Central nervous system effects of the histamine-3 receptor antagonist CEP-26401, in comparison with modafinil and donepezil, after a single dose in a cross-over study in healthy volunteers.

AIMS: In previous studies, the histamine-3 receptor antagonist CEP-26401 had a subtle effect on spatial working memory, with the best effect seen at the lowest dose tested (20 µg), and a dose-dependent disruption of sleep. In the current study, 3 low-dose levels of CEP-26401 were compared with modafinil and donepezil. METHODS: In this double-blind, placebo- and positive-controlled, randomized, partial 6-way cross-over study, 40 healthy subjects received single doses of placebo, CEP-26401 (5, 25 or 125 µg) or modafinil 200 mg or donepezil 10 mg. Pharmacokinetic and pharmacodynamic measurements were performed predose and at designated time points postdose. RESULTS: The main endpoint between-errors of the spatial working memory-10-boxes task only improved for the 125 µg dose of CEP-26401 with a difference of 2.92 (confidence interval [CI] -1.21 to 7.05), 3.24 (CI -1.57 to 8.04) and 7.45 (CI 2.72 to 12.19) for respectively the 5, 25 and 125 µg dose of CEP-26401, -1.65 (CI -0.572 to 1.96) for modafinil and - 3.55 (CI -7.13 to 0.03) for donepezil. CEP-26401 induced an improvement of adaptive tracking, saccadic peak velocity and reaction time during N-back, but a dose-related inhibition of sleep and slight worsening of several cognitive parameters at the highest dose. CEP-26401 significantly changed several subjective visual analogue scales, which was strongest at 25 µg, causing the same energizing and happy feeling as modafinil, but with a more relaxed undertone. DISCUSSION: Of the doses tested, the 25 µg dose of CEP-26401 had the most optimal balance between favourable subjective effects and sleep inhibition. Whether CEP-26401 can have beneficial effects in clinical practice remains to be studied.

Identification and human exposure prediction of two aldehyde oxidase-mediated metabolites of a methylquinoline-containing drug candidate.

1. Aldehyde oxidase (AO enzymes)-mediated oxidation predominantly occurs at a carbon atom adjacent to the nitrogen on aromatic azaheterocycles. In the current report, we identified that AO enzymes oxidation took place at both the C-2 and C-4 positions of the methylquinoline moiety of Compound A based on data from mass spectrometric analysis, AO enzymes "litmus" test, and comparison with authentic standards. 2. To assess the potential for inadequate coverage for these two AO enzyme-mediated metabolites in nonclinical safety studies, given concerns due to differences in AO enzymes expression between preclinical species and humans, the human circulating levels of the two AO enzyme-mediated metabolites were predicted prospectively using in vitro and in vivo models. Both formation clearance and elimination clearance of the two metabolites were predicted based on in vitro to in vivo correlation and comparison with in vivo data from rats. 3. The result showed that the 4-OH metabolite of Compound A would account for less than 3% of the total drug-related exposure in human plasma, while the exposure to the 2-oxo metabolite would be relatively high (∼70%). 4. The predicted human exposure levels for the two metabolites are in similar ranges as those observed in monkeys. These data taken together support the advancement to clinical development of Compound A.

Bioequivalence of fluticasone propionate and salmeterol (FS) given by the FS Spiromax® and Seretide Accuhaler® systems
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OBJECTIVE: To determine pharmacokinetic (PK) profiles of fluticasone propionate (FP) and salmeterol (SAL) in healthy volunteers following administration as two inhalations from the FS Spiromax 500/50 µg and Seretide Accuhaler 50/500 µg inhalers, without (study 1, n = 79) and with charcoal block (study 2, n = 77). Safety was also assessed. MATERIALS AND METHODS: In two single-center, open-label, randomized two-period crossover studies, PK parameters were calculated from plasma drug concentrations obtained pre-dose through 36 hours post-dose. Bioequivalence was established if the 90% confidence intervals for the geometric mean ratios of the area under the plasma drug concentration-time curve from time zero to the time of the last quantifiable concentration (AUC0-t) and the maximum observed plasma concentration (Cmax) for the comparison of both FP and SAL were within 0.80 - 1.25. RESULTS: In study 1, in subjects administered FS Spiromax, the mean (standard deviation (SD)) FP AUC0-t and Cmax were 1,622.64 (419.44) pg×h/mL and 151.36 (40.37) pg/mL, respectively, vs. 1,487.52 (341.25) pg×h/mL and 137.57 (33.64) pg/mL with Seretide Accuhaler. Mean (SD) SAL AUC0-t and Cmax with FS Spiromax were 408.42 (155.40) pg×h/mL and 269.48 (105.74) pg/mL, respectively, vs. 401.79 (125.32) pg×h/mL and 265.66 (87.28) pg/mL with Seretide Accuhaler. Comparable data were seen in study 2 with charcoal block. Bioequivalence of FS Spiromax with Seretide Accuhaler was observed both without and with charcoal block for FP and SAL for both AUC0-t and Cmax. Both study treatments were well tolerated, with a similar incidence of adverse events reported with the single use of FS Spiromax (23% study 1, 16% study 2) and Seretide Accuhaler (22%, 15%). CONCLUSION: FS Spiromax 500/50 µg (± charcoal block) was bioequivalent to Seretide Accuhaler 50/500µg.
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Pharmacokinetics and excretion of (14)C-omacetaxine in patients with advanced solid tumors.

Background Omacetaxine mepesuccinate is indicated in adults with chronic myeloid leukemia resistant and/or intolerant to ≥ 2 tyrosine kinase inhibitor treatments. This phase I study assessed the disposition, elimination, and safety of (14)C-omacetaxine in patients with solid tumors. Methods The study comprised a 7-days pharmacokinetic assessment followed by a treatment period of ≤ six 28-days cycles. A single subcutaneous dose of 1.25 mg/m(2) (14)C-omacetaxine was administered to six patients. Blood, urine, and feces were collected through 168 h or until radioactivity excreted within 24 h was <1 % of the dose. Total radioactivity (TRA) was measured in all matrices and concentrations of omacetaxine, 4'-desmethylhomoharringtonine (4'-DMHHT), and cephalotaxine were measured in plasma and urine. For each treatment cycle, patients received 1.25 mg/m(2) omacetaxine twice daily for 7 days. Results Mean TRA recovered was approximately 81 % of the dose, with approximately half of the radioactivity recovered in feces and half in urine. Approximately 20 % of the dose was excreted unchanged in urine; cephalotaxine (0.4 % of dose) and 4' DMHHT (9 %) were also present. Plasma concentrations of TRA were higher than the sum of omacetaxine and known metabolites, suggesting the presence of other (14)C-omacetaxine-derived compounds. Fatigue and anemia were common, consistent with the known toxicity profile of omacetaxine. Conclusion Renal and hepatic processes contribute to the elimination of (14)C-omacetaxine-derived radioactivity in cancer patients. In addition to omacetaxine and its known metabolites, other (14)C-omacetaxine-derived materials appear to be present in plasma and urine. Omacetaxine was adequately tolerated, with no new safety signals.

A Phase I, Open-Label, Single-Dose Safety, Pharmacokinetic, and Tolerability Study of the Sumatriptan Iontophoretic Transdermal System in Adolescent Migraine Patients.

OBJECTIVE: To evaluate the safety, tolerability, and pharmacokinetics of sumatriptan delivered by the iontophoretic transdermal system (TDS) in adolescent patients. BACKGROUND: Since nausea can be a prominent and early symptom of migraine, nonoral treatment options are often required. Sumatriptan iontophoretic TDS is approved for the acute treatment of migraine in adults. The present study evaluates the pharmacokinetics of sumatriptan administered via the iontophoretic TDS in adolescents, contrasting the findings with historical data from adults. DESIGN: Patients aged 12-17 years (inclusive) with acute migraine were treated with sumatriptan iontophoretic TDS for 4 hours. Blood samples for pharmacokinetic profiling of sumatriptan were obtained prior to dosing and at predetermined time points covering the 12 hours postonset of treatment. Key pharmacokinetic endpoints included Cmax (peak plasma drug concentration), tmax (time to Cmax ), AUC0-∞ (area under the plasma concentration-time curve from time 0 to infinity), and t½ (terminal elimination half-life). Safety was evaluated by monitoring of adverse events in addition to laboratory and clinical assessments. RESULTS: The sample consisted of 37 patients, and 36 were included in the PK evaluable population. Cmax , tmax , AUC0-∞ , and t½ values were all similar between male and female patients and between younger (12-14 years) and older (15-17 years) adolescents. When compared with historical adult data, adolescent patients demonstrated similar systemic exposures to those observed in adults (mean Cmax 20.20 (±6.43) ng/mL in adolescents vs 21.89 (±6.15) ng/mL in adults; mean AUC0-∞ 98.1 (±28.1) ng·h/mL in adolescents vs 109.7 (±26.1) ng·h/mL in adults). All adverse events were mild or moderate, with application-site paresthesia being the most common (32%). No clinically relevant changes in laboratory values, vital signs, or electrocardiogram findings were observed. CONCLUSIONS: The iontophoretic TDS produced mean systemic exposures to sumatriptan in younger and older adolescents, in line with what was seen in adult subjects. It was generally well tolerated.

Metabolite profiling of 14C-omacetaxine mepesuccinate in plasma and excreta of cancer patients.

Omacetaxine mepesuccinate (hereafter referred to as omacetaxine) is a protein translation inhibitor approved by the US Food and Drug Administration for adult patients with chronic myeloid leukemia with resistance and/or intolerance to two or more tyrosine kinase inhibitors. The objective was to investigate the metabolite profile of omacetaxine in plasma, urine and faeces samples collected up to 72 h after a single 1.25-mg/m2 subcutaneous dose of 14C-omacetaxine in cancer patients. High-performance liquid chromatography mass spectrometry (MS) (high resolution) in combination with off-line radioactivity detection was used for metabolite identification. In total, six metabolites of omacetaxine were detected. The reactions represented were mepesuccinate ester hydrolysis, methyl ester hydrolysis, pyrocatechol conversion from the 1,3-dioxole ring. Unchanged omacetaxine was the most prominent omacetaxine-related compound in plasma. In urine, unchanged omacetaxine was also dominant, together with 4'-DMHHT. In feces very little unchanged omacetaxine was found and the pyrocatechol metabolite of omacetaxine, M534 and 4'-desmethyl homoharringtonine (4'-DMHHT) was the most abundant metabolites. Omacetaxine was extensively metabolized, with subsequent renal and hepatic elimination of the metabolites. The low levels of the metabolites found in plasma indicate that the metabolites are unlikely to contribute materially to the efficacy and/or toxicity of omacetaxine.

Dose-ranging study of salmeterol using a novel fluticasone propionate/salmeterol multidose dry powder inhaler in patients with persistent asthma.

BACKGROUND: New inhalation devices with improved lung delivery may allow the use of lower salmeterol doses for treatment of asthma. OBJECTIVE: To determine the dose of salmeterol administered from a novel fluticasone propionate/salmeterol (FS) inhalation-driven, multidose dry powder inhaler (MDPI), which provides comparable efficacy and safety to FS dry powder inhaler (DPI). METHODS: This double-blind, six-period crossover, dose-ranging study randomized 72 patients (ages ≥12 years; with persistent asthma and predose maximum forced expiratory volume in 1 second [FEV1] of 40-85% of the predicted normal) to treatment sequences (one dose per treatment), which consisted of FS MDPI 100/6.25, 100/12.5, 100/25, 100/50 µg; fluticasone propionate (Fp) MDPI 100 µg; and open-label FS DPI 100/50 µg. The primary efficacy variable was the baseline-adjusted FEV1 area under the curve over 12 hours after the dose (AUC0-12). Pharmacokinetics and tolerability were also assessed. RESULTS: FEV1 AUC0-12 was significantly higher with all FS MDPI doses and FS DPI versus Fp MDPI (p < 0.0001), and with FS MDPI 100/50 µg versus FS DPI (least squares [LS] mean, 57.88 mL; p = 0.0017). FEV1 AUC0-12 trended toward higher efficacy with FS MDPI 100/25 µg (LS mean, 34.14 mL; p = 0.0624) and was comparable with FS MDPI 100/12.5 µg (LS mean, 3.42 mL; p = 0.8503) versus FS DPI. Salmeterol area under the plasma concentration-versus-time curve from time 0 to the time of the last measurable concentration (AUC0-t) for FS MDPI 100/12.5 µg and 100/25 µg was lower versus FS DPI 100/50 µg; AUC0-t for FS MDPI 100/50 µg was higher than FS DPI 100/50 µg. All FS MDPI doses were generally well tolerated. CONCLUSION: All FS MDPI doses produced greater efficacy versus Fp MDPI. FS MDPI 100/12.5 µg demonstrated similar efficacy to FS DPI 100/50 µg with less salmeterol exposure. Clinicaltrials.gov NCT02139644, NCT02175771, and NCT02141854.

Metabolite profiling of bendamustine in urine of cancer patients after administration of [14C]bendamustine.

Bendamustine is an alkylating agent consisting of a mechlorethamine derivative, a benzimidazole group, and a butyric acid substituent. A human mass balance study showed that bendamustine is extensively metabolized and subsequently excreted in urine. However, limited information is available on the metabolite profile of bendamustine in human urine. The objective of this study was to elucidate the metabolic pathways of bendamustine in humans by identification of its metabolites excreted in urine. Human urine samples were collected up to 168 h after an intravenous infusion of 120 mg/m(2) (80-95 µCi) [(14)C]bendamustine. Metabolites of [(14)C]bendamustine were identified using liquid chromatography (high-resolution)-tandem mass spectrometry with off-line radioactivity detection. Bendamustine and a total of 25 bendamustine-related compounds were detected. Observed metabolic conversions at the benzimidazole and butyric acid moiety were N-demethylation and γ-hydroxylation. In addition, various other combinations of these conversions with modifications at the mechlorethamine moiety were observed, including hydrolysis (the primary metabolic pathway), cysteine conjugation, and subsequent biotransformation to mercapturic acid and thiol derivatives, N-dealkylation, oxidation, and conjugation with phosphate, creatinine, and uric acid. Bendamustine-derived products containing phosphate, creatinine, and uric acid conjugates were also detected in control urine incubated with bendamustine. Metabolites that were excreted up to 168 h after the infusion included products of dihydrolysis and cysteine conjugation of bendamustine and γ-hydroxybendamustine. The range of metabolic reactions is generally consistent with those reported for rat urine and bile, suggesting that the overall processes involved in metabolic elimination are qualitatively the same in rats and humans.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the MK2 Inhibitor ATI-450 in Healthy Subjects: A Placebo-Controlled, Randomized Phase 1 Study.

PURPOSE: ATI-450 is an oral, small-molecule inhibitor of the p38α mitogen-activated protein kinase (MAPK)/MAPK-activated protein kinase 2 (MK2) inflammatory signaling pathway. This phase 1, single and multiple ascending dose (SAD, MAD) study evaluated ATI-450 safety, tolerability, pharmacokinetics, and pharmacodynamics. PATIENTS AND METHODS: Healthy adults were randomly assigned to SAD (10, 30, 50, 100 mg; n=24) and MAD (10, 30, 50 mg twice daily [BID] for 7 days; n=24) cohorts of ATI-450 or placebo (n=14). Safety and tolerability were evaluated through clinical and laboratory assessments. Pharmacokinetic parameters were evaluated in plasma samples; pharmacodynamic assessments included quantification of cytokine levels (tumor necrosis factor α [TNF-α], interleukin [IL]-1ß, IL-6, IL-8) and phosphorylation of the MK2 downstream substrate, heat shock protein 27 (p-HSP27). RESULTS: The most common adverse events were headache (10/48, 20.8%), dizziness (6/48, 12.5%), upper respiratory tract infection (3/48, 6.3%), and constipation (3/48, 6.3%). Pharmacokinetics were dose-proportional, with a terminal half-life of 9‒12 hours in the MAD cohorts on day 7. Dose- and concentration-dependent inhibition of ex vivo stimulated cytokines and target biomarker was observed. On day 7, patients in the 50 mg BID dose cohort recorded mean trough drug levels that were 1.4, 2.2, 2.3, and 2.4 times greater than the IC80 for TNF-α, IL-1ß, IL-8, and p-HSP27, respectively. Mean Cmax was 3.5, 5.4, 5.6, and 6.0 times greater than the IC80 for TNF-α, IL-1ß, IL-8, and p-HSP27, respectively. IL-6 inhibition >50% was noted for part of the dosing interval. CONCLUSION: ATI-450 was well tolerated at the doses investigated, exhibited dose- and time-independent (ie, linear) pharmacokinetics, and dose-related pharmacodynamic effects. These results support further study of ATI-450 in immunoinflammatory diseases in phase 2 trials.

Pharmacokinetics of Deutetrabenazine and Tetrabenazine: Dose Proportionality and Food Effect.

Deutetrabenazine (Austedo, Teva), an approved treatment of chorea in Huntington's disease and tardive dyskinesia in adult patients, is a rationally designed deuterated form of tetrabenazine. Two studies assessed the pharmacokinetics and safety of deutetrabenazine compared with tetrabenazine, and the effects of food on absorption of the deuterated active metabolites, α-dihydrotetrabenazine (α-HTBZ) and ß-dihydrotetrabenazine (ß-HTBZ). One study was an open-label 2-part study in healthy volunteers; the first part included a crossover single dose of two 15 mg candidate deutetrabenazine formulations in fed and fasted states compared with tetrabenazine 25 mg in the fasted state, and the second part included single and repeated dosing of the commercial formulation of deutetrabenazine (7.5, 15, and 22.5 mg) compared with tetrabenazine 25 mg. The second study was an open-label 5-way crossover study in healthy volunteers (n = 32) to evaluate relative bioavailability of 4 dose levels of the commercial formulation of deutetrabenazine (6, 12, 18, and 24 mg) with a standard meal and 18 mg with a high-fat meal. Both studies confirmed longer half-lives for active metabolites and lower peak-to-trough fluctuations for the sum of the metabolites (total [α+ß]-HTBZ) following deutetrabenazine compared with tetrabenazine (3- to 4-fold and 11-fold, respectively) in steady-state conditions. Deutetrabenazine doses estimated to provide total (α+ß)-HTBZ exposure comparable to tetrabenazine 25 mg were 11.4-13.2 mg. Food had no effect on exposure to total (α+ß)-HTBZ, as measured by AUC. Although the total (α+ß)-HTBZ Cmax of deutetrabenazine was increased by ≈50% in the presence of food, it remained lower than that of tetrabenazine.

Bendamustine treatment of Chinese patients with relapsed indolent non-Hodgkin lymphoma: a multicenter, open-label, single-arm, phase 3 study.

BACKGROUND: Bendamustine was approved in China on May 26th, 2019 by the National Medical Product Administration for the treatment of indolent B-cell non-Hodgkin lymphoma (NHL). The current study was the registration trial and the first reported evaluation of the efficacy, safety, and pharmacokinetics of bendamustine in Chinese adult patients with indolent B-cell NHL following relapse after chemotherapy and rituximab treatment. METHODS: This was a prospective, multicenter, open-label, single-arm, phase 3 study (NCT01596621; C18083/3076) with a 2-year follow-up period. Eligible patients received bendamustine hydrochloride 120 mg/m2 infused intravenously on days 1 and 2 of each 21-day treatment cycle for at least six planned cycles (and up to eight cycles). The primary endpoint was the overall response rate (ORR); and secondary endpoints were duration of response (DoR), progression-free survival (PFS), safety, and pharmacokinetics. Patients were classified according to their best overall response after initiation of therapy. Proportions of patients in each response category (complete response [CR], partial response [PR], stable disease, or progressive disease) were summarized along with a two-sided binomial exact 95% confidence intervals (CIs) for the ORR. RESULTS: A total of 102 patients were enrolled from 20 centers between August 6th, 2012, and June 18th, 2015. At the time of the primary analysis, the ORR was 73% (95% CI: 63%-81%) per Independent Review Committee (IRC) including 19% CR and 54% PR. With the follow-up period, the median DoR was 16.2 months by IRC and 13.4 months by investigator assessment; the median PFS was 18.6 months and 15.3 months, respectively. The most common non-hematologic adverse events (AEs) were gastrointestinal toxicity, pyrexia, and rash. Grade 3/4 neutropenia was reported in 76% of patients. Serious AEs were reported in 29 patients and five patients died during the study. Pharmacokinetic analysis indicated that the characteristics of bendamustine and its metabolites M3 and M4 were generally consistent with those reported for other ethnicities. CONCLUSION: Bendamustine is an active and effective therapy in Chinese patients with relapsed, indolent B-cell NHL, with a comparable risk/benefit relationship to that reported in North American patients. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, No. NCT01596621; https://clinicaltrials.gov/ct2/show/NCT01596621.

Pharmacokinetic and Metabolic Profile of Deutetrabenazine (TEV-50717) Compared With Tetrabenazine in Healthy Volunteers.

Deutetrabenazine (Austedo, Teva Pharmaceuticals) is a deuterated form of tetrabenazine. It is the first deuterated drug to receive US regulatory approval and is approved for treatment of chorea in Huntington's disease and tardive dyskinesia. Two oral single dose studies comparing deutetrabenazine (25 mg) with tetrabenazine (25 mg) in healthy volunteers evaluated the impact of deuteration on pharmacokinetics of the active metabolites, alpha-dihydrotetrabenazine (α-HTBZ) and beta-dihydrotetrabenazine (ß-HTBZ), metabolite profile, safety, and tolerability. In the two-way, cross-over study, the mean elimination half-life of deuterated total (α + ß)-HTBZ was doubled compared with nondeuterated total (α + ß)-HTBZ, with a twofold increase in overall mean exposure (area under the concentration-time curve from zero to infinity (AUC0-inf )) and a marginal increase in mean peak plasma concentration (Cmax ). In the mass balance and metabolite profiling study, there were no novel plasma or urinary metabolites of [14 C]-deutetrabenazine relative to [14 C]-tetrabenazine. Specific deuteration in deutetrabenazine resulted in a superior pharmacokinetic profile and an increased ratio of active-to-inactive metabolites, attributes considered to provide significant benefits to patients.

A pharmacokinetic comparison of single doses of once-daily cyclobenzaprine extended-release 15 mg and 30 mg: a randomized, double-blind, two-period crossover study in healthy volunteers.

OBJECTIVE: The purpose of this study was to compare the pharmacokinetics and tolerability of single oral doses of cyclobenzaprine extended-release (CER) 15- and 30-mg capsules. METHODS: This was a randomized, double-blind, 2-period crossover study in healthy adults aged 18 to 40 years. Subjects were assigned to receive a single dose of either CER 15 mg or 30 mg on days 1 and 15, separated by a 14-day washout. Study comparisons included the plasma cyclobenzaprine AUC to 168 hours after dosing (AUC(0-168)), AUC(0-infinity), and C(max). Plasma cyclobenzaprine T(max), terminal elimination t(1/2), and adverse events (AEs) were also assessed. RESULTS: Sixteen subjects (9 women, 7 men) were randomized to receive cyclobenzaprine 15 mg or 30 mg; 13 (81.3%) were white and 3 (18.8%) were black. Mean age and weight were 30.2 years and 70.7 kg, respectively. The shapes of the pharmacokinetic profiles for CER 15 and 30 mg were parallel. Mean observed values for dose-dependent pharmacokinetic parameters of CER 15 and 30 mg were as follows: AUC(0-168), 318.3 and 736.6 ng . h/mL, respectively; AUC(0-infinity)), 354.1 and 779.9 ng . h/mL; and C(max), 8.3 and 19.9 ng/mL. Dose-independent parameters were comparable across doses. Median observed Tmax was 6.0 hours for both CER doses; mean t(1/2) was 33.4 hours for CER 15 mg and 32.0 hours for CER 30 mg. The bioavailability of the 2 doses, as indicated by the least squares mean AUC(0-infinity), was 330.3 ng . h/mL for CER 15 mg and 755.1 ng . h/mL for CER 30 mg. During the CER 15-mg treatment sequence, 5 subjects experienced 5 AEs (headache, dizziness, musculoskeletal pain, dermatitis, and glossodynia); during the CER 30-mg treatment sequence, 2 subjects experienced 2 AEs (somnolence and dysmenorrhea). All AEs were mild in intensity. No serious AEs occurred during the study. CONCLUSIONS: Once-daily CER 15 and 30 mg exhibited similarly shaped pharmacokinetic profiles. AUC(0-168), AUC(0-infinity)), and C(max) values for the 30-mg dose were approximately double those for the 15-mg dose, a result consistent with previously reported data on the dose proportionality of cyclobenzaprine immediate release.

Comparison of steady-state plasma concentrations of armodafinil and modafinil late in the day following morning administration: post hoc analysis of two randomized, double-blind, placebo-controlled, multiple-dose studies in healthy male subjects.

BACKGROUND AND OBJECTIVE: Armodafinil, the R- and longer-lasting isomer of modafinil, may maintain higher plasma drug concentrations compared with racemic modafinil because of stereospecific differences in elimination of its isomers. This analysis set out to compare the steady-state pharmacokinetic profiles of armodafinil and modafinil on a milligram-to-milligram basis following once-daily administration. METHODS: A post hoc analysis of two multiple-dose pharmacokinetic studies in healthy male subjects aged 18-50 years was conducted to compare dose-normalized (200 mg/day) plasma drug concentration and pharmacokinetic data for subjects in each study who completed 7 days of once-daily (morning) administration of armodafinil (n = 34) or modafinil (n = 18). RESULTS: Dose-normalized plasma concentrations of armodafinil on day 7 were higher than those of modafinil, with the greatest differences being observed later in the day. Across the 24-hour dose interval, plasma drug concentration fluctuation and swing were 28% and 42% less, respectively, with armodafinil than with modafinil. In addition, average late-day (3 pm to 7 pm after an 8 am dosing) plasma drug concentrations and partial values for the area under the plasma concentration versus time curve for 7-11 hours after dosing were both 44% higher with armodafinil. CONCLUSIONS: At steady state, armodafinil produces consistently higher plasma drug concentrations late in the day than modafinil when compared on a milligram-to-milligram basis. The distinct pharmacokinetic profile of armodafinil compared with that of the racemate may result in fundamentally different durations of action. These differences between the two medications cannot be made equivalent by increasing the dose of the racemate without introducing potential safety concerns.

Armodafinil and modafinil have substantially different pharmacokinetic profiles despite having the same terminal half-lives: analysis of data from three randomized, single-dose, pharmacokinetic studies.

BACKGROUND AND OBJECTIVE: Armodafinil, a non-amphetamine, wakefulness-promoting medication, is the R- and longer-lasting isomer of racemic modafinil. Armodafinil has been shown to improve wakefulness in patients with excessive sleepiness (ES) associated with treated obstructive sleep apnoea, shift work disorder or narcolepsy. In comparison with modafinil, armodafinil maintains higher plasma concentrations later in the day in healthy subjects. The objective of this analysis was to characterize the pharmacokinetic parameters related to those higher concentrations. METHODS: Data from three randomized studies in healthy adult subjects receiving single doses of either armodafinil (50, 100, 200, 250, 300 or 400 mg) or modafinil (400 mg) were pooled, and subsequently dose-normalized to a 200 mg dose for each drug. Non-compartmental pharmacokinetic parameters were assessed. RESULTS: Armodafinil and modafinil both had a mean single-dose terminal elimination half-life of approximately 13 hours, with similar mean maximum plasma drug concentration (C(max)) and median time to C(max) values. After reaching C(max), plasma concentrations appeared to decline in a monophasic manner with armodafinil, but in a biphasic manner with modafinil due to the initial rapid elimination of its S-isomer. As a result, mean area under the plasma drug concentration versus time curve (AUC) from time zero to the time of the last measurable concentration (AUC(last)) and AUC from time zero to infinity (AUC(infinity)) values were 33% and 40% higher, respectively, with armodafinil compared with modafinil on a milligram-to-milligram basis. CONCLUSIONS: Despite similar half-lives, plasma concentrations following armodafinil administration are higher late in the day than those following modafinil administration on a milligram-to-milligram basis. The different pharmacokinetic profile of armodafinil may result in improved wakefulness throughout the day in patients with ES compared with modafinil.

Pharmacokinetic profile of armodafinil in healthy subjects: pooled analysis of data from three randomized studies.

BACKGROUND AND OBJECTIVES: Armodafinil (R-modafinil) is the R- and longer-lasting isomer of the racemic compound modafinil, a wakefulness-promoting medication. Armodafinil is eliminated approximately three times more slowly than the S-isomer of racemic modafinil. Published studies have demonstrated the efficacy of armodafinil for treating excessive sleepiness associated with obstructive sleep apnoea, shift work disorder and narcolepsy. The objectives of this study were to describe the pharmacokinetic profile, tolerability and safety of armodafinil in healthy subjects. METHODS: Pooled pharmacokinetic data from three separate randomized studies in 119 healthy subjects who received single or multiple (once daily for up to 14 days) oral doses of armodafinil ranging between 50 and 400 mg were analysed. The impact of food on the single-dose pharmacokinetic profile of armodafinil was also assessed in subjects following an overnight fast and after the consumption of a standard fatty meal. RESULTS: Armodafinil was readily absorbed and exhibited linear pharmacokinetics over the 50-400 mg dose range. Peak plasma concentrations were reached around 2 hours after administration in the fasted state. Food had no effect on the overall bioavailability of armodafinil; however, the peak concentration was delayed by approximately 2-4 hours. In the multiple-dose study, dose proportionality was confirmed by linear regression analyses of the log-transformed area under the plasma concentration versus time curve (AUC) and maximum plasma concentration (Cmax) values as a function of dose. After reaching the peak, plasma concentrations of armodafinil declined in a monophasic manner, with a mean elimination half-life of approximately 15 hours. Steady state appeared to be reached within 7 days. At steady state, the systemic exposure to armodafinil was 1.8 times that observed after single-dose administration. Armodafinil was generally well tolerated, the most frequent adverse events being headache, dizziness and nausea. CONCLUSIONS: In the present analysis, armodafinil exhibited linear pharmacokinetics over the dose range of 50-400 mg. While food affected the rate but not the extent of absorption, peak plasma concentrations were reached in approximately 2 hours when the drug was taken on an empty stomach. With once-daily dosing, steady state appeared to be reached within 7 days. After reaching peak plasma levels, concentrations of armodafinil declined monophasically, with a mean elimination half-life of around 15 hours. Armodafinil was generally well tolerated.

Interaction profile of armodafinil with medications metabolized by cytochrome P450 enzymes 1A2, 3A4 and 2C19 in healthy subjects.

BACKGROUND AND OBJECTIVE: Armodafinil, a wakefulness-promoting agent, is the pure R-enantiomer of racemic modafinil. The objective of this article is to summarize the results of three clinical drug-interaction studies assessing the potential for drug interactions of armodafinil with agents metabolized by cytochrome P450 (CYP) enzymes 1A2, 3A4 and 2C19. Study 1 evaluated the potential for armodafinil to induce the activity of CYP1A2 using oral caffeine as the probe substrate. Study 2 evaluated the potential for armodafinil to induce gastrointestinal and hepatic CYP3A4 activity using intravenous and oral midazolam as the probe substrate. Study 3 evaluated the potential for armodafinil to inhibit the activity of CYP2C19 using oral omeprazole as the probe substrate. METHODS: Healthy men and nonpregnant women aged 18-45 years with a body mass index of

Single-dose pharmacokinetics of once-daily cyclobenzaprine extended release 30 mg versus cyclobenzaprine immediate release 10 mg three times daily in healthy young adults : a randomized, open-label, two-period crossover, single-centre study.

BACKGROUND AND OBJECTIVE: Cyclobenzaprine immediate release (CIR) has shown efficacy in the treatment of muscle spasm associated with acute, painful musculoskeletal conditions. An extended-release formulation of cyclobenzaprine (CER) has been developed to provide effective muscle spasm relief with once-daily dosing. The objective of this study was to compare the pharmacokinetics of CER and CIR. METHODS: This was a single-centre study of 18 healthy young adults (aged 18-45 years). Healthy volunteers were assigned to receive either a single dose of CER 30 mg or three doses of CIR 10 mg on days 1 and 15 (separated by a 14-day washout) in an open-label, two-period crossover study. Pharmacokinetic parameters were monitored through 168 hours after the last dose in each dose period; adverse events (AEs) were monitored during the study through 3 weeks after the last dose of study drug. Cyclobenzaprine was administered as a single oral 30 mg dose of CER or three 10 mg oral doses of CIR given every 8 hours over 24 hours. Statistical tests were conducted against a two-sided alternative hypothesis at a 0.05 level of significance with equivalence limits of 80% and 125%. Measures included area under the plasma cyclobenzaprine concentration versus time curve (AUC) to 168 hours and infinity, maximum plasma cyclobenzaprine concentration (C(max)), and time to observed C(max) (t(max)). RESULTS: Eighteen subjects were randomized and 17 completed both periods of the study. CER exhibited a consistent concentration-time profile with a single peak, in contrast to the pharmacokinetic profile for CIR, which displayed multiple peaks and troughs over the 24-hour period. The pharmacokinetic profile of CER 30 mg was characterized by an absorption phase with a median t(max) of approximately 6 hours, compared with the initial peak of CIR (following the first dose) of about 4 hours. Mean plasma concentrations at 4 hours were comparable (12.1 ng/mL for CER; 12.4 ng/mL for CIR). Systemic cyclobenzaprine exposure (AUC and C(max)) was similar across both formulations. The C(max) for CER 30 mg was 19.2 ng/mL (median t(max) = 6 hours) and for CIR (following the third dose) was 18.1 ng/mL (median t(max) = 12 hours). All AEs were mild in intensity; the most common AE was somnolence. CONCLUSION: The pharmacokinetic profile of once-daily CER reflected the mode of administration, providing a controlled release of cyclobenzaprine with sustained plasma concentrations, in contrast to the fluctuating profile of CIR. CER 30 mg once daily and CIR 10 mg three times daily resulted in comparable systemic exposures.

Single-dose and steady-state pharmacokinetics of fentanyl buccal tablet in healthy volunteers.

This study evaluated the single-dose and steady-state pharmacokinetics of fentanyl buccal tablet 400 microg in healthy adult volunteers. After receiving naltrexone 50 mg to block opioid receptor-mediated effects of fentanyl, subjects received fentanyl buccal tablet 400 microg on day 1, then every 6 hours from day 4 to day 9 (21 doses). Naltrexone 50 mg was administered every 12 hours throughout the study. Plasma fentanyl concentrations were determined for 72 hours after administration of fentanyl buccal tablet 400 microg on day 1 and the last dose of fentanyl buccal tablet 400 microg on day 9. Following single- and multiple-dose administration of fentanyl buccal tablet, the median time to maximum concentration (tmax) was 52.2 and 49.8 minutes, respectively. Peak plasma concentration of fentanyl (Cmax) was 0.88 ng/mL for the single-dose regimen and 1.77 ng/mL for the multiple-dose regimen. Steady state was reached within 5 days, consistent with the observed median half-life of approximately 22 hours following multiple doses. Observed accumulation of fentanyl after multiple doses of fentanyl buccal tablet was slightly greater than would be expected based on the single-dose data. This was attributed to the redistribution of fentanyl from a deep tissue compartment into the plasma. This study indicates that fentanyl buccal tablet has predictable pharmacokinetics following multiple-dose administration.

Pharmacokinetics and Safety of Single-Dose Inhaled Loxapine in Children and Adolescents.

This multisite open-label study sought to characterize the pharmacokinetics and safety of a single dose of inhaled loxapine in children and adolescents. Loxapine powder for oral inhalation was administered via a single-use handheld drug device to children and adolescents (aged 10-17 years) with any condition warranting chronic antipsychotic use. Patients were dosed according to body weight and cohort (<50 kg [n = 15], 2.5 or 5 mg; ≥50 kg [n = 15], 5 or 10 mg); the first 6 patients (cohort 1) enrolled in each weight group received the lower dose. Patients were enrolled in the higher-dose group (cohort 2) after an interim pharmacokinetic and safety analysis of data from cohort 1. Blood samples were collected for 48 hours after dosing to determine the pharmacokinetic profile of loxapine and its metabolites. Safety was assessed using adverse event (AE), laboratory value, physical/neurologic examination, vital sign, electrocardiogram, suicidality, and extrapyramidal symptom assessment. Thirty patients were enrolled and evaluable for pharmacokinetics. Loxapine plasma concentrations peaked by 2 to 5 minutes in most patients; systemic exposure increased with dose in both weight subgroups. Loxapine terminal elimination half-life was ∼13 to 17 hours. The most common AEs were sedation and dysgeusia. Sedation was severe in 1 patient in the <50-kg group (2.5-mg dose) and 1 patient in the ≥50-kg group (5-mg dose). No AEs indicative of bronchospasm or other serious AEs were reported. Inhaled loxapine was rapidly absorbed and generally well tolerated in pediatric patients; no new safety signals were observed.