Characterization of Extended-Release Lorazepam

Purpose/Background

Once-daily extended-release (ER) lorazepam was developed to reduce fluctuations in plasma levels compared with lorazepam immediate-release (IR) for short-term anxiety relief. Here we report a series of phase 1 randomized, open-label, multiperiod crossover studies characterizing ER lorazepam pharmacokinetics and safety in healthy adults.

Methods/Procedures

These phase 1 studies assessed the pharmacokinetics of ER lorazepam administered: (study 1) 3 mg once daily versus IR lorazepam 1 mg 3 times a day (TID; every 8 hours), (study 2) with or without food, and (study 3) intact versus sprinkled onto food. Study 3 further evaluated the proportionality of 1 × 4- versus 4 × 1-mg doses. Safety was also monitored.

Findings/Results

There were 43, 27, and 29 subjects who completed studies 1, 2, and 3, respectively. The 90% confidence intervals for C_max,SS, C_min, and AUC_TAU,SS of once-daily ER lorazepam compared with IR given TID were within 80% to 125% limits establishing steady-state bioequivalence. Maximum mean lorazepam concentrations were achieved at 11 hours compared with 1 hour after dosing for ER versus IR lorazepam, respectively. Pharmacokinetic parameters (C_max, AUC_last or AUC_0–t, AUC_inf or AUC_0–inf) of ER lorazepam were bioequivalent whether taken with or without food, administered intact or sprinkled onto food, or administered as intact 1 × 4- versus 4 × 1-mg capsules. No serious safety concerns were found.

Implications/Conclusions

Once-daily ER lorazepam provided a pharmacokinetic profile bioequivalent to IR lorazepam given TID and was well tolerated in healthy adults across all phase 1 studies. These data suggest that ER lorazepam could be an alternative for patients currently treated with IR lorazepam.

Anxiety disorders are among the most frequently occurring psychiatric disorders in the United States, with an estimated 7.8% lifetime prevalence of generalized anxiety disorder in adults, and a cumulative 20% to 30% prevalence of all anxiety disorders among older adolescents/young adults.^1–3 These disorders can cause significant functional impairments, reductions in quality of life, patient and family burden, and increased utilization of healthcare services.³ Like many neuropsychiatric disorders, anxiety is associated with complex pathophysiology, including aberrant neural inhibition—which, in the central nervous system, is mediated in part through the predominant inhibitory neurotransmitter γ-aminobutyric acid (GABA) and its receptors.⁴ Indeed, GABA has long been a central therapeutic target for the treatment of neuropsychiatric symptoms.⁴ The benzodiazepines are a class of allosteric GABA receptor modulators commonly used to treat a range of disorders, including anxiety and sleep disorders.⁴

Lorazepam, a member of the benzodiazepine class, has long been used for the short-term treatment of anxiety, first receiving US Food and Drug Administration (FDA) approval in 1977 as an immediate-release (IR) formulation (Ativan).⁵ Historically, lorazepam has been clinically used as an antianxiety agent for acute or chronic anxiety, as a premedication before surgical procedures, as a sedative in intensive care settings, or to treat agitation in severe panic attacks.^6,7 Although lorazepam has been used in clinical practice for over 4 decades for a variety of indications, the overall prescription of benzodiazepines and lorazepam has declined over the past decade.^8–10 Current indications include the short-term treatment of excessive anxiety associated with anxiety neurosis and adjunct relief for severe anxiety related to upcoming surgical intervention.⁵ Oral, oral concentrate, sublingual, intravenous, and intramuscular administration modalities have subsequently become available to treat both the original indications and additional indications, including as an anticonvulsant aid.^6,7,11

Given the long history of lorazepam use, its pharmacokinetic (PK) and metabolic profile have been previously characterized.^6,7,11,12 When given orally, lorazepam is quickly absorbed in the gastrointestinal tract, with previous reports noting maximum plasma concentrations achieved approximately 2 to 3 hours after dosing and bioavailability ≥90%.^6,7,11 The half-life documented in previous reports is between 10 and 20 hours, with pharmacological effects typically dissipating after 6 to 8 hours.⁷ Lorazepam is metabolized in the liver, where it undergoes direct conjugation to glucuronic acid via glucuronyl transferase to form a pharmacologically inactive metabolite that is primarily excreted through the kidneys.^6,7 Of note, IR lorazepam has demonstrated a safe hepatic profile, with acute or clinically apparent liver injury or serum alanine aminotransferase elevations being quite rare.¹³

Traditionally, IR lorazepam is prescribed at doses usually ranging from 2 to 6 mg/day given in tablets 2 to 3 times daily (BID/TID), but the daily dose can be from 1 to 10 mg/day for some patients.^12,14 Although this dosing regimen can be effective for the treatment of short-term anxiety, the IR lorazepam formulation and IR benzodiazepines in general have limitations. First, serum concentrations of IR benzodiazepines rise quickly, which can lead to off-target effects such as memory loss and sedation.^15,16 Detrimental adverse effects such as impaired recall have been reported with IR lorazepam in a dose-related manner.⁵ Moreover, just as plasma concentrations of IR benzodiazepines rise quickly, they can also fall quickly to subtherapeutic levels, leading to a breakthrough effect in which anxiety symptoms reemerge before the next scheduled dose.¹⁶ Lastly, dosing multiple times throughout the day represents a high pill burden, which has been shown to reduce treatment adherence, thus worsening outcomes.¹⁵ As such, a formulation providing fewer fluctuations between peak and trough lorazepam serum concentrations would provide relief throughout the day while reducing rebound/breakthrough anxiety and risk for adverse events (AEs), and—if given with fewer pills—lessen the pill burden on patients.¹⁵

With these considerations in mind, extended-release (ER) lorazepam (Loreev XR) was approved by the FDA in August 2021¹⁷ for the treatment of anxiety disorders in adults who are already receiving stable, evenly divided, TID dosing of IR lorazepam tablets.¹⁸ Extended-release lorazepam is prescribed as a once-daily capsule (doses of 1, 1.5, 2, and 3 mg; with the 3-mg dose equivalent to the previous total TID IR dosage) that may be swallowed whole or opened and sprinkled onto soft food.¹⁸ Extended-release lorazepam may therefore provide flexible dosing administration options to patients already benefiting from IR lorazepam, with fewer fluctuations in drug levels throughout the day. Here we report PK data analyzed across a series of phase 1 studies comparing the bioequivalence of 3 mg once-daily ER lorazepam with IR lorazepam given TID, and the impact of food or sprinkling administration on PK characteristics of the ER formulation in healthy adults.

MATERIALS AND METHODS

Study Synopses

During the clinical development of ER lorazepam, multiple phase 1 studies were conducted to evaluate its PK and safety profile (summarized in Table 1). Because IR lorazepam is typically given TID, the first study compared the steady-state PK profile of once-daily ER lorazepam to TID (every 8 hours [q8h]) IR lorazepam. As flexible administration is an important property of an anxiolytic, the second study explored the impact of food on bioavailability of once-daily ER lorazepam. Finally, because some patients experience difficulty swallowing solid oral dosage formulations,^19,20 the third study examined the PK profile of ER lorazepam sprinkled onto soft food compared with that of intact capsule administration. This study also included a dose proportionality evaluation of the highest (1 × 4 mg) and lowest (4 × 1 mg) investigational dose forms for ER lorazepam (4 mg is higher than the maximum FDA-approved dose strength). Finally, a fourth study investigated ER lorazepam (4 mg once daily [QD]) compared with IR lorazepam 2 mg BID (every 12 hours), assessing the bioequivalence and safety of the ER formulation at a higher dose than the approved dose strength (Supplemental Materials, http://links.lww.com/JCP/A851).¹⁸

TABLE 1.

Summary of the Phase 1 ER Lorazepam Studies

Study	N*	Study Type	Primary Objective
1	43 ER/IR	Randomized, open-label, 2-period, 2-sequence, 2-treatment, relative bioavailability	Steady-state comparison of PK profile of ER lorazepam 3 mg QD and IR lorazepam 1 mg q8h (TID)
2	28	Randomized, open-label, 2-period, 2-sequence, 2-treatment, food-effect relative bioavailability	Comparison of PK profile of QD ER lorazepam 4 mg under fed and fasted conditions
3	30	Randomized, open-label, 3-period, 6-sequence, 3-treatment, relative bioavailability	Evaluation of the sprinkle effect of ER lorazepam 4 mg compared with the intact capsule; evaluation of dose proportionality of PK profile of ER lorazepam
Supplemental study 4	69 ER, 68 IR	Randomized, open-label, 2-period, 2-sequence, 2-treatment, relative bioavailability	Steady-state comparison of PK profile of ER lorazepam 4 mg QD and IR lorazepam 2 mg q12h (BID)

*Number of participants reflects the size of the PK population of each study.

q12h, every 12 hours.

Participants

For studies 1 to 3, participants were healthy adult men or women between the ages of 18 and 55 years, with a body mass index between 18 and 30 kg/m² and a weight ≥60 kg. Inclusion criteria required all participants to have no major recent or ongoing clinically significant pathology, active or chronic disease, or clinically significant findings upon physical examination, vital sign collection, 12-lead electrocardiogram (ECG), or laboratory assessments. All assessments were made by the investigator or a certified physician to rule out any existing pathology. In study 1, participants were further screened using the Columbia-Suicide Severity Rating Scale. Pregnant or breastfeeding female participants were excluded. All women underwent a serum pregnancy test, and all participants had a urine alcohol, drug (including but not limited to cannabinoids, opioids, cocaine, phenylcyclohexyl piperidine, amphetamines, barbiturates, and benzodiazepines), and cotinine screen performed. Among other medical history criteria, participants were excluded if they had a recent exposure to any pharmacological agents with known interactions with benzodiazepines or agents that could interfere with the evaluation of ER or IR lorazepam. Each study was performed at a single institutional review board–approved research unit, and all participants provided written informed consent (see Supplemental Materials, http://links.lww.com/JCP/A851). Randomization (1:1) schedules were prepared using Worldwide Clinical Trials and SAS software, with each participant receiving treatment according to their assigned randomization schedule.

Study End Points/Assessments

All participants who received at least 1 dose of study treatment and had at least 1 postbaseline measurement were included in the safety population, whereas all participants who completed at least 1 treatment period and provided sufficient data were included in the PK population. The completer population included all participants who completed both study periods and had no major protocol deviations. The following general PK parameters were calculated for each study (see individual study methods hereinafter for specific parameters): total plasma clearance (CL/F), maximum plasma concentration (C_max), time to reach maximum plasma concentration (T_max), and area under the plasma concentration-time curve (AUC). Plasma concentrations of lorazepam were measured by liquid chromatography with tandem mass spectrometry (see Supplemental Materials for further details, http://links.lww.com/JCP/A851). Concentration-time data for lorazepam were analyzed using Phoenix WinNonlin (Version 8.1; Certara, L.P.) in conjunction with the Pharsight Knowledgebase Server (PKSO; Version 4.0.4; Certara, L.P.). Pharmacokinetic parameters were considered bioequivalent if the 90% confidence intervals (CIs) of the geometric mean ratios fell within the range of 80% to 125%. In all presentations of data and summary statistics, concentrations below the limit of quantitation were set to zero.

Safety assessments across the 4 studies included monitoring AEs, clinical laboratory tests (serum chemistry, hematology, and urinalysis), vital signs, ECGs, and physical examinations. Additional safety assessments in study 1 and supplemental study 4 included monitoring responses to the Columbia-Suicide Severity Rating Scale.

Study 1 Specific Methods: ER Lorazepam (3 mg) Compared With IR Lorazepam TID

Study 1 was a randomized, open-label, 2-period, 2-sequence, 2-treatment, relative bioavailability, steady-state study comparing the steady-state PK profile of once-daily ER lorazepam 3 mg with that of IR lorazepam 1 mg q8h. The safety of once-daily ER lorazepam 3 mg and IR lorazepam 1 mg q8h after multiple doses to achieve steady-state levels was also evaluated. One hundred three participants were screened, and 46 were enrolled. Each participant received 2 separate multiple-dose administrations of treatment A (ER lorazepam 3 mg) QD or treatment B (IR lorazepam 1 mg) q8h. Participants were randomized to 1 of 2 treatment sequences, AB or BA, and were switched to the next treatment after a washout period of at least 10 days. During each treatment period, participants received their study medication each day from day 1 to day 8, and predose blood draws were taken on days 5 to 8 to verify that steady state had been achieved. Pharmacokinetic profile draws were then taken on day 8. For treatment A, these occurred each hour for the first 18 hours after dosing, then at 24, 36, 48, 72, 96, and 120 hours after dosing. For treatment B, blood draws occurred at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 8.5, 9, 9.5, 10, 11, 12, 14, 16, 16.5, 17, 17.5, 18, 19, 20, 22, 24, 30, 36, 48, 72, 96, and 120 hours after dosing. All participants received a standard diet while in the clinical research center and fasted overnight for a minimum of 8 hours before each morning dose on days 1 to 7 and for at least 4 hours after the morning dose on day 8. All participants had their meals between 4 and 10 hours after each morning dose and had a snack at least 13.5 hours after the morning dose. Participants receiving treatment B (q8h) took their evening meal at least 2 hours after the second (8-hour) dose and had a snack at least 2.5 hours before the third (16-hour) dose. Water was prohibited for 1 hour before each dose and for 2 hours after; at other times, it was allowed ad libitum.

Calculated PK parameters were analyzed using descriptive statistics and included maximum observed plasma concentration at steady state (C_max,SS), time to reach C_max,SS, minimum observed plasma concentration on day 8 at 24 hours after dosing (C_min), average concentration at steady state (C_av), area under the plasma concentration-time curve for the dosing interval (AUC_TAU,SS), area under the plasma concentration-time curve from time 0 to 24 hours after dosing (AUC_0–24), percent fluctuation (Flu%), swing, apparent total plasma clearance at steady state (CL_SS/F), and terminal elimination half-life (t_1/2). Steady-state conditions were determined using linear square regression for each predose concentration on days 5 to 8.

Relative bioavailability for ER and IR lorazepam under steady state (day 8) was evaluated using an analysis of variance (ANOVA) model with ln-transformed C_max,SS, C_min, and AUC_TAU,SS (AUC_0–24 was used for treatment B). The statistical model contained treatment, period, and sequence as fixed effects and participants nested within sequence as the random effect. Statistical analyses were performed using appropriate software; for example, Phoenix WinNonlin (Version 8.1; Certara, L.P.) and SAS (Version 9.4; SAS Institute Inc).

Study 2 Specific Methods: Effect of Food on Bioavailability and PK Profile of ER Lorazepam

Study 2 was a randomized, open-label, 2-period, 2-sequence, 2-treatment, relative food-effect bioavailability study, with the primary goal of comparing the PK profiles of once-daily ER lorazepam 4 mg under fed and fasted conditions in healthy adults. The study also included an evaluation of the safety and tolerability of once-daily ER lorazepam 4 mg.

Sixty-one participants were screened and 28 enrolled, with 27 completing both study periods. Participants reported to the facility at least 10 hours before the first scheduled dose and were assigned to either treatment sequence, AB or BA. During each treatment period, participants received a single dose of either treatment A (ER lorazepam 4 mg after an overnight fast of ≥10 hours; fasted condition) or treatment B (ER lorazepam 4 mg after an FDA-standard high-fat, high-calorie breakfast after an overnight fast of ≥10 hours, eaten 30 minutes before dosing; fed condition). The meal (~1000 calories total) consisted of 150 (15%) protein calories, 250 (25%) carbohydrate calories, and 500 to 600 (50%–60%) fat calories, with all meals and snacks being identical for all subjects. Participants were confined to the clinic from day −1 to 48 hours after dosing in each period. There was a washout of least 10 days between period 1 and period 2, upon which participants returned to the facility at day −1 of period 2 and received the alternate treatment as described previously. Pharmacokinetic profile blood draws occurred every hour from 0 (predose) to 16 hours after dosing, and then at 18, 24, 36, and 48 hours after dosing. Participants returned to the facility for subsequent blood draws at 72, 96, and 120 hours after dosing.

The following parameters were calculated for each participant in the PK population: CL/F, C_max, T_max, time at which the first quantifiable postdose concentration was observed (T_lag), t_1/2, AUC_0–12, AUC_0–24, area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUC_last), area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC_inf), and the percentage of AUC_inf based on extrapolation (AUC_Extrap). Comparisons of the PK parameters between treatments (fed vs fasted) were performed on ln-transformed C_max, AUC_last, and AUC_inf using an ANOVA model (PROC GLM) with sequence, treatment, and period as fixed effects and subjects nested within sequence as the random effect.

Study 3 Specific Methods: Effect of Sprinkling Administration on Bioavailability of Once-Daily ER Lorazepam and Dose Proportionality

Study 3 was a randomized, open-label, 3-period, 6-sequence, 3-treatment, relative bioavailability study with 2 primary goals: (1) to evaluate the PK profile of ER lorazepam 4 mg when sprinkled onto soft food compared with intact capsule administration in healthy adults, and (2) to evaluate the dose proportionality of the PK profile of ER lorazepam by comparing ER lorazepam 1 × 4-mg doses to ER lorazepam 4 × 1-mg dose under fasting conditions. Safety and tolerability of ER lorazepam were also evaluated.

Seventy-seven participants were screened and 30 enrolled, with 29 completing both study periods. Participants reported to the clinic on day −1 at least 12 hours before the first scheduled dose to ensure a 10-hour fast, and were assigned to 1 of 6 treatment sequences: ABC, BCA, CAB, CBA, ACB, or BAC, separated by a 10-day washout between doses in each period. Treatment A consisted of once-daily ER lorazepam 4 mg sprinkled on soft food (applesauce); treatment B was once-daily ER lorazepam 4 mg given as an intact capsule; and treatment C was once-daily ER lorazepam 1 mg given as 4 intact capsules.

From day −1 to 48 hours after dosing in each period, participants were confined to the clinic, with blood draws every hour from 0 (predose) to 16 hours after dosing, and then at 18, 24, 36, and 48 hours after dosing to obtain a PK profile. Participants returned to the facility for subsequent blood draws at 72, 96, and 120 hours after dosing. For each participant in the PK population, the following parameters were calculated: CL/F, C_max, T_max, T_lag, t_1/2, area under the plasma concentration-time curve from time zero to time of the last quantifiable concentration (AUC_0–t), AUC_0–inf, and AUC_Extrap.

Comparisons between treatment A and treatment B to assess the effect of administering ER lorazepam sprinkled over food were performed on ln-transformed C_max, AUC_0–t, and AUC_0–inf using an ANOVA model. Relative bioavailability for ER lorazepam 4 × 1-mg capsules (treatment C) to ER lorazepam 1 × 4-mg capsule (treatment B) was evaluated using an ANOVA model with ln-transformed C_max, AUC_0–t, and AUC_0–inf.

RESULTS

Study 1: ER Lorazepam (3 mg) Compared With IR Lorazepam TID

Study Population Demographics for Study 1

In study 1, of 46 participants (safety population), 43 completed both treatment periods and were included in the analysis (PK population). Three withdrew early in the study for reasons unrelated to AEs (Supplemental Fig. S1A, http://links.lww.com/JCP/A851). The study population included healthy female (n = 12) and male (n = 34) adults ranging from 22 to 55 years of age. The key demographic data are summarized in Supplemental Table S1, http://links.lww.com/JCP/A851.

PK Results for Study 1

In study 1, the concentration of lorazepam over time was similar throughout the 24-hour sampling window on day 8 for both ER and IR formulations (Fig. 1). Maximum mean concentrations of lorazepam were achieved at 11 hours after dosing for the ER (33.02 ± 9.83 ng/mL) compared with 1 hour after dosing for the IR (39.30 ± 12.69 ng/mL) formulation. As expected, participants treated with IR lorazepam q8h showed 3 peaks in lorazepam concentrations that corresponded to the timing of each of the 3 daily doses (Fig. 1). The PK profiles of ER and IR lorazepam were also similar on day 8, indicating similar bioavailability (see data summarized in Table 2).

FIGURE 1.

Mean plasma concentration over time of once-daily ER lorazepam (3 mg) versus IR lorazepam q8h (1 mg TID) 24 hours after dosing on a linear scale (study 1). Mean values plotted, with error bars denoting SE of the mean.

TABLE 2.

PK Parameters of Multiple Doses of ER Lorazepam and IR Lorazepam on Day 8

Study 1: Once-Daily ER Lorazepam Compared With IR Lorazepam TID on Day 8
Parameter, Mean (SD) Unless Otherwise Noted	ER Lorazepam QD 3 mg (n = 43)	IR Lorazepam q8h 1 mg (n = 43)
Tmax,SS, median (range), h	9.0 (4.0–14.0)	1.5 (0.8–3.0)
Cmax,SS, ng/mL	35.3 (10.4)	40.7 (12.9)
Cmin, ng/mL	24.8 (8.8)	29.1 (11.2)
Cav, ng/mL	28.9 (9.1)	31.9 (10.2)
AUCTAU,SS, h × ng/mL	694 (218.9)	264 (85.1)
AUC0–24, h × ng/mL	694 (218.9)	765 (244.4)
t1/2, h	17.8 (3.6)	17.6 (4.3)
Flu, % [(Cmax-SS − Cmin)/Cav]*	38.1 (12.9)	38.3 (12.0)
Swing, % [(Cmax,SS − Cmin,SS)/Cmin,SS]	47.0 (21.0)	44.0 (16.0)
CLss/F, L/h	4.8 (1.5)	4.3 (1.2)

*C_max,SS and C_min obtained between time 0 and tau, where tau = 24 hours on day 8.

Flu, fluctuation; T_max,SS, time to reach C_max at steady state.

Statistical Analyses for Study 1

Bioequivalence was designated if the 90% CIs between geometric means of PK parameters were within 80% to 125%. In study 1, the 90% CIs of all 3 geometric mean ratios (ER to IR lorazepam given TID) for systemic lorazepam exposure for C_max,SS, C_min, and AUC_TAU,SS fell within the bioequivalence range of 80% to 125% (Table 3). These data suggest that once-daily ER lorazepam 3 mg and IR lorazepam 1 mg q8h are bioequivalent.

TABLE 3.

Statistical Analyses of the Natural Log-Transformed Exposure of Multiple Doses of ER and IR Lorazepam in Study 1

Study 1: Once-Daily ER Lorazepam Compared With IR Lorazepam TID
PK Parameter, Natural Log-Transformed Exposure	ER Lorazepam* QD (n = 43) Geometric Mean	IR Lorazepam* q8h (n = 43) Geometric Mean	Geometric Mean Ratio ER/IR, %	90% CI
C max,SS	33.8	38.9	86.9	84.6–89.2
C min	23.2	27.2	85.3	82.2–88.5
AUCTAU,SS	661	730	90.6	88.4–92.8

*ER lorazepam administered as 3-mg dose QD; IR lorazepam as 1-mg dose q8h.

Safety Results for Study 1

There were no serious AEs (SAEs) leading to study withdrawal in study 1. Treatment-emergent AEs (TEAEs) were reported in similar numbers by participants in both treatment groups: 36 TEAEs were reported by 19 participants (41.3%) receiving once-daily ER lorazepam, and 38 TEAEs were reported by 20 participants (43.5%) receiving IR lorazepam q8h (Table 4). The most frequently reported TEAEs (n ≥ 5 participants overall) were constipation (13% ER, 21.7% IR lorazepam), headache (6.5% ER, 8.7% IR), dizziness (8.7% ER, 2.2% IR), and insomnia (6.5% ER, 4.3% IR). A majority of TEAEs were mild in severity (n = 15 [32.6%] ER, n = 12 [26.1%] IR), with 4 and 8 participants reporting moderate TEAEs after ER and IR lorazepam, respectively. Moreover, there were no reports of abnormal physical examinations, clinical laboratory results, vital signs, or ECGs, or reports of suicidality.

TABLE 4.

Safety Overview of ER and IR Lorazepam From Study 1, Safety Population

Study 1: Once-Daily ER Lorazepam Compared With IR Lorazepam TID
AEs	ER Lorazepam* QD (n = 46)	IR Lorazepam* q8h (n = 46)
All TEAEs, n (%), m	19 (41.3), 36	20 (43.5), 38
Most frequently reported TEAEs (n ≥ 5), n (%), m
Constipation	6 (13.0), 6	10 (21.7), 13
Headache	3 (6.5), 3	4 (8.7), 6
Dizziness	4 (8.7), 4	1 (2.2), 1
Insomnia	3 (6.5), 4	2 (4.3), 2
TEAEs by severity, n (%)
Mild	15 (32.6)	12 (26.1)
Moderate	4 (8.7)	8 (17.4)
Severe	0	0
TEAEs by relationship, n (%)†
Related to study drug	14 (30.4)	16 (34.8)
Not related	9 (19.6)	10 (21.7)
All treatment-related TEAEs, n (%), m
Constipation	6 (13.0), 6	10 (21.7), 12
Nausea	1 (2.2), 1	0
Headache	2 (4.3), 2	4 (8.7), 4
Dizziness	4 (8.7), 4	1 (2.2), 1
Somnolence	1 (2.2), 1	2 (4.3), 2
Paresthesia	1 (2.2), 1	1 (2.2), 1
Insomnia	2 (4.3), 3	1 (2.2), 1
Anhedonia	1 (2.2), 1	0
Euphoric mood	1 (2.2), 1	0
Vision blurred	3 (6.5), 4	1 (2.2), 1
Acne	1 (2.2), 1	0
Dermatitis acneiform	0	1 (2.2), 1
Decreased appetite	0	1 (2.2), 1
Back pain	0	1 (2.2), 1
SAEs, n (%)	0	0
TEAEs leading to study withdrawal, n (%)	0	0

*ER lorazepam administered as 3-mg dose QD; IR lorazepam as 1-mg dose q8h.

^†Participants were counted twice if they experienced both a related and an unrelated TEAE.

m, number of events; n, number of participants.

Study 2: Effect of Food on Bioavailability and PK Profile of ER Lorazepam, and Study 3: Effect of Sprinkling Administration on Bioavailability of Once-Daily ER Lorazepam and Dose Proportionality

Study Population Demographics for Study 2 and Study 3

Twenty-eight participants enrolled in study 2 (safety and PK population), with 27 completing both treatment periods and included in the statistical analysis (completer population). One participant withdrew consent for reasons unrelated to AEs (Supplemental Fig. S1B, http://links.lww.com/JCP/A851). Key study demographics are summarized in Supplemental Table S2, http://links.lww.com/JCP/A851: overall, participants were healthy female (n = 9) and male (n = 19) adults aged 18 to 54 years.

In study 3, 30 participants were enrolled (safety population), with all 30 included in the PK population and 29 participants who completed at least 2 study periods included in the statistical analysis (completer population, Supplemental Fig. S1C, http://links.lww.com/JCP/A851). One participant was withdrawn by the investigator for an AE of oral herpes before period 2. Participants were healthy women (n = 9) and men (n = 21) ranging from 26 to 55 years of age. See Supplemental Table S2 for a summary of study demographics, http://links.lww.com/JCP/A851.

PK Results for Study 2 and Study 3

Overall, mean lorazepam concentration-time profiles in study 2 were similar under either fasted or fed conditions (Fig. 2), with the first quantifiable lorazepam concentrations observed at 1 hour after dosing in both conditions. Maximum mean lorazepam concentrations were achieved 10 and 11 hours after dosing under fasted and fed conditions, respectively. Mean PK parameters were similar whether ER lorazepam was given with or without food, although administration with food delayed the median T_max by ~2 hours (Table 5).

FIGURE 2.

Mean plasma concentration-time profiles of once-daily ER lorazepam 4 mg taken under fasted or fed conditions, plotted on a linear scale (study 2). Mean values plotted, with error bars denoting SE of the mean.

TABLE 5.

PK Parameters of Once-Daily ER Lorazepam (4 mg) Administered in Fasted and Fed Conditions (Study 2)

PK Parameter, Mean (SD) Unless Otherwise Noted	Once-Daily ER Lorazepam (4 mg)
	Fasted (n = 27)	Fed (n = 28)
Tmax, median (range), h	10.0 (6.0–24.2)	12.0 (8.0–24.0)
Tlag, h	0.0 (0.0)	0.1 (0.5)
Cmax, ng/mL	19.2 (5.1)	19.6 (3.2)
AUC0–24, h × ng/mL	354 (92.5)	324 (54.0)
AUCinf, h × ng/mL	937 (386.7)*	895 (329.6)
t1/2, h	17.6 (6.7)*	17.4 (6.6)
CL/F, L/h	5.0 (2.2)*	5.1 (1.9)

*n for these values was 26.

In study 3, overall PK parameters, including median T_max, mean C_max, AUC_0–t, AUC_0–inf, and t_1/2 were similar for once-daily 4 mg (total daily dose) ER lorazepam regardless of being sprinkled on food, given intact, or given as 4 × 1-mg capsules (Figs. 3A, B; Table 6), where T_max occurred at approximately 11 hours across all treatments. Mean plasma concentration-time profiles were nearly identical when once-daily ER lorazepam 4 mg was administered intact versus sprinkled on soft food (Fig. 3A, Table 6). Similarly, when comparing the highest and lowest dose forms, mean plasma concentration-time profiles seemed superimposable for once-daily ER lorazepam administered as either 1 × 4- or 4 × 1-mg capsules (Fig. 3B).

FIGURE 3.

Mean plasma concentration-time profiles of once-daily ER lorazepam 4 mg sprinkled over food or taken as an intact capsule (A), and given as 1 × 4- or 4 × 1-mg capsules (B) plotted on linear scales (study 3). Mean values plotted, with error bars denoting SE of the mean.

TABLE 6.

PK Parameters of Once-Daily ER Lorazepam 4 mg When Sprinkled Onto Food, Taken as an Intact 1 × 4-mg capsule, or Taken as 4 × 1-mg capsules (Study 3)

PK Parameter, Mean (SD) Unless Otherwise Noted	Once-Daily ER Lorazepam
	Sprinkled (4 mg; n = 29)	Intact (1 × 4 mg; n = 30)	Intact (4 × 1 mg; n = 29)
Tmax, median (range), h	11.0 (5.0–24.0)	11.0 (5.0–24.0)	11.0 (8.0–24.0)
Tlag, h	0.0 (0)	0.0 (0)	0.0 (0)
Cmax, ng/mL	21.0 (4.4)	21.0 (4.1)	20.9 (5.0)
AUC0–t, h × ng/mL	930 (311.9)	921 (309.4)	927 (333.3)
AUC0–inf, h × ng/mL	950 (331.5)	939 (327.5)	949 (356.6)
t1/2, h	17.4 (3.9)	17.2 (3.6)	17.8 (4.3)
CL/F, L/h	4.7 (1.5)	4.8 (1.6)	4.8 (1.7)

Statistical Analyses for Study 2 and Study 3

Bioequivalence of ER lorazepam across administration modalities was also evaluated. In study 2, the observed intersubject variability (coefficient of variation [CV%]) for C_max and AUCs was slightly lower under fed conditions (16.53%–36.81%) compared with fasting conditions (26.17%–41.27%). However, the geometric mean ratios (fed to fasted) for C_max, AUC_last, and AUC_inf fell within the bioequivalence limits of 80% to 125%, demonstrating that food did not have a significant effect on bioavailability. Furthermore, in study 3, the 90% CIs of the geometric mean ratios for C_max, AUC_0–t, and AUC_0–inf also fell within the bioequivalence limits, indicating that administration of once-daily ER lorazepam sprinkled on food did not significantly affect bioavailability. These data suggest that ER lorazepam sprinkled onto soft food is bioequivalent to the intact dose. Lastly, the 90% CIs of the geometric mean ratios for C_max, AUC_0–t, and AUC_0–inf were also within the bioequivalence limits of 80% to 125% across dose strengths (Table 7), indicating that 1 × 4- and 4 × 1-mg ER lorazepam capsules are bioequivalent doses.

TABLE 7.

Statistical Analysis of the Ln-Transformed Systemic Exposure Parameters for ER Lorazepam 4 mg in Fasted or Fed Conditions, Sprinkled Onto Food or Given Intact, or Given as 1 × 4-mg capsule or as 4 × 1-mg capsules (Studies 2 and 3)

PK Parameter, Log-Transformed Exposure	Geometric Mean
	Fed (n = 27)	Fasted (n = 27)	Ratio Fed/Fasted, %	90% CI	ANOVA CV%
C max	19.3	18.6	103.9	98.4–109.7	11.7
AUClast	814	839	97.0	94.0–100.1	6.7
AUCinf *	833	861	96.8	93.6–100.1	7.1

Natural Log-Transformed Exposure	Sprinkled (n = 29)	Intact (n = 29)	Ratio Sprinkled/Intact, %	90% CI	ANOVA CV%
C max	20.5	20.5	100.1	95.7–104.7	10.0
AUC0–t	879	870	101.0	96.6–105.7	10.1
AUC0–inf	893	884	101.1	96.5–105.8	10.3

Natural Log-Transformed Exposure	1 × 4 mg (n = 29)	4 × 1 mg (n = 29)	Ratio 1 × 4 mg/4 × 1 mg, %	90% CI	ANOVA CV%
C max	20.3	20.5	98.9	94.9–103.1	9.3
AUC0–t	867	868	99.8	96.6–103.1	7.3
AUC0–inf	883	883	100.0	96.8–103.3	7.2

*n for these values was 26.

Safety Results for Study 2 and Study 3

No SAEs or AEs leading to study withdrawal were reported in study 2. Extended-release lorazepam given with food was generally well tolerated, with the most frequently reported TEAEs being headache (3.7% fasted and 3.6% fed) and somnolence (7.4% fasted, 0 fed). Treatment-emergent AEs were reported by 8 participants (4 per treatment arm) over the course of the study, with the majority being mild in severity. Two participants reported a moderate AE, 1 per treatment arm. No clinically significant abnormalities in ECGs, vital signs, or physical examinations were detected. Safety data are summarized in Table 8.

TABLE 8.

Safety Overview for Studies 2 and 3, Safety Population

Study 2: Effect of Food on Safety Profile of ER Lorazepam
AEs	Fasted (n = 27)	Fed (n = 28)
All TEAEs, n (%)	4 (14.8)	4 (14.3)
Most frequently reported TEAEs (n ≥ 2), n (%), m
Headache	1 (3.7), 1	1 (3.6), 1
Somnolence	2 (7.4), 2	0
TEAEs by severity, n (%)
Mild	3 (11.1)	3 (10.7)
Moderate	1 (3.7)	1 (3.6)
Severe	0	0
TEAEs by relationship, n (%)
Related to study drug	3 (11.1)	3 (10.7)
Not related	1 (3.7)	1 (3.6)
SAEs, n (%)	0	0
TEAEs leading to study withdrawal, n (%)	0	0

Study 3: Effect of Sprinkling Administration on Safety Profile of ER Lorazepam and Dose Proportionality
AEs	Sprinkled (4 mg; n = 29)	Intact (1 × 4 mg; n = 30)	Intact (4 × 1 mg; n = 30)
All TEAEs, n (%)	5 (17.2)	7 (23.3)	2 (6.9)
Most frequently reported TEAEs (n ≥ 2), n (%), m
Somnolence	3 (10.3), 3	1 (3.3), 1	1 (3.4), 1
Dizziness	0	2 (6.7), 2	0
Headache	0	2 (6.7), 2	0
Nausea	2 (6.9), 2	0	0
TEAEs by severity, n (%)
Mild	5 (17.2)	7 (23.3)	2 (6.9)
Moderate	0	0	0
Severe	0	0	0
TEAEs by relationship, n (%)*
Related to study drug	5 (17.2)	6 (20.0)	2 (6.9)
Not related	1 (3.4)	1 (3.3)	0
SAEs, n (%)	0	0	0
TEAEs leading to study withdrawal, n (%)	0	1 (3.3)	0

*Participants were counted twice if they experienced both a related and an unrelated TEAE.

m, number of events; n, number of participants.

Similarly, there were no SAEs reported during study 3, although 1 reported AE (oral herpes, considered unlikely related to treatment) led to study withdrawal as noted previously (Table 8). The most frequently reported TEAE was somnolence: n = 5 (16.7%) participants overall, with 3 after sprinkled dosing, 1 after intact 1 × 4-mg dosing, and 1 after 4 × 1-mg dosing. In addition, 2 participants (6.7%) reported dizziness and 2 (6.7%) reported headache after intact 1 × 4 mg ER lorazepam, and 2 participants (6.9%) experienced nausea after sprinkled ER lorazepam. A total of 16 TEAEs were reported by 12 participants over the course of the study, all of which were mild in severity. No clinically significant abnormalities in ECGs or vital signs were found, except for one clinically significant physical examination finding (the case of oral herpes noted previously, unrelated to treatment).

DISCUSSION

Results of the phase 1 studies reported here demonstrate that the PK profile of once-daily ER lorazepam (3 mg) is bioequivalent to that of IR lorazepam taken thrice daily, and that the bioavailability of ER lorazepam is similar whether taken under fasted or fed conditions, whether sprinkled over food or taken as an intact capsule, or whether it is administered as a single intact capsule or as a total-dose-equivalent number of smaller-dose capsules. Finally, no serious safety concerns were raised in any of the studies, including at the 4-mg dose investigated in studies 2 and 3, which is higher than the approved dosage of ER lorazepam used in clinical practice.¹⁸ Taken together, these results indicate that ER lorazepam can be flexibly administered to provide patients who may struggle with their multidose IR lorazepam regimens for a variety of reasons (eg, rebound anxiety or tolerability issues associated with fluctuating drug serum levels, high pill burden, etc) with an additional, bioequivalent treatment option. Once-daily ER lorazepam (1, 1.5, 2, and 3 mg), which was approved as a replacement therapy for thrice-daily IR lorazepam in 2021,^17,18 could therefore be a suitable alternative for some patients for the short-term treatment of anxiety.

Although widely prescribed, IR benzodiazepines are associated with an array of clinical concerns. Because of the nature of the entire dose being released all at once, IR formulations may lead to a higher C_max that surpasses the threshold for toxicity, producing unwanted adverse effects.¹⁶ Similarly problematic is that the serum concentration achieved with IR formulations rapidly falls after C_max, leaving a therapeutic window that may last only for a short time. Indeed, as reported here, IR lorazepam demonstrated 3 spikes in lorazepam levels when administered thrice daily and 2 spikes when given twice daily (Fig. 1; Supplemental Fig. S2, http://links.lww.com/JCP/A851). This caveat to the initial fast relief of an IR medication may be associated with breakthrough anxiety symptoms and so-called clock-watching effects, in which patients anxiously await the time of their next dose.¹⁶ In contrast, ER lorazepam demonstrated steady levels of lorazepam throughout the day after a single administration (Fig. 1; Supplemental Fig. S2, http://links.lww.com/JCP/A851). Moreover, the higher pill burden of IR formulations (eg, 3 daily doses) can lower treatment adherence, which has been identified as a major obstacle impeding positive outcomes in neuropsychiatric disease.²¹ Once-daily ER lorazepam could potentially improve outcomes for patients currently taking thrice-daily IR lorazepam who may be experiencing any of these issues.

Considering the outcomes that have been achieved with the development of ER formulations for other benzodiazepines, once-daily ER dosing of lorazepam holds potential for the treatment of anxiety disorders, in which tolerability, adverse effects, and risks of abuse liability remain obstacles. In the case of the benzodiazepine alprazolam, an ER formulation has demonstrated a profile of improved tolerability, better treatment compliance, and reduced abuse liability compared with the IR formulation, without compromising therapeutic efficacy, in patients with panic disorder or generalized anxiety disorder.¹⁶ Indeed, the T_max of ER alprazolam is prolonged from just 1 to 2 hours with the IR formulation to 4 to 12 hours with the ER formulation, which, along with less fluctuations in peak plasma drug concentrations, contributes to fewer adverse effects.¹⁶ This longer, slower release rate observed with ER alprazolam was further associated with lower abuse potential compared with IR alprazolam in a double-blind, crossover study in healthy adults with a history of sedative abuse.²² These studies suggest that, in addition to dose strength, the release rate of a benzodiazepine like alprazolam is a major determinant for its abuse liability.²² It is also believed that there is a lower risk for long-term cognitive effects with ER alprazolam than with the older IR formulation, with no deficits in attention, reaction time, or recall detected during an outpatient study of patients with panic disorder taking ER alprazolam for 6 weeks.²³ Such successes demonstrate the potential of ER formulations to provide steady drug levels with fewer adverse effects and neurocognitive risks for the patient. As anticipated in the current studies, once-daily ER lorazepam was found to be bioequivalent to the IR formulation given thrice daily, while providing plasma concentration-time profiles with fewer peaks and troughs in lorazepam levels throughout the day and a prolonged T_max (Fig. 1, Table 2). This profile suggests that ER lorazepam could similarly provide fewer long-term effects with lower abuse potential than the IR formula, although future studies investigating these specific outcomes in patient populations are warranted.

The present results support a well-tolerated safety profile of ER lorazepam, with no SAEs reported across all studies (Tables 4, 8). Moreover, of the 5 participants across the 4 studies who withdrew because of TEAEs, 4 withdrew from study 4 because of nausea and vomiting (3 cases of which occurred after receiving IR lorazepam and 1 after receiving ER lorazepam; Supplemental Table S6, http://links.lww.com/JCP/A851), and 1 patient withdrew from study 3 because of a TEAE deemed unrelated to ER lorazepam (Tables 4, 8; Supplemental Fig. S1 A-D, http://links.lww.com/JCP/A851). Once-daily ER lorazepam was further associated with a lower incidence of AEs than IR lorazepam given twice daily (Supplemental Table S6, http://links.lww.com/JCP/A851). This safety profile may be related to the lower C_max with less fluctuation in serum lorazepam levels achieved with the once-daily ER formulation (Supplemental Tables S4, S5, http://links.lww.com/JCP/A851). Overall, these data suggest that once-daily ER lorazepam exhibits a well-tolerated safety profile at doses bioequivalent to IR lorazepam.

In addition to assessing the bioequivalence of ER lorazepam doses to the existing IR formulation in study 1, studies 2 and 3 provided key data relevant to clinical practice on ease of administration. Difficulty swallowing is a common affliction, with an estimated 1 million new cases each year in the United States, and some studies suggest that as high as ~20% of the general population suffer from dysphagia.^19,24 This challenge is even more common among geriatric patients, particularly those in long-term care facilities, where 30% to 40% of elderly patients struggle with dysphagia and ~26% may have difficulties swallowing tablets.^19,20 The flexibility of administering ER lorazepam sprinkled onto soft food, while maintaining the same PK and safety profile to that of the intact capsule, may help patients suffering from anxiety and difficulty swallowing.²⁰ Because ER lorazepam was bioequivalent when administered with or without food as well, these data suggest that ER lorazepam adds a flexible administration option to the armamentarium of treatments for acute anxiety.

Despite these benefits, a potential limitation of ER drug administration is that a once-daily ER dose may not necessarily be suitable as a replacement for all IR dosing regimens for some patients. Although ER lorazepam exhibited bioequivalence across all evaluated PK parameters at the 3-mg dose level (Table 2), in supplemental study 4, once-daily 4 mg ER lorazepam demonstrated a slightly lower C_max,SS than IR lorazepam given twice daily, although minimum plasma concentration at steady state (C_min,SS) and AUC_TAU values were within the bioequivalence limits of 80% to 125% (Supplemental Tables S4, S5, http://links.lww.com/JCP/A851). Because IR lorazepam is usually prescribed at a daily dose ranging from 2 to 6 mg divided into twice- or thrice-daily doses,^3,7 dosing adjustments for patients already taking lorazepam would need to be appropriately considered when switching to a once-daily dosing regimen. Of note, the 4-mg ER lorazepam dose investigated in supplemental study 4 is higher than what is approved for use, with the 3-mg dose assessed in study 1 being the highest single dose available.¹⁸ Nonetheless, once-daily ER lorazepam provided less fluctuation in peak lorazepam levels throughout the day with fewer adverse effects compared with the IR dose given BID. Lastly, although branded ER formulations can generally be more expensive than generic, currently available IR formulations, prescription cost can vary by region and change over time because of market dynamics.^8,9

CONCLUSIONS

Results from multiple phase 1 studies assessing the PK profile of once-daily ER lorazepam demonstrate that the ER formulation achieves bioavailability comparable to that of IR lorazepam, consistent and predictable plasma concentration-time profiles, and a well-tolerated safety profile. The dosing of ER lorazepam is versatile, as it can be flexibly administered with or without food, and either as an intact capsule or sprinkled over soft food depending on patient needs or preferences. Once-daily ER lorazepam therefore represents an attractive alternative for patients currently taking thrice-daily IR lorazepam who may suffer from tolerability issues, rebound anxiety, or pill burden related to treatment. These comprehensive PK results suggest that ER lorazepam was bioequivalent to IR lorazepam and provided steady serum lorazepam levels throughout the day. Although the bioequivalence of ER lorazepam to IR lorazepam suggests that a similar efficacy profile could be expected, the efficacy and patient acceptability of ER lorazepam were not specifically evaluated here. Additional studies investigating ER lorazepam in patient populations with diagnosed anxiety disorders are warranted.