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BRIEF REPORTS/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 correspondence: Kimberly E. Vanover, PhD, current address, Intra-Cellular Therapies, Inc, 3960 Broadway, New York, NY 10032; e-mail: kvanover{at}intracellulartherapies.com.
Key Words: Antipsychotic • phase I • serotonin • 5-HT2A • inverse agonist
ACP-103, N-(4-flurophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy) phenylmethyl)carbamide (2R,3R)-dihydroxybutanedioate (2:1), is a potent inverse agonist at serotonin 5-HT2A receptors currently being developed as a novel antipsychotic drug.1 In a phase I clinical study, ACP-103 was found to be safe and well tolerated at single oral doses ranging from 20 to 300 mg and multiple doses up to and including 100 mg daily for 14 days in healthy volunteers.2
The first pharmacokinetic study in humans was conducted using an oral solution.2 Administration of this oral solution resulted in a bitter taste and was not well tolerated. In that first study, single doses greater than 50 mg were administered nasogastrically to avoid the local intolerance. ACP-103 was administered in powder-filled capsules for the multiple-dose study.2 Subsequently, ACP-103 was formulated in an immediate-release coated tablet. The purpose of the present study was to compare the pharmacokinetics after administration of the formulated coated tablet to those after administration of the solution of ACP-103. Furthermore, the effects of food on the pharmacokinetics of ACP-103 after a single oral administration were evaluated in healthy male subjects.
METHODS
Study Design
This study was conducted as part of a larger single-dose tolerance study.2 The present study component focused on the comparison of the solution to the coated tablet formulation and the effect of food on ACP-103 pharmacokinetics. This study was conducted as a single-center, randomized, open-label, 3-way incomplete crossover design in 8 subjects. Subjects checked in on day -1 and were housed for a total of 5.5 days for each treatment. On day 1, all subjects received a single ACP-103 dose (100 mg) under either fasted or fed conditions. Serial blood samples were collected up to 216 hours after administration of ACP-103. ACP-103 was administered as follows:
Treatment A: 100 mg ACP-103 (5 mL of a 20-mg/mL ACP-103 solution) via nasogastric tube under fasted conditions
Treatment B: 100 mg ACP-103 (5 x 20-mg tablets) orally under fasted conditions
Treatment C: 100 mg ACP-103 (5 x 20-mg tablets) orally under fed conditions
Two subjects each were randomized to receive 1 of the following treatment sequences: ABC, CBA, BAC, or CAB. For the fed treatment, the single oral dose of ACP-103 was administered immediately following a high-fat breakfast. The treatments were separated by at least 14 days.
The active pharmaceutical ingredient ACP-103, N-(4-flurophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide (2R,3R)-dihydroxybutanedioate (2:1), and the 20-mg ACP-103 coated tablets were supplied by ACADIA Pharmaceuticals. For the solution, powder ACP-103 was reconstituted with water to a concentration of 20 mg/mL and administered as a solution via a polyvinyl chloride nasogastric tube. After ingestion of either the solution or the tablets, subjects were asked to drink sufficient water to allow a total volume of 240 mL to be ingested.
This study was conducted at Guy's Drug Research Unit (GDRU) Quintiles Limited, United Kingdom. An independent ethics committee approved the clinical study protocol, amendments to the clinical study protocol, informed consent document(s), and any other appropriate study-related documents. Written informed consent specific to this study was obtained for all subjects before conducting any study-related procedures. The study was conducted in accordance with the principles of the International Conference on Harmonization good clinical practice guidelines of the European Union, the ethical principles laid down in the current revision of the Declaration of Helsinki, and standard operating procedures for clinical investigations.
Subjects
Healthy, young, nonsmoking males between the ages of 18 and 45 years with a body mass index (BMI) of 19 to 28 kg/m2 were selected for participation in this study. Details for inclusion and exclusion are described elsewhere2 and summarized here. Subjects were excluded if they had significant abnormal vital signs or clinical laboratory evaluations upon screening or had a serious physical illness within 1 year prior to study start. Subjects also were excluded from participation in the study if they had any history of alcohol or drug abuse (or a positive urine drug or alcohol test at screening). 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, and serology screening, were performed before check-in of each treatment period along with inclusion/exclusion criteria.
All subjects scheduled to receive treatment A or B (fasted) began fasting after the evening snack on day -1 and continued to fast overnight for 10 hours. ACP-103 was administered after the 10-hour fast. Subjects scheduled to receive treatment C (fed) were given a high-fat breakfast 30 minutes prior to dosing on day 1. Treatment C subjects were required to consume the entire breakfast within 25 minutes (ie, within 5 minutes of drug administration). The high-fat breakfast consisted of 2 eggs fried in butter, 2 strips of bacon, 2 pieces of buttered toast, 4 ounces of hash brown potatoes, and 8 ounces of whole milk (approximately 55 g fat, 33 g protein, and 58 g carbohydrate). The exact time of all dose administrations and breakfast times was accurately recorded for day 1 of each treatment period. Lunch on day 1 of each study period was served 4 hours after dosing for all subjects. All other meals were served at the same time for all subjects and were identical within a given mealtime for all dose groups in the 3 periods. Water was allowed ad libitum beginning 2 hours after dosing.
Blood samples (7 mL each) were collected 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, processed immediately, and plasma samples stored frozen. Analyses were 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 heparinized human plasma had a standard curve range of 0.50 to 500 ng/mL according to methods described previously.2
Extensive safety monitoring was conducted and described elsewhere.2 Briefly, modified physical examinations, vital signs, and 12-lead and lead-II ECGs were conducted. 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. All subjects with pharmacokinetic parameter data from at least 1 treatment period were included in the statistical analysis.
Treatment comparisons were evaluated for the natural log-transformed AUC0-
, AUC0-z, and Cmax. Analysis of variance (ANOVA), with terms for sequence, subject within sequence, period, and treatment, was performed for each parameter. From this ANOVA, least squares means for each treatment, estimated treatment differences, and 90% confidence intervals (CIs) for treatment differences were calculated. These log-transformed results were transformed to the original scale by exponentiation to obtain adjusted means, treatment ratios, and 90% confidence intervals for these ratios. To assess relative bioavailability of the tablet formulation, the ACP-103 ratio of pharmacokinetic parameters following administration of tablets and solution to fasted subjects was calculated. Solution was used as a reference. To assess the effect of a high-fat meal on the pharmacokinetics (PK) of ACP-103, the PK parameters of the tablet "fed" treatment were compared with the PK parameters of the tablet "fasted" treatment, where tablet "fasted" was used as the reference. The primary statistical comparison was based on AUC0- and Cmax. The hypothesis of no food effect on the PK of ACP-103 was accepted if the 90% confidence interval of ratios of AUC0- and Cmax fell within the interval from 70% to 143%.
Safety Analysis
The numbers of subjects 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 also presented. Baseline was defined as a value of the laboratory characteristic measured at predose. 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).
RESULTS
Subject Demographics
A total of 8 healthy, nonsmoking male subjects were enrolled and completed all study procedures. The mean age of enrolled subjects was 28.3 ± 7.4 years (mean ± standard deviation; range, 19-40 years), with an average BMI of 24.1 ± 2.3 kg/m2 (range, 21-28 kg/m2). Of the 8 healthy male subjects who participated, 7 (87.5%) were white, and 1 (12.5%) was of a race other than white, black, or Asian.
Pharmacokinetics
The mean pharmacokinetic profile of each treatment group is shown in Figure 1. Mean ACP-103 plasma concentrations reached a maximum at approximately 6 hours postdose and then declined monoexponentially. There was little difference in systemic exposure across treatments.
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Median tmax was 6 hours for treatments A and B and 10.5 hours for treatment C. Mean Cmax was approximately 51 ng/mL, 57 ng/mL, and 52 ng/mL, respectively, for treatments A, B, and C (Table I, Figure 1). Mean AUC0- values for treatments A, B, and C were 3847, 3871, and 4269 ng·h/mL, respectively. Intra- and intersubject variability for Cmax and AUC0- were low. Intersubject variability was 11% for both Cmax and AUC0-, whereas intrasubject variability ranged from 16% for Cmax to 20% for AUC0-. Values of half-life and oral clearance were similar across treatments.
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Statistical pairwise comparisons were performed for the following pairs: treatment B/treatment A and treatment C/treatment B. The 90% CI was within the 80% to 125% interval for each comparison, indicating bioequivalence of tablet formulation and solution, as well as the absence of food effect on ACP-103 pharmacokinetics. Relative bioequivalence of the tablet formulation was 99.7%.
In period 2 and period 3, 3 and 6 subjects, respectively, had nonzero plasma concentrations in predose samples. Carryover concentrations were less than 5% of correspondent Cmax; therefore, these concentrations were used as is for pharmacokinetic and statistical analysis.
Safety and Tolerability
A total of 23 related treatment-emergent adverse events (TEAEs) were reported in 5 (62.5%) fasted subjects administered the 100-mg ACP-103 solution, 4 (50.0%) fasted subjects administered the 100-mg ACP-103 tablets, and 5 (62.5%) fed subjects administered the 100-mg ACP-103 tablets. There were no apparent treatment-related differences in the TEAEs.
The most common related TEAE was somnolence (drowsiness) followed by postural dizziness. Headache was reported in 1 subject in each of the 3 ACP-103 treatment groups. There were no serious adverse events observed. There were no clinically meaningful changes in clinical laboratory values, vital signs, or ECG parameters.
DISCUSSION
The relative bioavailability of a 20-mg ACP-103 immediate-release coated tablet formulation compared to an ACP-103 solution was studied in 8 subjects. The results demonstrated that the solution and tablet formulations were 99.7% bioequivalent. Furthermore, ACP-103 was safe and well tolerated at a single oral dose of 100 mg. These data are consistent with previous findings of the safety and tolerability of ACP-103 up to and including 300 mg when administered as a single oral or nasogastric dose.2
The pharmacokinetic profile of ACP-103, including the half-life of about 55 to 60 hours, was consistent across treatment groups and was consistent with that reported previously.2 Although at least 2 weeks were allowed for washout among treatments, a carryover effect was observed. However, carryover concentrations were less than 5% of correspondent Cmax; therefore, these concentrations were thought to have little affect on the overall interpretation of the pharmacokinetic data. Given the long half-life of ACP-103, future crossover trial designs using a similar dose of ACP-103 should consider a longer washout period.
Absorption and pharmacokinetics of drugs can be altered by food intake.3 For some drugs, it is recommended that they be taken with a meal, whereas other drugs must be taken on an empty stomach. A high-fat meal did not affect systemic exposure of ACP-103 when administered as a tablet formulation, indicating that food does not alter its absorption, exposure, or clearance. Therefore, future clinical studies can be conducted without controlling for food intake around the time of dose administration of ACP-103. Similar to ACP-103, a high-fat meal had little effect on the plasma AUC of quetiapine or sertindole, atypical antipsychotic drugs with high serotonin 5-HT2A receptor affinity.4,5 In contrast, another atypical antipsychotic drug, ziprasidone, showed an increase in systemic exposure and shorter duration of action when administered with a high-fat meal.6 Although another novel antipsychotic drug in development, iloperidone, did not show any differences in the pharmacokinetic parameters of AUC, tmax, and Cmax when administered with food, the incidence of its side effects was reduced when taken with food.7 This was not the case with ACP-103, as the generally mild adverse events reported were similar across fed and fasted conditions.
In conclusion, ACP-103 shows high relative oral bioavailability with or without food when administered as a formulated coated tablet compared to a solution. ACP-103 has a long half-life consistent with once-daily administration in the clinic. ACP-103 is safe and well tolerated at a relatively high dose of 100 mg orally. These data support the continued development of a tablet formulation of ACP-103 for the treatment of psychosis.
ACKNOWLEDGEMENTS
Financial disclosure: The authors were employees (Dr Vanover, Dr van Kammen, Dr Davis, Dr Weiner) or contractors (Dr Robbins-Weilert, Dr Wilbraham, Dr Mant) for ACADIA Pharmaceuticals Inc.
REFERENCES
1. Vanover KE, Weiner DM, Makhay M, et al. Pharmacological and behavioral profile of N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-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.
2. Vanover KE, Robbins-Weilert D, Wilbraham DG, et al. Pharmacokinetics, tolerability, and safety of ACP-103 following single or multiple oral dose administration in healthy volunteers. J Clin Pharmacol. 2007;47: 704-714.
3. Melander A. Influence of food on the bioavailability of drugs. Clin Pharmacokinet. 1978;3: 337-351.[Web of Science][Medline] [Order article via Infotrieve]
4. DeVane CL, Nemeroff CB. Clinical pharmacokinetics of quetiapine: an atypical antipsychotic. Clin Pharmacokinet. 2001;40: 509-522.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
5. Wong SL, Linnen P, Mack R, Granneman GR. Effects of food, antacid, and dosage form on the pharmacokinetics and relative bioavailability of sertindole in healthy volunteers. Biopharm Drug Dispos. 1997;18: 533-541.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
6. Hamelin BA, Allard S, Laplante L, et al. The effect of timing of a standard meal on the pharmacokinetics and pharmacodynamics of the novel atypical antipsychotic agent ziprasidone. Pharmacotherapy. 1998;18: 9-15.[Web of Science][Medline] [Order article via Infotrieve]
7. Sainati SM, Hubbard JW, Chi E, Grasing K, Brecher MB. Safety, tolerability, and effect of food on the pharmacokinetics of iloperidone (HP 873), a potential atypical antipsychotic. J Clin Pharmacol. 1995;35: 713-720.[Abstract]
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