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Lorcaserin is a serotonin 2C receptor agonist indicated for chronic weight management as an adjunct to diet and exercise. The initial approved formulation is a 10-mg, immediate-release (IR) tablet for administration BID. These studies investigated the single- and multiple-dose pharmacokinetic properties of a new, recently US Food and Drug Administration–approved, extended-release, 20-mg once-daily formulation.
Methods
We performed 2 separate 2-period, 2-sequence crossover studies in 36 healthy adults: a study comparing the IR formulation to the extended-release formulation under fasting conditions and a study comparing the extended-release formulation under fed and fasted conditions.
Findings
Compared with lorcaserin IR, the Tmax after a single dose of lorcaserin extended-release was greater (median, 12 vs 3 hours), and the Cmax was 26% lower (38.8 vs 52.3 ng/mL). AUC data were bioequivalent for the 2 formulations in both single- and multiple-dose regimens, confirming no formulation effect on lorcaserin bioavailability. In fasted and fed conditions, Tmax after a single dose was identical (median, 12 hours), but Cmax was approximately 45% higher in the fed state (mean, 38.5 ng/mL fasted vs 56.1 ng/mL fed). However, at steady state, Cmax and AUC were determined to be bioequivalent between the fasted and fed states, indicating no clinically relevant food effect on the pharmacokinetic properties of lorcaserin extended-release. The safety profile was consistent between the 2 formulations.
Implications
Overall, the results indicate that lorcaserin extended-release is a suitable once-daily alternative to the approved IR BID formulation.
Obesity (body mass index [BMI] ≥30 kg/m2) and overweight (BMI ≥25 and <30 kg/m2) have become highly prevalent conditions in the United States, with the most recent estimates indicating that >69% of American adults are affected.
Both obesity and overweight are associated with increased risk of numerous comorbidities, including cardiovascular disease, hypertension, orthopedic disability, type 2 diabetes mellitus (T2DM), and certain cancers.
Lorcaserin has been approved in multiple countries as a 10-mg tablet for BID dosing and is indicated for long-term weight management in adults with obesity or overweight in the presence of ≥1 weight-related comorbidity as an adjunct to a reduced-calorie diet and increased physical activity.
Lorcaserin is a highly selective serotonin (5-HT) 2C receptor agonist that has approximately 14-fold and 61-fold greater potency at the 5-HT2C receptor than at 5-HT2A and 5-HT2B receptors, respectively.
Although the exact mechanism of action is unknown, it is thought that lorcaserin promotes satiety, and thereby decreases food consumption, through the selective activation of 5-HT2C receptors on anorexigenic pro-opiomelanocortin neurons within the hypothalamus.
The safety and efficacy of lorcaserin were found in 3 Phase III studies: Behavioral Modification and Lorcaserin for Overweight and Obesity Management (BLOOM), Behavioral Modification and Lorcaserin Second Study for Obesity Management (BLOSSOM) in patients without T2DM, and Behavioral Modification and Lorcaserin for Obesity and Overweight Management in Diabetes Mellitus (BLOOM-DM) in patients with T2DM.
These studies indicate that patients receiving lorcaserin as an adjunct to a prescribed diet and exercise program had significantly greater weight loss after 52 weeks than those receiving diet and exercise counseling only (−5.8% vs −2.5%, P < 0.001 for patients without T2DM
). Furthermore, more than twice as many patients receiving lorcaserin compared with placebo achieved weight losses of ≥5% (47.1% vs 22.6%, P < 0.001 for patients without T2DM
Lorcaserin is highly soluble and highly permeable, meeting the criteria for Biopharmaceutics Classification System Class 1. Lorcaserin is rapidly absorbed after oral dosing (Tmax, 1.5–2 hours)
and has a plasma t½ of approximately 11 hours. Lorcaserin is metabolized in the liver by multiple human cytochrome P450 enzymes and flavin-containing monooxygenase 1.
Lorcaserin sulfamate (M1) is the major circulating metabolite, and the N-carbamoyl glucuronide of lorcaserin (M5) is the major excreted metabolite. Multiple sulfotransferases and uridine 5׳-diphospho-glucuronosyltransferases are responsible for the formation of M1 and M5, respectively. These metabolites are not pharmacologically active.
Studies have found that decreasing the frequency of dose administration is associated with higher adherence rates in a variety of patient groups being treated for different illnesses.
Importantly, in long-term Phase III clinical studies, population pharmacokinetic/pharmacodynamic modeling revealed a highly significant and predictive association between probability of weight loss and lorcaserin AUC after twice-daily administration of an immediate-release (IR) formulation. On the basis of this association, an extended-release formulation that achieves bioequivalence to the IR formulation with respect to AUC would be expected to achieve equivalent efficacy. In addition, the finding that lorcaserin Cmax values are no greater after multiple dosing of an extended-release formulation than the IR formulation would support a conclusion that the safety database developed for the IR formulation is relevant to the extended-release formulation. The extended-release formulation of lorcaserin was recently approved by the US Food and Drug Administration.
Overall, the aim of pharmacokinetic/pharmacodynamic-based bridging from the lorcaserin Phase III program is to reveal the following: (1) an equivalent extent of absorption of the extended-release compared with the IR formulation based on AUC and (2) that Cmax is not higher for the extended-release compared with the IR formulation. In a previous Phase I study (data on file, APD356-031), the pharmacokinetic properties of 3 prototype 20-mg lorcaserin extended-release formulations (designated slow, medium, and fast release based on in vitro dissolution profiles) were evaluated. For all extended-release formulations, tablet dissolution was delayed by functional excipients to modify lorcaserin release. The study found that AUC, Cmin, and Cmax of each 20-mg lorcaserin extended-release prototype were within target levels compared with a single dose of the approved 10-mg IR formulation. AUC of the 20-mg lorcaserin extended-release formulation was approximately twice that of the 10-mg IR formulation. Of the 3 prototype extended-release formulations, the designated slow-release prototype had the optimal characteristics (lowest Cmax, highest Cmin, best preservation of AUC) and was selected for further development.
We present the results of a study designed to determine bioequivalence with respect to AUC of 20-mg lorcaserin extended-release administered once daily compared with 10-mg lorcaserin IR BID in healthy individuals under fasted conditions. In addition, we present the results of a second study designed to determine the effect of a high-fat meal on the rate and extent of absorption of 20-mg lorcaserin extended-release once daily after a single dose and at steady-state conditions.
Methods
Ethics
An institutional review board (IntegReview, Austin, Texas) approved the study protocols presented here, and each participant gave written informed consent before any protocol-specified procedures or evaluations were performed. These studies were conducted at a single center in the United States in adherence with the ethical principles embodied in the Declaration of Helsinki.
Participants
Two studies were conducted. Study 1 compared lorcaserin extended-release with the IR formulation in fasted individuals. Study 2 compared lorcaserin extended-release in fasted vs fed individuals. Each study included a unique set of 36 healthy, nonsmoking men and women, 18 to 45 years of age, with BMIs of 18 to 45 kg/m2. Individuals were excluded if they had previous exposure to lorcaserin; a history of severe allergies to medications or other allergens; a history of clinically significant cardiovascular conditions; uncontrolled hypertension, defined as systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg on 2 readings taken on 2 different days; a recent history of major depression, anxiety, or other psychiatric disease requiring treatment with prescription medication; a history of chronic kidney or hepatic disease; any clinically significant screening laboratory or echocardiographic abnormalities; or if prescription or over-the-counter medications were taken within 30 days before study start or during the study (allowance was made for acetaminophen and hormonal contraceptives).
Study Design
Both studies were single-center, 2-treatment, 2-period, 2-sequence, randomized, single- and multiple-dose, balanced crossover studies of lorcaserin in healthy individuals. Specific details of each study are as follows.
Study 1
Two treatments were administered to each participant, separated by a 5-day inpatient washout period. Treatment A was a 1-day treatment with 10-mg lorcaserin IR BID under fasted conditions, followed by a 3-day washout, followed by 5 days of treatment with 10-mg lorcaserin IR BID under fasted conditions. Treatment B was a 1-day treatment with 20-mg lorcaserin extended-release once daily under fasted conditions, followed by a 3-day washout, followed by 5 days of treatment with 20-mg lorcaserin extended-release once daily under fasted conditions. The treatments were administered in 1 of 2 sequences to 18 participants each, such that each participant received both treatments in either sequence 1 or sequence 2 (Figure 1).
Figure 1Study design. In study 1, treatment (TX) A consisted of 10-mg lorcaserin immediate release twice daily, and TX B consisted of 20-mg lorcaserin extended-release once daily; both TX A and B were in the fasted state. In study 2, TX A consisted of 20-mg lorcaserin extended-release once daily in the fasted state, and TX B consisted of 20-mg lorcaserin extended-release once daily in the fed state.
Two treatments were administered to each participant, separated by a 5-day inpatient washout period. Treatment A was a 1-day treatment with 20-mg lorcaserin extended-release once daily under fasted conditions, followed by a 3-day washout, followed by 5 days of treatment with 20-mg lorcaserin extended-release once daily under fasted conditions. Treatment B was a 1-day treatment with 20-mg lorcaserin extended-release once daily under fed conditions, followed by a 3-day washout, followed by 5 days of treatment with 20-mg lorcaserin extended-release once daily under fed conditions. The treatments were administered in 1 of 2 sequences to 18 participants each, such that each participant received both treatments in either sequence 1 or sequence 2 (Figure 1).
For individuals receiving lorcaserin extended-release or IR in the fasted state, the study drug was administered in the morning after an overnight fast (≥10 hours); those receiving lorcaserin IR received the second dose approximately 12 hours after the morning dose and after having fasted ≥2 hours before the dose. Participants were maintained in the fasted state for 4 hours after the morning dose and for 2 hours after the evening dose. For individuals receiving lorcaserin extended-release in the fed state (study 2 only), the study drug was administered in the morning after an overnight fast (≥10 hours) and 30 minutes after the start of a standardized high-fat meal. The meal consisted of 800 to 1000 total calories, with approximately 150, 250, and 500 to 600 calories from protein, carbohydrate, and fat, respectively; approximately 50% of the total caloric content of the meal was fat.
Pharmacokinetic and Statistical Analysis
For individuals in study 1 and study 2, 88 and 60 venous blood samples were withdrawn, respectively, at regular intervals. For individuals in study 1, those in the 1-day treatment period had 25 and 17 total samples drawn when receiving the IR and extended-release formulations, respectively; those in the multiple-dose treatment period had 27 and 19 total samples drawn when receiving the IR and extended-release formulations, respectively. For individuals in study 2, those in the 1-day treatment period had 14 total samples drawn in each of the fasted and fed states; those in the multiple-dose treatment period had 16 total samples drawn in each of the fasted and fed states.
For both studies, the plasma concentrations for lorcaserin were measured at Tandem Labs (Salt Lake City, Utah) using validated liquid chromatography–tandem mass spectrometry (platform: API 5000; ionization type: electrospray, positive and negative; MS operation mode: selected reaction monitoring), with a quantitation range of 0.508 to 203 ng/mL (lower limit of quantitation, 0.508 ng/mL; assay precision [%CV], 4.5%–6.1%; assay accuracy [% bias], −5.8 to −1.6%). The pharmacokinetic data were then analyzed using WinNonlin Phoenix, version 6.4 (Pharsight Corporation, Mountain View, California) using appropriate noncompartmental techniques. Cmax, Tmax, and time to first observable plasma concentration (Tlag) were obtained directly from experimental observations. AUC0–t and AUC0−24 were calculated using the linear trapezoidal rule. AUC0−∞ was calculated as , where Ct is the last quantifiable lorcaserin concentration and λz is the terminal-phase rate constant. The t1/2z was calculated as . CL/F was calculated as dose/AUC0−∞. In addition, for study 1, fluctuation and swing parameters were analyzed. Degree of fluctuation was calculated as fluctuation=(Cmax,ss-Cmin,ss)/Cav,ss, where Cmax,ss, Cmin,ss, and Cav,ss are the respective steady-state measurements of Cmax, Cmin, and average concentration (Cav). Swing was calculated as swing=(Cmax,ss-Cmin,ss)/Cmin,ss.
To assess the bioequivalence of lorcaserin extended-release once daily to lorcaserin IR BID in fasted individuals (study 1) and of lorcaserin extended-release once daily in fed and fasted states (study 2), lorcaserin Cmax and AUC parameters after administration of a single dose or multiple doses were analyzed using an ANOVA model appropriate for the 2-period, crossover designs of each study. Both ANOVA models contained factors for sequence, subject within sequence, period, and treatment (reported in the Appendix and Supplemental Tables I and II in the online version at http://dx.doi.org/10.1016/j.clinthera.2016.08.016). AUC and Cmax geometric mean ratios (GMRs) were determined for extended-release/IR (study 1) and fed/fasted states (study 2). If the resulting 90% CIs were inclusive of the prespecified 90% CI boundaries (0.800 and 1.250) for bioequivalence, bioequivalence was claimed. In addition, Tmax of the extended-release or IR formulations in the fasted state (study 1) and of extended-release in the fed and fasted states (study 2) were analyzed using the Wilcoxon signed-rank test for paired samples at the level of significance of 0.05.
Safety
Individuals were monitored throughout the study for adverse reactions to the study drug and procedures. Safety assessments included physical examinations, clinical laboratory tests, vital signs, 12-lead ECGs, and adverse event reporting.
Results
Baseline Characteristics
Individuals in study 1 were predominantly male (58.3%), were predominantly black or African American (58.3%), and had a mean BMI of 29.3 kg/m2. Individuals in study 2 were predominantly female (52.8%), were predominantly white (50.0%), and had a mean BMI of 28.5 kg/m2. A full description of the disposition and demographic characteristics of the study participants is given in Supplemental Table III.
Evaluable Study Participants
A total of 36 individuals were enrolled into each study. Thirty-four individuals in study 1 and all individuals in study 2 completed their respective studies. Two individuals in study 1 withdrew consent before study completion; data from 1 of these individuals were missing a single data point only and were therefore included in the data analysis. Data from the other individual were incomplete, and the individual was excluded. Relative to the rest of the study population, as well as the entire Phase I and Phase III population pharmacokinetic database, 1 individual in study 1 had highly disparate drug exposures during the IR dosing sequences, suggesting that a dose was not taken or not absorbed. Although this patient had normal lorcaserin exposures during the extended-release dosing sequences, the decision was made to exclude this person from all primary pharmacokinetic analyses.
Pharmacokinetic Analysis Comparing Lorcaserin Immediate- and Extended-Release Formulations in Fasting Participants (Study 1)
After a single dose of the IR and extended-release formulations, the median Tmax values were 3 and 12 hours, respectively (Figure 2). Geometric mean (%CV) Cmax values of 52.3 ng/mL (24.0%) and 38.8 ng/mL (30.8%) and AUC0–∞ values of 1240 hr·ng/mL (24.2%) and 1217 hr·ng/mL (27.9%) were observed for IR and extended-release formulations, respectively (Table I). Absorption of lorcaserin from the IR formulation was rapid, with plasma levels observed at the first time point taken (median Tlag, 0 hours; range, 0–0.5 hours). In contrast, the median Tlag after administration of the extended-release formulation was 0.5 hours and ranged from 0.25 to 1.5 hours.
Figure 2Mean (SD) lorcaserin immediate-release (IR) and extended-release plasma concentration–time profiles after single dose and at steady state (N = 34). Inset: Semi-log plot. TX = treatment.
Time to plasma steady state was achieved after 5 consecutive dosing days, irrespective of formulation. Under steady-state conditions, the median Tmax,ss values were 1.5 and 10 hours for the IR and extended-release formulations, respectively (Figure 2). Geometric mean (%CV) Cmax,ss values of 80.1 ng/mL (25.7%) and 73.9 ng/mL (31.1%) and AUC0–24,ss values of 1328 hr·ng/mL (26.5%) and 1235 hr·ng/mL (28.2%) were observed for IR and extended-release formulations, respectively (Table I). The t1/2z was not affected by formulation type or repeat dosing, and under steady-state conditions, the Cav was similar between IR and extended-release dosing formulations. Although the dosing intervals differed between the IR and extended-release formulations (12 vs 24 hours), both formulations were comparable with respect to swing (1.26 [26.5%] and 1.42 [46.4%] for IR and extended-release, respectively) and fluctuation (0.800 [19.6%] and 0.824 [25.4%] for IR and extended-release, respectively) parameters.
The GMR and associated 90% CI of the extended-release to IR ratio for lorcaserin exposure values AUC0–t (0.968; 90% CI, 0.931–1.007) and AUC0–∞ (0.987; 90% CI, 0.948–1.028) after a single dose were within the statistical boundaries for bioequivalence (Figure 3 and Supplemental Table IV). At steady state, the GMR 90% CI of both AUC0–24,ss (0.932; 90% CI, 0.891–0.975) and Cmax,ss (0.924; 90% CI, 0.876–0.975) were within the statistical boundaries and deemed bioequivalent (Figure 3 and Supplemental Table IV).
Figure 3Geometric mean ratio (GMR) (90% CI) of 20-mg extended-release/10-mg immediate release (IR) after a single dose or multiple doses of lorcaserin (N = 34). BE = bioequivalence.
Pharmacokinetic Analysis Comparing the Lorcaserin Extended-Release Formulation in Fasted and Fed States (Study 2)
After a single dose of the 20-mg lorcaserin extended-release formulation, the median Tmax was 12 hours in both the fasted and fed states, indicating that food did not affect the time to Cmax of the extended-release formulation (Figure 4). Absorption of lorcaserin was similar in both the fasted and fed states, with median Tlag ranging from 0 to 2 hours (mean, 0.4 hours in the fasted state and 0.8 hours in the fed state) for all the study participants (Table II). Geometric mean (%CV) Cmax values of 38.5 ng/mL (39.4%) and 56.1 ng/mL (31.8%) and AUC0–∞ values of 1141 hr·ng/mL (48.6%) and 1332 hr·ng/mL (28.6%) were observed for individuals in the fasted and fed states, respectively. Elimination of lorcaserin was not affected by the presence of food or dosing paradigm because the mean t1/2z of lorcaserin was 13.0 hours in the fasted state and 12.4 hours in the fed state after a single dose.
Figure 4Mean (SD) lorcaserin extended-release plasma concentration–time profiles after sequential single and multiple dosing to steady state in fasted and fed individuals (N = 36). Inset: Semi-log plot. IR = immediate release; TX = treatment.
Table IILorcaserin extended-release pharmacokinetic parameters after a single dose and under steady-state conditions in fasted and fed individuals (n = 36).
Lorcaserin plasma concentrations achieved steady state after 5 consecutive once-daily administrations of 20-mg lorcaserin extended-release under both the fasting and fed conditions. Lorcaserin concentrations at all time points in the steady-state interval were similar between the fasted and fed states, suggesting that food has no effect on the absorption or elimination of lorcaserin under steady-state conditions (Figure 4). After multiple-dose administration of lorcaserin extended-release, the median tmax was 10 hours in the fasted state and 12 hours in the fed state. Geometric mean (%CV) Cmax,ss values of 69.5 ng/mL (38.4%) and 78.7 ng/mL (30.9%) and AUC0–24,ss values of 1216 hr·ng/mL (40.4%) and 1318 hr·ng/mL (29.5%) were observed for individuals in fasted and fed states, respectively (Table II). Mean t1/2z was 12.4 hours in the fasted state and 12.0 hours in the fed state after multiple dosing. Bioequivalence between fasted and fed states was achieved at steady state in both Cmax,ss (GMR, 1.134; 90% CI, 1.071–1.199) and AUC0–24,ss (GMR, 1.084; 90% CI, 1.027–1.145) parameters (Figure 5 and Supplemental Table V).
Figure 5Geometric mean ratio (GMR) (90% CI) of fed/fasted after multiple doses of 20-mg lorcaserin extended-release (N = 36). BE = bioequivalence.
A total of 150 treatment-emergent adverse events (TEAEs) were reported by 50 individuals (69.4%) after administration of lorcaserin in these studies (multiple occurrences of the same TEAE in the same individual in the same treatment period were counted only once) (Table III). Overall, the number of individuals reporting TEAEs was similar between the treatment groups in each study, and in both studies, all TEAEs were mild to moderate in intensity; no serious TEAEs or deaths occurred, and no TEAE led to study discontinuation.
Table IIINumber (percentage) of TEAEs reported in ≥5% of individuals in any treatment group in either study.
In study 1, 33 TEAEs were reported by 18 individuals (50%) during treatment with lorcaserin IR, and 32 TEAEs were reported by 17 individuals (48.6%) during treatment with lorcaserin extended-release. More than twice as many individuals reported headache after treatment with the IR formulation (16 [44.4%]) than with the extended-release formulation (7 [20%]); dizziness was reported by more individuals after treatment with lorcaserin extended-release (3 [8.6%]) than lorcaserin IR (1 [2.8%]), but the incidence was similar to what was reported in the washout period (4 [11.1%]); reports of nausea were generally similar between the 2 groups. Treatment-related TEAEs were reported by fewer individuals during treatment with lorcaserin extended-release than with lorcaserin IR (12 vs 18). Other common TEAEs included constipation, somnolence, and fatigue. Constipation was reported by 3 individuals (8.3%) receiving lorcaserin IR and 1 individual (2.9%) receiving lorcaserin extended-release. Somnolence and fatigue were reported by 3 (8.6%) and 2 (5.7%) subjects, respectively, during treatment with lorcaserin extended-release, whereas no events of somnolence or fatigue were reported during treatment with lorcaserin IR.
In study 2, 30 TEAEs were reported by 13 individuals (36.1%) receiving lorcaserin extended-release in the fasted state, and 21 TEAEs were reported by 13 individuals (36.1%) receiving lorcaserin extended-release in the fed state. Headache was similarly reported during both the fasted (5 [13.9%]) and fed (7 [19.4%]) treatment periods; nausea was reported more frequently in the fasted group (4 [11.1%]) than in the fed group (1 [2.8%]). Reports of constipation were generally similar between the treatment groups: 2 individuals (5.6%) in the fasted group versus 1 individual (2.8%) in the fed group. Other common TEAEs included abdominal pain (3 individuals [8.3%] in the fasted group vs 0 in the fed group) and back pain (1 individual in each treatment group).
Discussion
The results of the 2 studies presented here indicate that, under fasting conditions, a 20-mg lorcaserin extended-release formulation administered once daily is bioequivalent with respect to AUC to the currently marketed 10-mg lorcaserin IR formulation administered BID and that bioequivalence was achieved between fed and fasted conditions. Although these studies did not directly address the efficacy of the extended-release formulation, in Phase III clinical studies of lorcaserin IR, pharmacokinetic/pharmacodynamic modeling revealed a predictive relationship between lorcaserin AUC and probability of achieving weight loss,
indicating that an AUC-bioequivalent extended-release formulation would be expected to have equivalent efficacy in weight loss. Furthermore, there is no evidence from the pharmacokinetic analysis that suggests the extended-release formulation would behave differently in the target population. The exposure-response relationship established for lorcaserin is independent of Cmax; therefore, Cmax was not used as a necessary criterion for IR–extended-release bioequivalence. However, for safety purposes, Cmax was evaluated, and it was confirmed that the Cmax of lorcaserin extended-release was similar to or lower than that of lorcaserin IR. This finding confirms the relevance of the safety database developed based on the IR formulation for reference to the extended-release formulation.
Absorption of lorcaserin into the systemic circulation as measured by Tmax was significantly slower than that of the IR formulation after both single-dose and multiple-dose administrations. The extended-release and IR formulations were determined to be bioequivalent based on AUC after single doses under fasting conditions; furthermore, in a multiple-dosing regimen, the 2 formulations were found to be bioequivalent by both Cmax and AUC parameters in fasting individuals.
Evaluation of modified-release formulations in fasted and fed states is important for identifying any potential safety risk from the co-administration of medications with food, which can result in the dose being more rapidly released compared with fasted conditions.
There was no evidence of dose dumping in this study. Although food slightly increased the extent of drug absorption in both single-dose and multiple-dose treatments, co-administration of the lorcaserin extended-release tablet with a high-fat meal did not alter Tmax, either after a single dose or under steady-state conditions. After a single dose of lorcaserin extended-release, the mean Cmax was approximately 46% higher after a standard high-fat meal compared with fasting conditions, and mean AUC values, although slightly higher with food, achieved bioequivalence with respect to AUC0–∞. However, under steady-state dosing conditions, bioequivalence in both Cmax and AUC0–24 parameters was achieved for the extended-release formulation between fed and fasted conditions. Therefore, although there was a small effect of a high-fat, high-calorie meal on lorcaserin pharmacokinetic properties after a single dose of the extended-release formulation, the results at steady state indicate that the difference is not clinically meaningful.
Both the 10-mg lorcaserin IR and 20-mg lorcaserin extended-release formulations were generally well tolerated by individuals in these studies. In study 1, the number of individuals reporting TEAEs was similar during treatment with the IR and extended-release formulations of lorcaserin (18 vs 17). However, treatment-related TEAEs were reported by fewer individuals during treatment with the extended-release formulation compared with the IR formulation (12 vs 18). This difference is primarily accounted for by the fewer incidences of headache reported by individuals taking the extended-release formulation (7 vs 16) and may be the result of the lower mean Cmax and longer Tmax of the extended-release formulation relative to the IR formulation. Adverse events related to gastrointestinal disorders also occurred less frequently with the extended-release formulation compared with the IR formulation. In study 2, the number of individuals reporting TEAEs was the same between the treatment groups (13 each), but the number of TEAEs reported by individuals in the fasted state was higher than that reported by individuals in the fed state (30 vs 21). This difference could be largely accounted for by the greater number of individuals reporting TEAEs related to gastrointestinal disorders in the fasted state (11 vs 3 in the fed state). Most TEAEs across both studies were related to the System Organ Classes of nervous system disorders (headache, dizziness) and gastrointestinal disorders (nausea, constipation), consistent with earlier trials of lorcaserin IR.
A potential limitation of the data presented here is the disparity in the demographic characteristics between the 2 studies, as well as compared with the general population. Individuals self-reported as black or African American were overrepresented by approximately 4-fold when compared with the most recent US Census information.
Although these studies on lorcaserin extended-release were not powered to detect exposure differences among individuals of different ethnicities, we consider that such differences are unlikely to manifest themselves because previous pharmacokinetic studies have found that plasma concentrations do not differ among racial subgroups after exposure to lorcaserin IR.
The results of these studies indicate that the 20-mg lorcaserin extended-release formulation is bioequivalent to the commercially available IR tablet and may be dosed without regard to food. The lorcaserin extended-release formulation was generally well tolerated in this sample of healthy adults and is expected to maintain the safety and efficacy profile of the IR formulation while theoretically improving patient adherence with the prescribed dosing regimen for weight management. The development of a lorcaserin extended-release formulation enables the possibility of changing the therapeutic dosing regimen from BID to once daily.
AUTHOR CONTRIBUTIONS
RC provided substantial contributions to study design, acquisition of data, analysis and interpretation of data; drafted the article and critically revised the manuscript for important intellectual content; and gave final approval of the version to be published. MM participated in experimental design, data analysis, interpretation of data, and manuscript development; critically revised the manuscript for important intellectual content, and gave final approval of the version to be published. JF participated in study design, interpretation of data, manuscript development and finalization; critically revised the manuscript for important intellectual content; and gave final approval of the version to be published. BR participated in study design, interpretation of data, and manuscript development; critically revised the manuscript for important intellectual content; and gave final approval of the manuscript to be published.
YT provided substantial contributions to acquisition of data, analysis and interpretation of data; critically revised the manuscript for important intellectual content; and gave final approval of the version to be published. AK participated in the interpretation of data and manuscript development; critically revised the manuscript for important intellectual content; and gave final approval of the version to be published. WS participated in protocol design, interpretation of data, and manuscript development; critically revised the manuscript for important intellectual content; and gave final approval of the version to be published.
Conflicts of Interest
Arena Pharmaceuticals and Eisai Corporation were the study sponsors for the studies reported herein. The authors were involved in the study design, collection, analysis, interpretation of data and drafting of the manuscript.
RC, MM, YT, and WS were employees and shareholders of Arena Pharmaceuticals, Inc., and JF, AK, and BR were employees of Eisai Inc. when this study was conducted and the manuscript was written.
Acknowledgments
This work was funded by Arena Pharmaceuticals, Inc. Editorial support was provided by Imprint Science, New York, NY, and was funded by Eisai Inc.
Supplementary Table SIAnalysis of Lorcaserin Pharmacokinetic Parameters in Study 1: 20-mg Lorcaserin extended-release versus 10-mg Lorcaserin IR in Fasting Subjects (N=34)
ANOVA=analysis of variance; AUC0-∞=area under the plasma concentration–time curve from time zero to infinity; AUC0-t=area under the plasma concentration–time curve from time zero to the time of the last quantifiable plasma concentration; AUC0-24=area under the plasma concentration–time curve from time zero to 24 hours at steady state; Cmax=maximum plasma concentration; Cmax,ss=maximum plasma concentration at steady state; IR=immediate release; Tmax=time to maximum plasma concentration.
Supplementary Table SIIAnalysis of Lorcaserin Pharmacokinetic Parameters in Study 2: 20-mg Lorcaserin extended-release in Fasting Versus Fed Subjects (N=36)
ANOVA=analysis of variance; AUC0-∞=area under the plasma concentration–time curve from time zero to infinity; AUC0-t=area under the plasma concentration–time curve from time zero to the time of the last quantifiable plasma concentration; AUC0-24,ss= area under the plasma concentration–time curve from time zero to 24 hours at steady state; Cmax=maximum plasma concentration; Cmax,ss=maximum plasma concentration at steady state; IR=immediate release; tmax=time to maximum plasma concentration.
In Study 1, Treatment A consisted of 1 day of treatment with 10-mg lorcaserin IR twice daily followed by a 3-day washout before 5 days of treatment with 10-mg lorcaserin IR twice daily under fasted conditions. Treatment B consisted of 1 day of treatment with 20-mg lorcaserin extended-release once daily followed by a 3-day washout before 5 days of treatment with 20-mg lorcaserin extended-release once daily under fasted conditions.
In Study 2, Treatment A consisted of 1 day of treatment with 20-mg lorcaserin extended-release once daily in the fasted state followed by a 3-day washout before 5 days of treatment with 20-mg lorcaserin extended-release once daily in the fasted state. Treatment B consisted of 1 day of treatment with 20-mg lorcaserin extended-release once daily in the fed state followed by a 3-day washout before 5 days of treatment with 20-mg lorcaserin extended-release once daily in the fed state.
All statistics are presented as mean (standard error of the mean) unless otherwise noted.
33.14 (1.14)
33.00 (1.65)
33.28 (1.62)
33.92 (1.19)
34.17 (1.57)
33.67 (1.83)
Race, n (%)
American Indian or Alaska Native
1 (2.8%)
1 (5.6%)
0 (0.0%)
1 (2.8%)
1 (5.6%)
0 (0.0%)
Black or African American
21 (58.3%)
11 (61.1%)
10 (55.6%)
16 (44.4%)
6 (33.3%)
10 (55.6%)
White
14 (38.9%)
6 (33.3%)
8 (44.4%)
18 (50.0%)
10 (55.6%)
8 (44.4%)
Other
0 (0.0%)
0 (0.0%)
0 (0.0%)
1 (2.8%)
1 (5.6%)
0 (0.0%)
Height (cm)
166.45 (2.00)
167.53 (2.84)
165.37 (2.88)
168.69 (1.63)
169.25 (2.26)
168.14 (2.41)
Weight (kg)
80.94 (2.95)
82.29 (4.36)
79.58 (4.07)
81.51 (2.96)
85.77 (4.05)
77.26 (4.18)
BMI (kg/m2)
29.27 (1.01)
29.43 (1.57)
29.11 (1.32)
28.49 (0.82)
29.78 (1.10)
27.20 (1.16)
Completers, n (%)
34 (94.4%)
17 (94.4%)
17 (94.4%)
36 (100%)
18 (100%)
18 (100%)
Subjects withdrawn due to withdrawal of informed consent, n (%)
2 (5.6%)
1 (5.6%)
1 (5.6%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
AB=treatment A before treatment B; BA=treatment B before treatment A; BMI=body mass index; IR=immediate release.
In Study 1, Treatment A consisted of 1 day of treatment with 10-mg lorcaserin IR twice daily followed by a 3-day washout before 5 days of treatment with 10-mg lorcaserin IR twice daily under fasted conditions. Treatment B consisted of 1 day of treatment with 20-mg lorcaserin extended-release once daily followed by a 3-day washout before 5 days of treatment with 20-mg lorcaserin extended-release once daily under fasted conditions.
† In Study 2, Treatment A consisted of 1 day of treatment with 20-mg lorcaserin extended-release once daily in the fasted state followed by a 3-day washout before 5 days of treatment with 20-mg lorcaserin extended-release once daily in the fasted state. Treatment B consisted of 1 day of treatment with 20-mg lorcaserin extended-release once daily in the fed state followed by a 3-day washout before 5 days of treatment with 20-mg lorcaserin extended-release once daily in the fed state.
‡ All statistics are presented as mean (standard error of the mean) unless otherwise noted.
Lower and upper limits of 90% confidence interval on the GMR.
Single dose
AUC0-∞ (hr·ng/mL)
1219
1235
0.987
(0.948, 1.028)
AUC0-t (hr·ng/mL)
1169
1207
0.968
(0.931, 1.007)
Cmax (ng/mL)
39.0
52.2
0.748
(0.705, 0.793)
Steady state
AUC0-24,ss (hr·ng/mL)
1234
1324
0.932
(0.891, 0.975)
Cmax,ss (ng/mL)
73.8
79.9
0.924
(0.876, 0.975)
AUC0-∞=area under the plasma concentration–time curve from time zero to infinity; AUC0-24,ss=area under the plasma concentration–time curve from time zero to 24 hours post-dose at steady state; BID=twice daily; CI=confidence interval; Cmax=maximum plasma concentration; Cmax,ss=maximum plasma concentration at steady state; GMR=geometric mean ratio; IR=immediate release; QD=once daily.
Geometric mean of the test/reference (20 mg extended-release QD/10 mg IR BID) ratio.
† Lower and upper limits of 90% confidence interval on the GMR.
Lower and upper limits of 90% confidence interval on the GMR.
Fed State
Fasting State
Single dose
AUC0-∞ (hr·ng/mL)
1332
1141
1.167
(1.092, 1.247)
AUC0-t (hr·ng/mL)
1294
1097
1.179
(1.103, 1.260)
Cmax (ng/mL)
56.1
38.5
1.459
(1.345, 1.581)
Steady state
AUC0-24,ss (hr·ng/mL)
1318
1216
1.084
(1.027, 1.145)
Cmax,ss (ng/mL)
78.7
69.5
1.134
(1.071, 1.199)
AUC0-∞=area under the plasma concentration–time curve from time zero to infinity; AUC0-t=area under the plasma concentration–time curve from time zero to the time of the last quantifiable plasma concentration; AUC0-24,ss=area under the plasma concentration–time curve from time zero to 24 hours post-dose at steady state; CI=confidence interval; Cmax=maximum plasma concentration; Cmax,ss=maximum plasma concentration at steady state; GMR=geometric mean ratio.
Geometric mean of the test/reference (Fed State/Fasting State) ratio.
† Lower and upper limits of 90% confidence interval on the GMR.
ANOVA comparison of lorcaserin pharmacokinetic parameters showed no significant difference between sequence (AUC and Cmax) or treatment (AUC only) after single doses, suggesting that AUC was similar, independent of which formulation was dosed first in fasting subjects (Supplementary Table SI). As the extended-release formulation was designed to produce a lower Cmax compared to the IR formulation, a significant treatment effect (P<0.0001) was seen in Cmax values between extended-release and IR treatments. There was no apparent pharmacokinetic carryover effect, as the pre-dose lorcaserin concentrations prior to period 2 were below the limit of quantitation or less than 5% of Cmax.
After multiple-dose treatment in fasting subjects, ANOVA comparison results showed no significant difference between treatment sequence or period effects in either AUC0-24,ss or Cmax,ss (Supplementary Table SI).
IR and extended-release formulation median tmax values were significantly different in both single-dose and steady-state regimens, as determined by a Wilcoxon signed-rank test (Supplementary Table SI). As expected for the extended-release formulation, absorption of lorcaserin into the systemic circulation was slower than that of the IR formulation.
ANOVA analyses for Study 2
ANOVA comparison of lorcaserin pharmacokinetic parameters Cmax, Cmax,ss, AUC0-t, AUC0-∞, and AUC0-24 following single- and multiple-dose treatments of lorcaserin extended-release in fed and fasted subjects showed a statistically significant (P<0.05) effect of sequence, potentially confounding the treatment (food) effect (Supplementary Table SII). Pharmacokinetic carryover, insufficient dosing to reach steady state, selection bias due to randomization issues, and the impact of outliers were all explored as potential factors, but none appeared to be major contributors to the observed sequence effect. As both sequences were comparable and consistent with regard to the food effect on lorcaserin absorption, the observed sequence effect may reflect the high power of the study to detect a small quantitative difference of minimal clinical importance.
A Wilcoxon signed-rank test showed that there was no statistically significant difference between the tmax values in fasted and fed states across dosing paradigms following oral administration of 20-mg lorcaserin extended-release QD (Supplementary Table SII). Food, therefore, does not affect the rate or extent of lorcaserin absorption from the extended-release formulation.
Analysis of bioequivalence after single doses in Study 2
Bioequivalence between fasted and fed states using Cmax (GMR, 1.459; 90% CI [1.345, 1.581]) and AUC0-t (GMR, 1.179; 90% CI [1.103, 1.260]) was not achieved after a single dose. However, by extrapolating to infinity (AUC0-∞) and thereby capturing greater than 90% of the exposure, bioequivalence was achieved between fasted and fed states (GMR, 1.167; 90% CI [1.092, 1.247]) (Supplementary Figure S1).
References
Flegal K.M.
Carroll M.D.
Kit B.K.
Ogden C.L.
Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999-2010.
Steady state achieved after 5 consecutive days of dosing.
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