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PHARMACOKINETICS |
From ACADIA Pharmaceuticals Inc, San Diego, California (Dr Vanover, Dr van Kammen, Dr Davis, Dr Weiner); Quintiles, Inc, Kansas City, Missouri (Dr Robbins-Weilert); and GDRU Quintiles, Limited, London, United Kingdom (Dr Wilbraham, Dr Mant).
Address for reprints: Kimberly E. Vanover, PhD, current address, Intra-Cellular Therapies, Inc, 3960 Broadway, New York, NY 10032; e-mail: kvanover{at}intracellulartherapies.com.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSPHARMACOKINETICSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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(706-10 798 h·ng/mL), and multiple doses (50-150 mg) resulted in dose-proportionate mean Cmax,ss (93-248 ng/mL) and AUC0-,ss (1839-4680 h·ng/mL). The half-life of ACP-103 was approximately 55 hours, with a tmax at 6 hours. ACP-103 was well tolerated at single doses up to and including 300 mg and multiple doses up to 100 mg once daily for 14 days.
Key Words: Antipsychotic • phase I • serotonin • 5-HT2A • inverse agonist
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METHODS |
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TOPABSTRACTMETHODSRESULTSPHARMACOKINETICSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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ACP-103, N-(4-flurophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide (2R,3R)-dihydroxybutanedioate (2:1), was supplied by ACADIA Pharmaceuticals. For the single-dose study, ACP-103 was administered as an oral solution (20- and 50-mg doses) or as a solution via a polyvinyl chloride (PVC) nasogastric tube (100-, 200-, and 300-mg doses). Placebo consisted of a diluted bitrex (denatonium benzoate: 0.000005%, Macfarlan Smith Limited, Edinburgh, UK) solution and was administered in an identical manner as the active drug. For the multiple-dose study, ACP-103 was administered in 50-mg powder-filled gelatin capsules. Placebo consisted of lactose-filled visually matching gelatin capsules.
This study was conducted at Guy's Drug Research Unit (GDRU) Quintiles Limited, United Kingdom. The study was conducted in accordance with the principles of the International Conference on Harmonization good clinical practice (ICH GCP) guidelines of the European Union, the ethical principles laid down in the current revision of the Declaration of Helsinki, and standard operating procedures (SOPs) for clinical investigations. The clinical study protocol, amendments to the clinical study protocol, informed consent document(s), and any other appropriate study-related documents were approved by an independent ethics committee (IEC). Study-specific informed consent for all subjects was obtained in writing before conduct of any study-related procedures.
Subjects
Nonsmoking, healthy young males between 18 and 45 years of age and a body mass index (BMI) of 19 to 28 kg/m2 were selected for participation in this study. Subjects were excluded if they had a significant organ abnormality or disease, abnormal vital signs or clinical laboratory evaluation results upon screening, or a serious physical illness within 1 year before the start of the study. Subjects with a history of renal, hepatic, gastrointestinal, cardiovascular, or hematologic disease; seizure, epilepsy, severe head injury, multiple sclerosis, or other known neurological condition; hepatitis B or C (or a positive test result for hepatitis B surface antigen or hepatitis C antibody) or HIV; or alcohol or drug abuse (or a positive urine drug or alcohol test result at screening) were excluded from participation. Those who were considering or scheduled to undergo any surgical procedure during the duration of the study were excluded also from participation. Furthermore, any subject who had donated plasma or blood within 30 days of study start, required treatment with medications within 14 days of study start, had received any known hepatic or renal clearance–altering agents within a period of 3 months before study start, ingested any investigational medication or used any investigational device within 3 months before study start, or required a special diet were excluded. Subjects were required to have mental capacity sufficient to provide legal consent.
Procedures
Screening procedures, including medical history, physical examination, 12-lead electrocardiogram (ECG), clinical laboratory evaluations, vital signs, urine drug screen, neurological screen, and serology screen, were performed before day –2 (check-in) along with the assessment of inclusion/exclusion criteria.
Blood samples were collected for determination of plasma ACP-103 concentrations. In the single-dose study, samples were collected after a 10-hour fast at 0 hours (predose) and 1, 2, 4, 6, 9, 12, 24, 36, 48, 72, 96, 120, 144, and 216 hours after administration of ACP-103. For the first dose, sampling only occurred out to 48 hours but was extended for subsequent doses by a protocol amendment out to 216 hours after the long half-life was observed. In the multiple-dose study, samples were collected at 0 hours (predose); 1, 2, 4, 6, 9, 12, 16, and 24 hours after the first administration; predose on days 4, 7, 10, and 13; and again 0 hours (predose) and 1, 2, 4, 6, 9, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 216 hours after the last dose. Blood samples (7 mL each) were processed immediately and plasma samples stored frozen. Bioanalysis was performed by the Bioanalytical Sciences Department at Quintiles Inc (Kansas City, Mo). A validated high-performance liquid chromatography/tandem mass spectrometric (LC/MS/MS) method for the quantitative determination of ACP-103 concentrations in 100 µL heparinized human plasma had a standard curve range of 0.5 to 500 ng/mL. Human plasma samples were prepared for analysis by precipitating the proteins with acetonitrile. To each 100-µL sample, except blank plasma samples, 100 µL of 1:1 acetonitrile/water and 300 µL of 100-ng/mL AC-90179 (a structurally related internal standard, 2-(4-methoxy-phenyl)-N-(4-methyl-benzyl)-N-(1-methylpiperidin-4-yl)-acetamide hydrochloride) in acetonitrile were added. To each 100-µL blank plasma sample, a 400-µL volume of 1:1 acetonitrile/water was added so the blanks would have the same volume and matrix as the samples. Samples were then vortexed and centrifuged. A 150-µL volume of each sample was transferred to a 96-well plate, and each sample was diluted with 600 µL of 1:1 acetonitrile/water. A 40-µL aliquot was then injected onto the LC/MS/MS system. ACP-103 and the internal standard were separated by reversed-phase liquid chromatography using a Phenomenex Luna column (50 x 2.0 mm, 5 µm), and analytes were quantified using positive ion electrospray ionization with mass spectrometric detection with mass transitions 428.30 m/z 
223.3 m/z (ACP-103) and 367.3 m/z 263.30 m/z (internal standard). Interbatch mean accuracy data for ACP-103 calibration standards ranged from 98.6% to 103.0%, with precision ranging from 1.95% to 8.16%. Assay mean accuracy and precision data for ACP-103 in heparinized human plasma were measured at 4 quality control (QC) sample concentrations ranging from 0.500 to 376 ng/mL. Assay mean accuracy of ACP-103 heparinized human plasma QC samples ranged from 104.80% to 108.13%, and precision ranged from 3.30% to 4.05%. The ACP-103 dilution QC (5000 ng/mL) had a mean accuracy of 89.00%, with a mean precision of 3.03%. Five replicate heparinized human plasma QC samples were measured at 4 concentrations over the range 0.500 to 376 ng/mL. Intrabatch accuracy of the assay for ACP-103 in heparinized human plasma ranged from 102.40% to 110.00%, and precision ranged from 2.57% to 5.07% across the QC range examined. The dilution QC (5000 ng/mL) had a mean accuracy ranging from 88.40% to 91.80%, with a mean precision ranging from 1.25% to 3.72% for ACP-103. Plasma protein binding of ACP-103 was evaluated by equilibrium dialysis in samples collected at 6, 12, and 24 hours postdose from subjects administered a single dose of 300 mg ACP-103 and from selected samples on day 1 and day 14 in subjects receiving the lowest (50 mg/d) and highest (150 mg/d) dose levels in the multiple-dose study.
The following variables were collected during the study to assess safety: modified physical examinations, 3-positional blood pressure and pulse rate (5 minutes supine, 1 minute sitting, and 3 minutes standing), respiratory rate, oral temperature, a neurological screen, and 12-lead ECGs. In addition, continuous lead-II ECG monitoring was performed for the first 6 hours following the 20-mg ACP-103 dose and for the first 12 hours following each subsequent ACP-103 dose for the single-dose study and for day 1 of each dose level of the multiple-dose study. Clinical laboratories were measured after an 8-hour fast and included hematology, serum chemistry, and urinalysis.
Pharmacokinetic Analysis
Pharmacokinetic parameters were calculated from plasma concentrations of ACP-103 as a free base by noncompartmental techniques using WinNonlin Professional Version 4.01 (Pharsight Corp, Mountain View, Calif). All calculations of the plasma pharmacokinetics were based on actual sampling times.
Dose proportionality of the primary pharmacokinetic parameters for ACP-103 (Cmax and Cmax,ss, and AUC0- for the single-dose study; AUC(0-24),1 and AUC(0-24),14 for the estimates on day 1 and day 14 of the multiple-dose study) over the administered dose range was investigated for each study using the following power model:
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Dose proportionality was assessed based on whether 95% confidence intervals (CIs) constructed for the estimate of b included a value of 1.0. The hypothesis of dose proportionality was not tenable if the 95% CIs constructed on the estimate of b excluded a value of 1.0.
For the multiple-dose study, the extent of drug accumulation was assessed within each of the dose groups, with day 1 as reference, using an analysis of variance (ANOVA) model with treatment day and subject effects.
Time to reach steady state was estimated by graphic evaluation of the trough plasma samples, but this estimation was guided by statistical testing. Within each dose level, the statistical analysis was conducted via a stepwise analysis procedure, using repeated-measures ANOVAs with subject and treatment day effects. Initially, all time points were included in the model. The null hypothesis was that no time effect was present, which was tested at the 10% significance level. If the null hypothesis was rejected, the earliest time point was removed, and the procedure was repeated, dropping the smallest time point at each stage until a model was reached at which the null hypothesis was no longer rejected.
Safety Analysis
The numbers of subjects (incidence) with adverse events were tabulated. Clinical laboratory values, vital signs, neurological assessments, and 12-lead ECG data collected throughout the study were summarized with descriptive statistics. Routine clinical laboratory findings (serum chemistry, hematology, blood coagulation, and urinalysis) were summarized by dose using descriptive statistics. Change from baseline at each sampling time of study was calculated also. Baseline was defined as the value of the laboratory characteristic measured at day –2. Based on laboratory normal ranges, these laboratory test results were categorized according to the normal range as low (less than lower normal limit), normal (within normal range), and high (greater than upper normal limit).
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RESULTS |
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TOPABSTRACTMETHODSRESULTSPHARMACOKINETICSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Multiple Dose
Twenty-four healthy, nonsmoking male subjects were enrolled in the multiple-dose study, and again, subject demographics across dose groups were similar (Table I). The mean age of enrolled subjects was 25.9 ± 3.9 years (range, 19-35 years), with an average BMI of 24.21 ± 1.89 kg/m2 (range, 22.0-28.0 kg/m2). All of the subjects in the multiple-dose study were white.
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PHARMACOKINETICS |
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TOPABSTRACTMETHODSRESULTSPHARMACOKINETICSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Mean pharmacokinetic profiles after the single dose are presented in Figure 2, and ACP-103 single-dose pharmacokinetic parameters are provided in Table II. ACP-103 was slowly absorbed, with a median tmax consistently close to 6 hours for all doses tested. Following administration of 20 to 300 mg ACP-103, mean Cmax increased from 9 to 152 ng/mL, and mean AUC0- values increased from 706 to 10 798 ng·h/mL. Half-life of ACP-103 ranged between 53 and 58 hours. Oral clearance ranged between 23 and 34 L/h. The half-life and oral clearance were dose independent over the studied dose range. Generally, pharmacokinetic parameters demonstrated low intersubject variability, and the coefficient of variation (CV%) was <30% for Cmax and <40% for AUC.
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Dose proportionality after single oral or nasogastric administration was evaluated by linear regression analysis using log-transformed values of pharmacokinetic parameters. Values of intercept estimates of Cmax and AUC0- were –1.05 (95% CI, –1.55 to –0.56) and 3.28 (95% CI, 2.65-3.90), respectively. Values of slope estimates of Cmax and AUC0- were 1.07 (95% CI, 0.96-1.17) and 1.05 (95% CI, 0.91-1.19), respectively. The 95% CI for slope estimates included 1.0, indicating a dose-proportionate increase of the pharmacokinetic parameters value with escalation of ACP-103 dose from 20 to 300 mg. Plots of individual and mean Cmax and AUC0- against dose are shown in Figure 3. The plots illustrate the dose-proportionate increase in Cmax and AUC0-.
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Multiple Dose
All subjects who received 50, 100, or 150 mg ACP-103 had quantifiable ACP-103 concentrations over the collection interval during the study, including up to 12 days after the last dose administration of ACP-103. Mean pharmacokinetic parameters after the first dose on day 1 and the last dose on day 14 are presented in Table II. Mean plasma ACP-103 concentration-time profiles on day 14 are shown in Figure 4. Trough concentrations were compared among treatment day groups using the repeated-measures ANOVA model with type 3 tests for treatment day and subject effects. The results of the test indicated that steady state was achieved on day 7 for 50-mg, 100-mg, and 150-mg ACP-103 doses, which was supported by graphic evaluation of the study data.
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ACP-103 steady-state oral clearance was dose independent, and the estimates obtained following 14 days of ACP-103 administration were similar to those obtained following single-dose administration of ACP-103. Mean steady-state half-life ranged from 48 to 60 hours and was independent of dose. The accumulation of ACP-103 following 14 days of once-daily dose administration ranged from 3.5- to 4.7-fold for Cmax and from 3.7- to 5.2-fold for AUC0-24 and was independent of ACP-103 dose. Fluctuation of steady-state ACP-103 concentrations (defined as [Cmax – Cmin]/Cavg) was low in all dose groups and ranged from 42% to 49%.
All single- and multiple-dose pharmacokinetic parameters demonstrated low intersubject variability, and the CV% was <34% for Cmax and 
37% for AUC.
Select 6- and 24-hour plasma samples on day 1 and day 14 in subjects receiving the lowest (50 mg/d) and highest (150 mg/d) ACP-103 dose levels were evaluated for ACP-103 protein binding. ACP-103 was highly protein bound (range, 91.23%-96.57%) in all samples. Protein binding appeared to be dose independent and did not change significantly between day 1 and day 14.
Tolerability
Single Dose
There were no serious adverse events reported following single oral or nasogastric doses of 20 to 300 mg ACP-103. There were no premature discontinuations. None of the treatment-related adverse events reported were considered dose limiting, and a maximum tolerated dose was not reached.
Treatment-related adverse events were observed in 12 (60%) subjects who received a single dose of ACP-103 and 1 (20%) subject who received placebo (Table III). No related adverse events were observed in the 20-mg ACP-103 group. There was no apparent increase in the number of subjects with related adverse events over the 50- to 300-mg ACP-103 dose groups. The most common related adverse event was postural dizziness, observed in 3 (75%) subjects receiving 50 mg ACP-103, 2 (50%) subjects receiving 200 mg ACP-103, and 2 (50%) subjects receiving 300 mg ACP-103.
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The 4 subjects who received the 50-mg oral solution dose of ACP-103 reported either bitter or acid taste or a burning sensation in the mouth. Due to these events, subsequent ACP-103 doses of 100 to 300 mg ACP-103 were administered via nasogastric tube.
Overall, adverse events were generally mild in nature. Two subjects experienced adverse events of moderate intensity that were deemed possibly related to study drug. One subject who received 200 mg ACP-103 experienced a vasovagal episode on day 1 approximately 4 hours postdose. The vasovagal episode resolved without intervention, and the subject completed the study without any further vasovagal episodes. Another subject, who received 200 mg ACP-103, experienced syncope approximately 2 hours postdose followed by postural dizziness, which lasted approximately 7 hours. The syncope and postural dizziness resolved without intervention, and the subject completed the study without any further syncope or postural dizziness.
Multiple Dose
There were no serious adverse events reported. A total of 157 treatment-related adverse events were reported in 23 (95.8%) subjects exposed to study medication in the multiple-dose study (Table III). Of those reported, 128 related adverse events were observed in 17 (94.4%) subjects who received ACP-103, and 29 related adverse events were observed in 6 (100%) subjects who received placebo.
Of the 24 enrolled subjects, 5 subjects discontinued prematurely from the study: 3 subjects (100 mg: 1 subject on day 4; 150 mg: 2 subjects, 1 on day 7 and the other on day 12) due to adverse events of nausea and vomiting; 1 subject (placebo: day 5) due to dyspepsia, chest tightness, dizziness, and general weakness; and 1 subject was lost to follow-up after completing all other study procedures.
After multiple-dose administration of ACP-103, adverse events were generally mild or moderate in nature. Two adverse events of severe intensity were reported during the study. One subject experienced nausea and vomiting approximately 71 hours after initiation of oral dosing with 100 mg of ACP-103 and was withdrawn from the study on day 4 by the investigator. Another subject experienced a vasovagal episode 4 hours after receiving the initial oral dose of 150 mg ACP-103. This episode resolved without intervention, and the subject completed the 14-day study without any further vasovagal episodes or severe adverse events.
Two subjects receiving 150 mg ACP-103 experienced gastrointestinal-related events of moderate severity, which were judged possibly related to study drug by the investigator and led to study discontinuation. One subject was withdrawn on day 7 due to moderate vomiting and dyspepsia, whereas another subject was withdrawn at predose on day 12 due to nausea and vomiting. At follow-up, both of these subjects' gastrointestinal-related events were resolved.
Safety
Single Dose
There were no clinically meaningful changes or trends observed in clinical laboratory data and vital signs with administration of increasing single doses of ACP-103. Clinical laboratory data and vital signs were similar between ACP-103-treated subjects and placebo-treated subjects. No hematology, vital sign, or oral temperature values were reported as adverse events.
Lead-II monitoring was within normal limits, except for 2 subjects. One subject, who received 200 mg ACP-103, experienced extreme bradycardia close to time of syncope (with approximately a 2- to 8-second pause), which then returned to normal values. Another subject, who received 300 mg ACP-103, experienced vasovagal symptoms associated with a 2.9-second pause, which then returned to normal values. These events were considered not to be of clinical significance. There were no clinically relevant changes in individual 12-lead ECG findings. There were no clinically relevant differences observed in mean ECG parameters between the ACP-103 treated subjects and placebo-treated subjects. No adverse events were reported for ECG abnormalities.
Individual neurological examination data from baseline through to the end of study were recorded. There were no changes in behavior, coordination, or gait observed in any subject. There were no tremors observed during the scheduled neurological examinations. One subject, a healthy 31-year-old male who received 100 mg ACP-103, had an abnormal finding of nystagmus on day 1 approximately 6 hours after dose administration. Visual disturbances were also reported in the same subject at the same time. The nystagmus resolved within approximately 14 hours of dose administration. Additional neurological examination findings were normal for this subject.
Multiple Dose
There were no clinically meaningful changes or trends observed in mean or median laboratory values from baseline to end of study for any of the treatment groups. Clinical laboratory data were similar between ACP-103-treated subjects and placebo-treated subjects. There were no adverse events reported or clinically meaningful changes for vital sign abnormalities, oral temperatures, or physical examination results.
There were no clinically relevant changes in individual 12-lead ECG assessments. Lead-II monitoring was normal, except for 1 subject who received oral doses of 150 mg ACP-103. The lead-II results for this particular subject showed asystole for approximately 15 seconds during a vasovagal episode, which then returned to normal. This vasovagal event was considered to be of clinical significance. A total of 27 events (26 in ACP-103-treated subjects and 1 placebo subject) of ECG intervals outside of normal limits were observed during the study. Three subjects who received oral doses of 100 mg ACP-103 once daily met the outlier criteria for PR interval (>200 ms), but 2 of those subjects had intermittent PR intervals of greater than 200 ms at baseline. The 1 subject with intermittent high postdose PR intervals also met the outlier criteria for QRS interval but only at a single time point that was predose on day 10. Seven subjects receiving ACP-103 met the outlier criteria for QT interval of at least 1 postdose QT reading greater than 430 ms, which was absent at baseline. There were no subjects with QTcB or QTcF values greater than 450 ms.
During the neurological assessment, there were no changes reported in ACP-103 treated subjects or placebo-treated subjects for behavior, coordination, nystagmus, or gait examinations. No tremors were reported during the neurological examinations. However, 2 subjects receiving ACP-103 experienced mild tremors, which were recorded as adverse events.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSPHARMACOKINETICSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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The extended half-life may be explained partly by high protein binding of ACP-103. Between 91.2% and 96.8% of ACP-103 was bound to plasma proteins in the select plasma samples examined. Binding was both dose independent and time independent. The plasma protein binding of ACP-103 was a little higher than that observed with other antipsychotic drugs, such as olanzapine (90%-93%), quetiapine (83%), and risperidone (90%).2-4 Future studies may be planned to examine the potential interaction of ACP-103 with other highly protein-bound drugs.
ACP-103, with a half-life at approximately 55 hours, has a longer duration of action than olanzapine, with a mean half-life in healthy volunteers of 33 hours.2 Both ACP-103 and olanzapine have considerably longer half-lives than quetiapine, with a mean terminal half-life of around 7 hours.3 Risperidone has a half-life ranging from 0.8 to 3 hours but also has an active metabolite, 9-hydroxyrisperidone, that has a half-life ranging from 3.2 to 48 hours depending on the ability of an individual to metabolize risperidone.5 Taken together, these pharmacokinetic results indicate reliable and predictable exposure across subjects of ACP-103 after single oral doses. Furthermore, the long half-life is consistent with once-daily dosing in a therapeutic setting, which may be advantageous compared to drugs such as risperidone that have to be administered twice daily.
The results of this study demonstrate that ACP-103 is well tolerated at single oral/nasogastric doses ranging from 20 to 300 mg in 25 healthy male volunteers. Overall, adverse events were generally mild in nature, and a maximally tolerated dose was not defined in the single-dose study. In the multiple-dose study, a once-daily dose of 100 mg ACP-103 was considered to be the maximum tolerated dose in healthy male subjects. Administration of oral doses of ACP-103 up to 100 mg daily for 14 days was considered well tolerated without any apparent increase in adverse events as a function of escalating ACP-103 dose. Nausea and vomiting were considered to be the dose-limiting adverse events following daily oral administration of 150 mg ACP-103.
The most common related adverse event across the doses in the single-dose study was mild postural dizziness, which was not dose related. In these studies, subjects remained in a reclined position for an extended duration after administration of drug and were required to stand quickly during assessment of 3-positional vitals; this may have contributed to the reports of dizziness.
Oral administration of the ACP-103 solution was not well tolerated due to reports of bitter or acid taste at the 50-mg single dose. It was assumed that oral and nasogastric administration would result in similar absorption; in fact, plasma levels were linear regardless of route of administration. Local tolerance improved with the switch to nasogastric administration at the higher single doses, and when powder-filled capsules were used for the multiple-dose study, taste was no longer an issue. The bitter or acid taste that the subjects reported for the oral solution was likely due to the tartrate salt form of the drug and can be masked in future studies using powder-filled capsules or formulated coated tablets.
The lack of pharmacological interaction of ACP-103 at other monoaminergic receptors other than 5-HT2A and 5-HT2C1 is consistent with the high tolerability in the present study. In contrast, other antipsychotic drugs have multiple pharmacological interactions and exhibit a wide variety of side effects.6,7 The typical antipsychotic drugs, such as chlorpromazine and haloperidol, are limited in their use due to severe motor side effects such as parkinsonism, akathisia, and tardive dyskinesia. Some of the older typical antipsychotic drugs also caused other side effects such as cardiovascular changes and sedation. The atypical antipsychotics, such as clozapine, olanzapine, and quetiapine, are well known for their reduced liability for motor side effects but have increased liability for weight gain, diabetes mellitus, sedation, and cardiovascular risk. Risperidone at lower doses appears to have reduced liability for motor side effects, but the incidence of these effects increases with dose. The typical antipsychotics and risperidone also cause hyperprolactinemia.
The safety of ACP-103 was demonstrated across a wide variety of measures, including clinical laboratory data and vital signs, collected in both studies. The cardiovascular and ECG profile of antipsychotic drugs has been increasingly scrutinized following reports of prolonged QTc measures with some antipsychotic drugs.8-10 In the single-dose study, there were no clinically significant events as measured by lead-II or 12-lead ECG monitoring after single ACP-103 administration. Importantly, there was no evidence for QTc prolongation after ACP-103 administration of single doses ranging from 20 to 300 mg. In the multiple-dose study, no adverse events were reported for ECG abnormalities. There were no trends or clinically meaningful changes in 12-lead ECG parameters, including HR and PR and QRS intervals. QTc intervals over the 14 days of ACP-103 (or placebo) dosing were generally within the normal range of baseline variability seen in this study. Small increases in QTc intervals were observed on days 7 to 15 in subjects receiving 100 mg and 150 mg ACP-103, respectively, but these small increases were within the normal range of baseline variability for this study.
ACP-103 is a novel, selective, potent, and efficacious 5-HT2A receptor inverse agonist that is well tolerated at single oral doses up to and including 300 mg. The pharmacokinetic profile of ACP-103 is dose proportional, has low variability, and appears reproducible across studies, suggesting predictable exposure for future clinical trials. The present data support moving safely forward into clinical evaluations in patient populations.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSPHARMACOKINETICSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSPHARMACOKINETICSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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1. Vanover KE, Weiner DM, Makhay M, et al. Pharmacological and behavioral profile of N-(4-fluorophenylmethyl)-N-(1-ethylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide (2R,3R)-dihydroxybutanedioate (2:1) (ACP-103), a novel 5-HT2A receptor inverse agonist. J Pharmacol Exp Ther. 2006;317: 910-918.
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5. Huang M-L, Van Peer A, Woestenborghs R, et al. Pharmacokinetics of the novel antipsychotic agent risperidone and the prolactin response in healthy subjects. Clin Pharmacol Ther. 1993;54: 257-268.[Web of Science][Medline] [Order article via Infotrieve]
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7. Worrel JA, Marken PA, Beckman SE, Ruehter V. Atypical antipsychotic agents: a critical review. Am J Health-Syst Pharm. 2000;57: 238-255.
8. Cubeddu LX. QT prolongation and fatal arrhythmias: a review of clinical implications and effects of drugs. Am J Ther. 2003;10: 452-457.[CrossRef][Medline] [Order article via Infotrieve]
9. Haddad PM, Anderson IM. Antipsychotic-related QTc prolongation, torsade de pointes and sudden death. Drugs. 2002;62: 1649-1671.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
10. Harrigan EP, Miceli JJ, Anziano R, et al. A randomized evaluation of the effects of six antipsychotic agents on QTc, in the absence and presence of metabolic inhibition. J Clin Psychopharmacol. 2004;24: 62-69.[CrossRef][Web of Science][Medline]
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  K. E. Vanover, D. Robbins-Weilert, D. G. Wilbraham, T. G. K. Mant, D. P. van Kammen, R. E. Davis, and D. M. Weiner The Effects of Food on the Pharmacokinetics of a Formulated ACP-103 Tablet in Healthy Volunteers J. Clin. Pharmacol., July 1, 2007; 47(7): 915 - 919. [Full Text] [PDF]
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