range Elimination rate constant (hours-‘) /;;;;SD) Half-life (hours) ;;$“I
Two 1-mgTablets
54.1(9.0)
97.7 j17.0)
42.0-70.4
72.2-148
1.9(1.3) 0.33-2.0
1.9(2.0) 0.33-8.0
1,050 (292) 555-1,440
One 2.mg Tablet
98.6(18.1) 74.7-131
1,930(501) l,llO-3,050
0.0464(0.0156) 0.0494 (0.0148) 0.0252-0.07520.032&0.0851 14.9* 9.2-27.5
14.0* 8.1-21.7
iarmonic mean.
the three estazolam regimens appear in Figure 2. Table I summarizes the mean pharmacokinetic parameters for each regimen. There were no significant differences between the mean T,,, or the harmonic mean half-lives for the three regimens. The overall harmonic mean for the three regimens together was 14.4 hours. For the 2-mg dose regimens, there were no significant differences between the mean C,,, or mean AUC. The ratio of mean AUC (two 1-mg tablets:one 2-mg tablet) was 0.94, with a 95 percent 3A-4S
March 2, 1990
One Two One
1 mg Tablet 1 rnb Tablets 2 mg Tablet
(hours)
profiles of estazolam following 1-mg and 2-mg oral doses of estazolam in 17 healthy subjects.
TABLE I
Parameter
- 4 0-a
The American Journal of Medicine
confidence interval of 0.85 to 1.04. The mean C,,, and AUC values for the 1-mg regimen were significantly lower than the values for either 2-mg regimen. The ratio of mean AUC (one 1-mg tablet:one 2-mg tablet) was 0.51, with a 95 percent confidence interval of 0.46 to 0.57. COMMENTS The data generated in this study have confirmed that estazolam is rapidly absorbed from orally administered tablets. Detectable estazolam concentrations generally appeared in plasma by the first sampling time, 20 minutes after dosing. The mean times of maximal plasma concentration were less than two hours for each dosing regimen examined in this study. The similarity of the values of T,,,, C,,,, and AUC for the two 2-mg dosage regimens indicated that the rate and extent of absorption of estazolam from two 1-mg tablets or one 2-mg tablet were virtually identical. The relationship between C,,, and AUC for the l- and 2-mg dosing regimens supported proportional absorption of l- and 2-mg doses of estazolam. The observed value for the AUC ratio (one 1-mg tablet:two 1-mg tablets) was 0.51, which agreed very well with the predicted ratio of 0.5. Elimination of estazolam appeared to be independent of the dose and dosage strength administered. The harmonic mean half-lives were very similar for the three estazolam regimens. The half-life values calculated from this study’s data were within the range previously reported in the literature. There was some tendency, however, for the current results to be toward the shorter end of the previously reported spec-
Volume 88 (suppl 3A)
SYMPOSIUM
trum. These pharmacokinetic characteristics are consistent with the clinical evidence that estazolam decreases sleep latency and/or increases sleep duration in patients with transient or chronic insomnia. ACKNOWLEDGMENT We wash to thank Drs. G. Richard Granneman, Joseph M. Machinist, and Mark W. Prerce of Abbott Laboratories for helpful discussrons.
REFERENCES 1. Roehrs T, Lorick F, Lord N, Koshorek GL, Roth T: Dose-related effects of estazolam on sleep of patients with insomnia. J Clin Psycho1 1983; 3: 152-156. 2. Lamphere J, Roehrs T, Zorrck F, Koshorek G, Roth T: Chronic hypnotic efficacy of estarolam, Drugs Exp Clan Res 1986; 12: 687-691. 3. Walsh JK, Targum SD, Pegram V, eta/: A multicenter clinical rnvestigatron of estazolam:
ON INSOMNIA / GUSTAVSON and CARRIGAN
short-term efficacy. Curr Ther Res 1984; 36: 866-874. 4. Domrnguez RA, Goldstein BT, Jacobson AF, Sternbrook RM: Comparatrve efficacy of estazolam, flurazepam and placebo in outpatients with insomnia. J Clin Psychiatry 1986; 47: 362-365. 5. Sekr T: Clknical pharmacology of D40TA. Rrnsho Yakun 1973; 4: 76-86. 6. Allen MD, Greenblatt DJ, Arnold JD: Single- and multiple-dose kinetics of estazolam, a triazolo benzodiazepine. Psychopharmacology 1979; 66: 267-274. 7. Mancinelli A, Guise G, Garattinr S, Urso R, Caccia S: Kinetic and pharmacological studies on estazolam in mice and man. Xenobiotica 1985; 15: 257-265. 8. Machrnist JM, Bopp BA, Anderson DJ, Granneman GR, Sonders RC: Metabolrsm of ‘%estazolam In dogs and humans. Xenobiotica 1986; 16: 11-20. 9. Rowland M, Tozer TN: Clinical pharmacokinetrcs: concepts and applrcations. Philadelphra: Lea & Febiger, 1980. 10. Miller RJ: Simultaneous statistical inference. New York: McGraw-Hill, 1964; 3770. 11. Flnney DJ: Statistical method in brological assay, 3rd ed. New York: MacMillan PublishIng Co., 1978; 80-82.
March 2, 1990
The American Journal of Medicine
Volume 88 (suppi 3A)
3A-5S
