Tolerability Of Multiple Doses Research Articles

Pharmacokinetics, Safety and Tolerability of Anacetrapib, a Novel Cholesteryl Ester Transfer Protein (CETP) Inhibitor, After Single and Multiple Doses in Healthy Chinese Subjects.

Anacetrapib is a novel, powerful cholesteryl ester transfer protein (CETP) inhibitor with bidirectional lipid regulation, which was developed for dyslipidemia. The aim of this study is to evaluate the single- and multiple-dose pharmacokinetics (PK), safety and tolerability of anacetrapib in healthy Chinese subjects and assess the PK difference between Chinese and other populations. Forty subjects were enrolled in an open-label study consisting of three panels (50mg single dose; 100mg single dose followed by 100mg once-daily multiple doses for 10days; a 200mg single dose). Safety and tolerability were evaluated by monitoring adverse events, laboratory safety tests, ECGs, vital signs and physical examination. PK were evaluated and compared with historical data in black and white subjects. Anacetrapib was absorbed after administration of a single oral dose, with a median Tmax of 3.0-5.0h and elimination half-life of 105.3-122.3h. The AUC and Cmax of anacetrapib increased in a slightly less than dose-proportional manner over a dose range of 50-200mg. Once-daily administration of 100mg of anacetrapib for 10days resulted in a median Tmax of 5.0h with an apparent half-life of 193.7h on Day 10 of multiple dosing. Anacetrapib accumulation ratios (Day 10 of multiple dosing/Day 1) were 1.39 (AUC0-24h), 1.11 (Cmax) and 2.57 (C24h). The PK properties of anacetrapib in Chinese subjects are comparable to those observed in the black population and in white subjects. Single and once-daily administration of anacetrapib was generally well tolerated in healthy Chinese subjects observed in this study. chinadrugtrials.org.cn identifier number CTR20130983.

A Study to Evaluate the Safety and Tolerability of Multiple Doses of Gerilimzumab in Rheumatoid Arthritis Patients

A Study to Evaluate the Safety and Tolerability of Multiple Doses of Gerilimzumab in Rheumatoid Arthritis Patients

Single- and multiple-dose tolerability, safety, pharmacokinetics, and pharmacodynamics of the dual endothelin receptor antagonist aprocitentan in healthy adult and elderly subjects.

BackgroundAprocitentan is an orally active, dual endothelin (ET) receptor antagonist developed for the treatment of hypertension in which, despite available treatments, a medical need exists for drugs with a new mechanism of action.Subjects and methodsIn this study, the single- and multiple-dose tolerability, safety, pharmacokinetics (PK), and pharmacodynamics of up to 600 mg (single doses) and 100 mg once a day (qd; multiple doses) of aprocitentan were investigated in healthy male and female subjects. The effect of age on the tolerability and PK parameters was investigated at a dose of 100 mg qd.ResultsAprocitentan was well tolerated across all doses. No serious adverse events (AEs) occurred. The most frequently reported AE was headache. Small increases in body weight were recorded in subjects receiving 100 mg qd. Plasma concentration–time profiles of aprocitentan were similar after single- and multiple-dose administration, and support a qd dosing regimen based on a half-life of 44 hours. After multiple doses, PK was dose proportional. Accumulation at steady state, reached by Day 8, was 3-fold. Only minor differences in exposure between healthy females and males, healthy elderly and adult subjects, and fed and fasted conditions were observed. Plasma ET-1 concentrations, reflecting ETB receptor antagonism, significantly increased with doses ≥25 mg. Time-matched analysis of electrocardiogram (ECG) parameters did not suggest drug-induced ECG effects. Exposure–response analysis indicated no QTc prolongations at plasma levels up to 10 µg/mL.ConclusionAprocitentan was well tolerated in healthy subjects with a PK profile favorable for qd dosing.

Abstract 427: An Oral, Rising, Multiple-dose Tolerance, Pharmacokinetic, and Pharmacodynamic Study of Gemcabene in Healthy Volunteers

Background: Gemcabene is a novel lipid-regulating compound being developed as an adjunct to diet and statin therapy for the treatment of dyslipidemia. Gemcabene was administered in a randomized, double-blind, rising, multiple-dose safety, tolerance, pharmacokinetic, and pharmacodynamic study in healthy subjects. Methods: Fifty healthy subjects (34 men and 16 women), with a mean age of 39.7 years and mean baseline LDL-C of 116.7 mg/dL were randomized (6:1) to either gemcabene 50, 150, 300, 450, 600/750, or 900 mg or placebo once daily for 29 days in six rising-dose cohorts. Results: Forty-seven subjects completed the study. Gemcabene significantly lowered total cholesterol by 18-21%, low-density lipoprotein-cholesterol (LDL-C) by 26-32%, and apolipoprotein B (apoB) by 8-21% from both baseline and placebo at the 450, 750/600, and 900 mg doses ( Table below ). Gemcabene was rapidly absorbed with dose proportional increases in maximum plasma concentration (Cmax) and area under plasma concentration time curve from 0 to 24 hours (AUC (0-24) ) values. Elimination half-life values were independent of dose and averaged 32-41 hours. Multiple doses of gemcabene up to 900 mg for 29 days were generally well-tolerated. There were no treatment-related serious adverse events. Adverse events reported were generally mild to moderate in intensity. Conclusion: Gemcabene exposure increased proportional with dose, was well tolerated, and was observed to significantly lower total cholesterol, LDL-C, and apo B at once daily doses of 450 to 900 mg. Gemcabene is being developed as an oral, lipid-altering agent to be used as an adjunctive therapy for the treatment of dyslipidemia, including the rare indication of HoFH. Clinical Implications: Gemcabene is being developed as a potential treatment for dyslipidemia.

A Rising Multiple-Dose Tolerability, Safety, and Pharmacokinetic Study of Intravenous Tildrakizumab in Patients With Psoriasis

A Rising Multiple-Dose Tolerability, Safety, and Pharmacokinetic Study of Intravenous Tildrakizumab in Patients With Psoriasis

A novel CRTH2 antagonist: Single- and multiple-dose tolerability, pharmacokinetics, and pharmacodynamics of ACT-453859 in healthy subjects.

The chemoattractant receptor-homologous molecule expressed on T-helper 2 cells (CRTH2) is a G-protein-coupled receptor for prostaglandin D2 , a key mediator in inflammatory disorders. In this randomized, double-blind, placebo-controlled study we investigated the single- and multiple-dose tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) up to a dose of 800 mg once a day of ACT-453859, a potent and selective CRTH2 antagonist. ACT-453859 was moderately rapidly absorbed and followed a biphasic elimination pattern, with an elimination half-life between 11 and 20 hours. Steady-state conditions were reached after 1 day, and ACT-453859 did not accumulate. Urinary excretion of unchanged ACT-453859 did not exceed 1.4% of the administered dose. Administration of ACT-453859 resulted in a dose-dependent blockadeof CRTH2 on the surface of eosinophils. The maximum PD effect of ACT-453859 was reached about 2.0 hours after dosing, which corresponded to the highest concentration at which PD were assessed. At steady state, 100 and 800 mg ACT-453859 once a day resulted in blockade of CRTH2 over 24 hours. In this entry-into-humans study, ACT-453859 showed good tolerability at all doses and a PK and PD profile compatible with once-daily dosing.

Effects of four traditional Chinese medicines on the pharmacokinetics of simvastatin

1. Concomitant traditional Chinese medicines (TCMs) could be the reason for relative poor efficacy of statins in dyslipidemia patients in China.2. An open-label, randomized, 5-period crossover study in healthy Chinese was designed to evaluate the pharmacokinetic interaction and tolerability of multiple doses of certain TCMs on a single dose of simvastatin. In each period, subjects received one of five treatments. In Treatment A, subjects received a single dose of 20 mg simvastatin. In Treatment B, C, D or E, subjects received Tong Xin Luo, Nao Xin Tong, Guan Mai Ning or Yin Xing Ye for 7 days and a single dose of 20 mg simvastatin on Day 7. The washout period was 7 days.3. The 97.5% confidence interval of the AUC0–48 h geometric mean ratio of simvastatin acid and simvastatin for simvastatin given after multiple oral doses of one of the TCMs versus simvastatin given alone were fully contained within the prespecified bounds of (0.50, 2.00).4. Exposures to simvastatin acid and simvastatin following a single dose of simvastatin alone were similar to those following coadministration of a single dose of simvastatin with multiple doses of each of the TCM preparations tested. Simvastatin and these TCMs were well tolerated.

Pharmacokinetics, safety, and tolerability of single and multiple-doses of pinocembrin injection administered intravenously in healthy subjects

Ethnopharmacological relevancePinocembrin is the most abundant flavonoid in propolis. Preclinical studies have suggested that pinocembrin protects rat brain against oxidation and apoptosis induced by ischemia–reperfusion both in vivo and in vitro. To investigate the safety, tolerability and pharmacokinetics of a new neuroprotective agent, pinocembrin. Materials and methodA double-blind, placebo-controlled, randomized study was carried out in 58 healthy subjects. Single ascending doses of pinocembrin (20–150mg) were evaluated in 5 cohorts. Multi-dose was studied at pinocembrin 60mg. ResultsPinocembrin was well tolerated. No serious adverse events occurred. No subjects were discontinued because of a treatment emergent AE. Treatment related adverse event was acute urticaria. Two subjects in 150mg cohort developed grade II urticaria during the study. One subject discontinued after 3 days at 60mg bid because of diarrhea. In the single-dose study, the mean peak plasma pinocembrin concentration was obtained at the end of the 30-min infusion. The Cmax ranged from 0.28μgmL−1 to 2.46μgmL−1. AUC (0,∞) ranged from 10.34μgmL−1min to 89.34μgmL−1min. The T1/2 was similar across 5 dose groups, ranging from 40 to 55min. Both urinary and feces excretion levels of pinocembrin were extremely low and similar among each dose groups, with mean values ranging from 0.07% to 0.17% and 0.94% to 1.94% of the administered dose, respectively. Linear increases in Cmax and AUC(0,∞) were observed. The pharmacokinetics of pinocembrin in multiple-dose was similar to those observed in the single-dose study, with no evidence of accumulation. Both urinary and feces excretion levels of pinocembrin were extremely low. ConclusionsPinocembrin displayed linear plasma pharmacokinetics over the dose range, 20–150mg and was well tolerated up to 120mg day−1 when administered intravenously to healthy adults. No major safety concerns were identified that would preclude further clinical development of pinocembrin injection.

Single- and multiple-dose tolerability and pharmacokinetics of the CRTH2 antagonist setipiprant in healthy male subjects.

Chemoattractant receptor-homologous molecule expressed on T helper (Th) 2 cells (CRTH2) is a G-protein-coupled receptor for prostaglandin D2 (PGD2), a key mediator in inflammatory disorders such as asthma and allergic rhinitis. In this study, we investigated the single- and multiple-dose tolerability and pharmacokinetics (PKs) of setipiprant, an orally active, potent, and selective CRTH2 antagonist. This randomized, double-blind, placebo-controlled study was performed in two parts in healthy male subjects. In study Part A, single oral doses of up to 2000 mg setipiprant or placebo were given to sequential groups of eight subjects each. Additionally, the impact of food on the PKs was investigated in one-dose group. In study Part B, two groups of subjects received 500 or 1000 mg setipiprant or placebo b.i.d. during 5.5 days. At regular intervals, tolerability variables and plasma and urine levels of setipiprant were determined. Setipiprant was well tolerated after single- and multiple-dose administration. Headache was the most frequently reported adverse event. No treatment effect on tolerability variables was observed. After single- and multiple-dose administration, setipiprant was rapidly absorbed and followed a biphasic elimination pattern with an elimination half-life between 10 and 18 h. Steady-state conditions were reached after 2-3 days and setipiprant did not accumulate. Exposure to setipiprant was lower in the presence of food. Urinary excretion of unchanged setipiprant did not exceed 7% of the administered dose. In this entry-into-human study, setipiprant showed good tolerability and a favorable PK profile, thus warranting its development in the treatment of inflammatory disorders.

Multiple-dose tolerability, pharmacokinetics, and pharmacodynamics of ponesimod, an S1P1receptor modulator: Favorable impact of dose up-titration

This multiple-ascending-dose study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of ponesimod, an S1P1 receptor modulator and a potential new treatment for autoimmune diseases. In part A, 10 healthy male and female subjects received once daily oral doses of ponesimod (5, 10, or 20 mg) or placebo for 7 days. Sinus bradycardia and, in some subjects, atrioventricular (AV) block occurred primarily on the first day of dosing, as desensitization developed to ponesimod-induced heart rate (HR) reduction and PR-prolongation. This elicited the design of an up-titration schedule in 17 subjects to a dose of 40 mg in part B. The up-titration regimen reduced HR and PQ/PR effects. Reported adverse events were mainly related to the cardiac and respiratory systems. Respiratory effects increased with higher doses. Ponesimod multiple-dose pharmacokinetics were slightly more than dose-proportional and characterized by a time to maximum concentration and an elimination half-life varying from 2.5 to 4.0 hours and 30.9 to 33.5 hours, respectively, and an accumulation of about 2.3-fold. Ponesimod caused a dose-dependent sustained decrease in total lymphocyte count, reversible within 7 days of discontinuation. A pharmacokinetic-pharmacodynamic model enabled comparing day 1 and steady-state conditions. These results warrant further investigation of ponesimod in patients.

Pharmacokinetics, Pharmacodynamics, and Tolerability of ACT-077825, a New Direct Renin Inhibitor After Multiple-ascending Doses in Healthy Subjects

This study was conducted to characterize the multiple-dose tolerability, pharmacokinetics, and pharmacodynamics of ACT-077825, a new direct renin inhibitor, in healthy male subjects. In this single-center, double-blind, placebo-controlled, active-controlled (20 mg of enalapril), randomized multiple-ascending dose study, ACT-077825 was administered once a day. for 7 days in the 50-1000 mg dose range to sodium- and potassium-restricted subjects. ACT-077825 pharmacokinetics on days 1 and 7 were characterized by dose-proportional increases in Cmax and AUCτ. At steady state, accumulation was modest (1.5- to 1.7-fold). Enalapril caused an increase in plasma active renin concentration and plasma renin activity (PRA). ACT-077825 dose dependently increased active renin on days 1 and 7 and inhibited PRA dose dependently only on day 1. On day 7, the maximal PRA inhibition was attained after 250 mg of ACT-077825. In contrast to enalapril, ACT-077825 did not induce any consistent lowering effect on blood pressure when compared with placebo. Of the reported adverse events, diarrhea, headache, and postural dizziness were more frequent. The incidence of diarrhea was greater in the 1000-mg group and a dose of 500 mg of ACT-077825 was identified as the maximum tolerated dose. Overall, pharmacokinetic, pharmacodynamic, and tolerability profiles warrant the further investigation of ACT-077825 in patients with hypertension.

Orexin receptor antagonism: an ascending multiple-dose study with almorexant

The objectives of this study were to investigate the multiple-dose tolerability, safety, pharmacokinetics, and pharmacodynamics of the dual orexin receptor antagonist almorexant. Healthy subjects received daily doses of almorexant (100, 200, 400 or 1000 mg) or placebo in the morning for four days followed by two days with evening administration (Days 5-6). Each dose level was investigated in a new group of 10 subjects (eight active, two placebo, 1:1 sex). Dose-dependent increases in frequency and intensity were observed for somnolence and other adverse events. Pharmacokinetics at steady state showed rapid absorption, low concentrations eight hours post-dose, and minimal accumulation. Following evening, administration absorption was delayed and C(max) decreased. Almorexant at 400 and 1000 mg administered in the morning reduced vigilance, alertness, visuomotor coordination, and motor coordination assessed in a psychometric test battery. Polysomnography recordings following evening administration showed a trend towards shorter latency to sleep stages 3 and 4, and shorter latency to, and longer time in, rapid-eye-movement sleep at higher doses when compared to placebo. Whether these findings in healthy subjects translate into relevant sleep-enabling effects in insomnia patients needs to be investigated in future studies.

Pharmacokinetics, Safety, and Tolerability Following Multiple Oral Doses of Varenicline Under Various Titration Schedules in Elderly Nonsmokers

This study was designed to investigate the multiple-dose pharmacokinetics, safety, and tolerability of the selective α4β2 nicotinic acetylcholine partial agonist, varenicline, in elderly (65-85 years old) nonsmokers. Fifty male and female subjects with normal renal function for their age were randomized to receive varenicline or placebo once or twice daily for 3 weeks in an investigator- and subject-blinded parallel-group design. Treatment regimens included weekly titration (n = 14; days 1-7, 0.5 mg once daily; days 8-14, 0.5 mg twice daily; days 15-21, 1 mg twice daily); 2-week twice-daily titration (n = 13; days 1-14, 0.5 mg once daily; days 15-21, 0.5 mg twice daily); 2-week once-daily titration (n = 13; days 1-14, 0.5 mg once daily; days 15-21, 1 mg once daily); and placebo (n = 10). Approximate dose-proportional increases in systemic exposure of varenicline at steady state, based on maximum concentration and area under the plasma concentration-time curve over the 24-hour period at steady state, were observed across the dose range of 0.5 to 2 mg/d. Median time to maximum concentration was 3 hours. Mean elimination half-life was estimated to be approximately 24 to 32 hours and independent of dose. Varenicline was considered to be safe and well tolerated in this elderly nonsmoking population.

A phase I study of neoadjuvant chemoradiotherapy with S-1/oxaliplatin in patients with gastric cancer.

51 Background: To determine the maximum tolerated dose (MTD) of concurrent radiotherapy with S-1 and oxaliplatin, and antitumor activity of the combination treatment in patients with gastric cancer. Methods: This was a phase I, escalating multiple-dose tolerability trial. S-1 and oxaliplatin were administered concurrently with radiotherapy for 4 weeks before surgery. The dose escalation scheme is provided in the table below. S-1 was continuously administered during radiotherapy and oxaliplatin was administered weekly for 4 weeks during radiotherapy. Results: From March 2009 to June 2010, twelve patients were entered at two dose levels. The most common dose-related grade 1 and 2 adverse events were nausea, vomiting, anorexia and abdominal pain. Two of six patients treated at level 1 developed DLT (disabling abdominal pain, stomach perforation). The dose of S-1/oxaliplatin was reduced to 30 mg/m2 bid and 40 mg/m2 (Level -1). There one DLT (vomiting and anorexia, grade 3) observed in the expanded cohort of 6 patients at Level -1. Among 12 patients, 1 patient demonstrated pathological CR after neoadjuvant chemoradiation therapy. Conclusions: Neoadjuvant CCRT with S-1/oxaliplatin was well tolerated, at a dose 30 mg/m2 bid for S-1 and 40 mg/m2 for oxaliplatin that at which antitumor activity was seen. Phase II study is planned to investigate further the efficacy, tolerability and optimal dose. [Table: see text] No significant financial relationships to disclose.

Single-dose bioavailability of levetiracetam intravenous infusion relative to oral tablets and multiple-dose pharmacokinetics and tolerability of levetiracetam intravenous infusion compared with placebo in healthy subjects

Background: Antiepileptic drugs are usually administere dorally, but alternative routes of drug delivery may be required when oral administration is not feasible. Objective: The purpose of this study was to evaluate the single-dose bioavailability of an IV formulation of levetiracetam relative to oral tablets and the multiple-dose tolerability and pharmacokinetics of this formulation compared with placebo in healthy subjects. Methods: This study consisted of 2 phases. Subjects entered the first phase, which was a single-dose, randomized, open-label, 2-way crossover bioavailability comparison of a 15-minute IV infusion of levetiracetam 1500 mg and three 500-mg oral tablets. Subjects then entered the second phase, a multiple-dose, randomized, double-blind, placebo-controlled (2:1), parallel-group tolerability and pharmacokinetic study, in which they received 9 successive doses of levetiracetam 1500 mg IV or placebo at 12-hour intervals. Plasma levetiracetam concentrations were determined by gas chromatography with nitrogen-phosphorus detection. The comparison of bioavailability was based on the 90% CIs around the geometric mean ratios for AUC and C max (IV/oral). Results: Eighteen subjects (9 men, 9 women) participated in the study. All subjects were white. Their mean (SD) age was 35.0 (9.3) years, mean weight 73.3 (14.2) kg, and mean body mass index 23.9 (2.5) kg/m 2. After a single dose, the IV infusion and oral tablet were similar in terms of C max (50.5 and 47.7 μg/mL, respectively) and AUC (392.4 and 427.9 pg · h/mL). The geometric mean IV/oral ratios were 92.2 (90 % CI, 89.0-95.6) for AUC and 103.7 (90% CI, 91.6-117.4) for C max indicating that the IV and oral formulations were bioequivalent. After multiple twice-daily infusions, steady state was reached within 48 hours. Seventeen (94%) of 18 subjects had ≥1 treatment-emergent adverse event after single-dose administration. During the single-dose phase, the incidence of treatment-emergent adverse events was 89% (16/18) for the IV formulation and 72% (13/18) for the oral tablets; during the multiple-dose phase, the incidence of treatment-emergent adverse events was 67% (8/12) in the IV levetiracetam group and 33% (2/6) in the placebo group. The most common adverse events in the single-dose phase were somnolence (61% IV vs 28% oral) and postural dizziness (17% vs 39%, respectively). The most common adverse events with IV levetiracetam in the multiple-dose phase were also somnolence (33% vs 17% placebo) and postural dizziness (25% vs 0% placebo). Conclusions: In these healthy subjects, single doses of levetiracetam 1500 mg administered as a 15-minute IV infusion and as oral tablets were bioequivalent. General and local tolerability during multiple dosing were good. Steady state was reached within 48 hours. Despite the limitations of a study of short duration and small size conducted in healthy subjects, the findings suggest that use of a 15-minute IV infusion of levetiracetam should be further investigated.

755. Phase II Clinical Trial Demonstrates the Safety and Tolerability of Multiple Doses of Autologous CD4+ T Cells Transduced with VRX496, a Lentiviral Vector Delivering Anti-HIV Antisense in Patients Failing 1 or More HAART Treatment

Gene therapy for HIV-1 infection has been proposed as an alternative to antiretroviral drug regimens due to emerging drug resistance and toxicity that raises concerns about HAART as a long term therapy. We have previously reported the successful completion of our Phase I clinical trial testing the safety and tolerability of a single dose of autologous HIV infected CD4+ T cells transduced with a lentiviral vector delivery system expressing a 937-base antisense gene against the HIV envelope (VRX496) for use in T cell therapy for HIV/AIDS. These results have lead us to initiate a Phase II clinical trial to evaluate the safety, tolerability, and biological activity of repeated infusions (4 or 8 doses) of autologous VRX496 transduced T cells. The study will enroll up to 40 male and female HIV-positive subjects in up to 8 centers. Subjects will be 18 years of age and over who have failed or are intolerant to at least one triple combination of antiretroviral drugs. Subjects will have, a viral load between 5,000 and 200,000 copies/ml and a CD4+ count of |[ge]|150. Additionally, subjects must have a Karnofsky Performance score of 80 or higher, have no evidence of active opportunistic infection, congestive heart failure, hemodynamic instability, bleeding diathesis and no contraindications for leukapheresis. Patients will receive repeated doses by i.v. of |[sim]|1|[ast]|1010 genetically modified autologous T-cells, every two weeks. The primary safety objectives will include incidence of adverse events, changes in viral load, changes in CD4+ T cells, changes in TCR v beta repertoire, and tests for replication competent lentivirus (RCL). Tissue trafficking of gene modified cells will also be monitored in GALT tissue. The first part of the study is evaluating the safety and tolerability of multiple dosing using a repeat dosing design. All patients in the 4 dose cohort have received their infusions as scheduled and have reached the 3 month post-infusion visit, and one patient in the 8 dose cohort has received all of the doses as scheduled. To date, all of the doses have been well tolerated and preliminary results suggest multiple infusions are safe, with no SAE's due to the product, no changes in hematology or chemistry laboratory evaluations, and no detection of VSVG DNA or RCL. In the second part, we are determining an optimal dosing regimen for future confirmatory trials. To date 18 patients have been enrolled and 11 have started receiving infusions. The data generated from the current clinical trial demonstrates the clinical utility of lentiviral vector technology as an alternative for treatment of HIV infection.

Single- and Multiple-Dose Pharmacokinetics and Tolerability of Gepirone Extended-Release

To determine the single- and multiple-dose pharmacokinetic profile of gepirone extended-release (ER) in healthy individuals. The single- and multiple-dose pharmacokinetics of gepirone-ER were investigated in three randomised, placebo-controlled studies of 115 healthy subjects. Dosages ranged from 10 to 75 mg/day for 6 days (study 1), 20 mg/day for 7 days (study 2), and 120 mg/day for 7 days (study 3). Blood samples were obtained to measure plasma levels of gepirone and the l-pyrimidinyl-(2-pipera-zine) [1-PP] metabolite prior to the first dose and other intervals on the first and last treatment days. Pharmacokinetic parameters included peak plasma level (Cmax), time to peak plasma level (tmax), and area under the concentration-time curve (AUC). In single-dose studies, peak gepirone-ER plasma concentrations were reached in approximately 4 to 5 hours and slowly declined over the next 20 hours. Steady-state plasma gepirone concentrations were reached by day 2 during multiple-dose studies; Cmax, minimum trough plasma concentration (Cmin) and AUC were dose proportional. Greater fluctuations in plasma concentrations were observed with gepirone solution than with gepirone-ER. The AUC for gepirone-ER was approximately 80% of that for gepirone solution. A similar pharmaco-kinetic profile was observed for the 1-PP metabolite. Gepirone-ER was generally well tolerated at all doses in all age groups except for 120 mg/day. The incidence of adverse events, including headache, dizziness and nausea, tended to be higher in gepirone-ER than in placebo recipients. Gepirone and 1-PP exhibited linear pharmacokinetic profiles. Peak/trough fluctuations in plasma gepirone concentrations were reduced by gepirone-ER, while total exposure to drug (AUC) was maintained. Overall, gepirone-ER was well tolerated. As a result of lower peak plasma levels, gepirone-ER may be expected to reduce the incidence of adverse events compared with gepirone immediate-release and thus has the potential to improve response.

Rizatriptan, a Novel 5-HT<SUB>1D/1B</SUB> Agonist for Migraine: Single- and Multiple-Dose Tolerability and Pharmacokinetics in Healthy Subjects

Rizatriptan is a novel 5-HT1D/1B agonist for relief of migraine headache. The pharmacokinetics, metabolite profiles, and tolerability of rizatriptan were examined in a multiple-dose study in healthy subjects. Rizatriptan (N = 24) (or placebo, N = 12) was administered as a single 10 mg dose, followed 48 hours later by administration of one 10 mg dose every 2 hours for three doses on 4 consecutive days, corresponding to the maximum daily dose for a migraine attack. The AUC of rizatriptan and its active N-monodesmethyl metabolite after three 10 mg doses was approximately threefold greater than the plasma concentrations following a single 10 mg dose. Metabolite profiles were similar after single and multiple doses. Adverse events during rizatriptan were mild and transient; similar events occurred during placebo, with a somewhat reduced incidence. Diastolic blood pressure tended to increase compared with placebo (approximately 5 mmHg), particularly on the first multiple-dose day (p < .01 vs. placebo). In conclusion, rizatriptan is well tolerated by healthy subjects during multiple-dose administration, with no unexpected accumulation of drug in plasma.

1124 Multiple-dose pharmacokinetics, safety, and tolerance of desloratadine in healthy volunteers

1124 Multiple-dose pharmacokinetics, safety, and tolerance of desloratadine in healthy volunteers

The role of positron emission tomography in the drug development of M100907, a putative antipsychotic with a novel mechanism of action.

Antipsychotic drug development has been a slow process since the discovery of chlorpromazine more than 45 years ago. Researchers identify a large number of potential compounds; screen them for antipsychotic activity in in vitro and animal test models; devise appropriate formulations; perform preclinical pharmacology, pharmacokinetic, and toxicology studies; perform healthy volunteer and then patient clinical studies; and finally negotiate with regulatory agencies for drug approval. In the United States, this process takes an average of 10 to 12 years and costs more than $500 million per approved drug. More recently, the pharmaceutical industry is benefiting from a new wave of technologic innovations that have advanced our understanding of the biology of disease processes and increased the efficiency of the research and development process. However, while these new technologies may appear to be expensive, by providing the basis for early go/no-go decisions, technologies such as PET can actually be cost-effective. To ensure that innovative drug research continues, a practical strategy (rational drug design) to evaluate drugs more efficiently in terms of both time and cost (fewer studies with fewer patients) must be developed for each new drug candidate. One of the most important and difficult steps in the drug development process is defining the dose-response relationship. Using M100907 as an example, we demonstrated that mechanism-based research promotes cost-effective drug development. The therapeutic index of M100907 was defined in phase I single- and multiple-dose tolerability studies. Nuclear imaging using PET technology was then used to confirm the mechanism of action of M100907 in the target organ (living human brain) and to target an appropriate dose range and regimen. With these data, clear go/no-go decision points could be established early within the clinical drug development process, and the selection of M100907 doses to carry forward into large-scale clinical trials in patients with schizophrenia could be narrowed.