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.

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.

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.

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.

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 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.

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.

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.

Pharmacokinetics, pharmacodynamics and safety of CEP-26401, a high-affinity histamine-3 receptor antagonist, following single and multiple dosing in healthy subjects.

CEP-26401 is a novel orally active, brain-penetrant, high-affinity histamine H3 receptor (H3R) antagonist, with potential therapeutic utility in cognition enhancement. Two randomized, double-blind, placebo-controlled dose escalation studies with single (0.02 to 5 mg) or multiple administration (0.02 to 0.5 mg once daily) of CEP-26401 were conducted in healthy subjects. Plasma and urine samples were collected to investigate CEP-26401 pharmacokinetics. Pharmacodynamic endpoints included a subset of tasks from the Cambridge Neuropsychological Test Automated Battery (CANTAB) and nocturnal polysomnography. Population pharmacokinetic-pharmacodynamic modeling was conducted on one CANTAB and one polysomnography parameter of interest. CEP-26401 was slowly absorbed (median tmax range 3-6 hours) and the mean terminal elimination half-life ranged from 24-60 hours. Steady-state plasma concentrations were achieved within six days of dosing. CEP-26401 exhibits dose- and time-independent pharmacokinetics, and renal excretion is a major elimination pathway. CEP-26401 had a dose-dependent negative effect on sleep, with some positive effects on certain CANTAB cognitive parameters seen at lower concentrations. The derived three compartment population pharmacokinetic model, with first-order absorption and elimination, accurately described the available pharmacokinetic data. CEP-26401 was generally well tolerated up to 0.5 mg/day with most common treatment related adverse events being headache and insomnia. Further clinical studies are required to establish the potential of low-dose CEP-26401 in cognition enhancement.

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.

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.

Evaluation of potential pharmacokinetic drug-drug interaction between armodafinil and risperidone in healthy adults.

BACKGROUND AND OBJECTIVE: Patients with bipolar I disorder and schizophrenia have an increased risk of obstructive sleep apnea. The effects of armodafinil, a weak cytochrome P450 (CYP) 3A4 inducer, on pharmacokinetics and safety of risperidone, an atypical antipsychotic used to treat major psychiatric illness, were investigated. METHODS: Healthy subjects received 2 mg risperidone alone and after armodafinil pretreatment (titrated to 250 mg/day). Pharmacokinetic parameters were derived from plasma concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone (formed via CYP2D6 and CYP3A4), collected before and over 4 days after risperidone administration, and from steady-state plasma concentrations of armodafinil and its circulating metabolites, R-modafinil acid and modafinil sulfone. Safety and tolerability were assessed. RESULTS: Thirty-six subjects receiving study drug were evaluable for safety; 34 were evaluable for pharmacokinetics. Risperidone maximum plasma concentration (C max) decreased from mean 16.5 ng/mL when given alone to 9.2 ng/mL after armodafinil pretreatment (geometric mean ratio [90 % CI] 0.55 [0.50-0.61]); area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) decreased from 92.3 to 44.5 ng·h/mL (geometric mean ratio [90 % CI] 0.51 [0.46-0.55]). C max and AUC0-∞ for 9-hydroxyrisperidone were also reduced (geometric mean ratios [90 % CI] 0.81 [0.77-0.85] and 0.73 [0.69-0.77], respectively). Adverse events were consistent with known safety profiles. CONCLUSION: Consistent with CYP3A4 induction, risperidone and 9-hydroxyrisperidone systemic exposure was reduced in the presence of armodafinil. Concomitant armodafinil and risperidone use may necessitate risperidone dosage adjustment, particularly when starting or stopping coadministration of the two drugs. However, any such decision should be based on patient disease state and clinical status.

Pharmacokinetic and pharmacodynamic profile of bendamustine and its metabolites.

PURPOSE: Bendamustine is a unique alkylating agent indicated for the treatment of chronic lymphocytic leukemia and rituximab-refractory, indolent B cell non-Hodgkin's lymphoma. Despite the extensive experience with bendamustine, its pharmacokinetic profile has only recently been described. This overview summarizes the pharmacokinetics, pharmacokinetic/pharmacodynamic relationships, and drug-drug interactions of bendamustine in adult and pediatric patients with hematologic malignancies. METHODS: A literature search and data on file (including a human mass balance study, pharmacokinetic population analyses in adult and pediatric patients, and modeling analyses) were evaluated for inclusion. RESULTS: Bendamustine concentrations peak at end of intravenous infusion (~1 h). Subsequent elimination is triphasic, with the intermediate t 1/2 (~40 min) as the effective t 1/2 since the final phase represents <1 % of the area under the curve. Bendamustine is rapidly hydrolyzed to monohydroxy-bendamustine and dihydroxy-bendamustine, which have little or no activity. Cytochrome P450 (CYP) 1A2 oxidation yields the active metabolites γ-hydroxybendamustine and N-desmethyl-bendamustine, at low concentrations, which contribute minimally to cytotoxicity. Minor involvement of CYP1A2 in bendamustine elimination suggests a low likelihood of drug-drug interactions with CYP1A2 inhibitors. Systemic exposure to bendamustine 120 mg/m(2) is comparable between adult and pediatric patients; age, race, and sex have been shown to have no significant effect on systemic exposure in either population. The effect of hepatic/renal impairment on bendamustine pharmacokinetics remains to be elucidated. Higher bendamustine concentrations may be associated with increased probability of nausea or infection. No clear exposure-efficacy response relationship has been observed. CONCLUSIONS: Altogether, the findings support dosing based on body surface area for most patient populations.

Evaluation of the potential for pharmacokinetic drug-drug interaction between armodafinil and carbamazepine in healthy adults.

PURPOSE: Polypharmacy is common in psychiatry practice and can lead to an increased risk of drug interactions. Armodafinil, a wakefulness-promoting agent, has been studied as adjunctive therapy for the treatment of major depressive episodes associated with bipolar I disorder. Armodafinil and the mood stabilizer carbamazepine are both inducers of and substrates for cytochrome P450 (CYP3A4). This study was designed to evaluate the bidirectional carbamazepine-armodafinil pharmacokinetic drug-drug interaction. METHODS: This was an open-label, single-center study conducted in healthy adult men. Subjects assigned to group 1 received a dose of carbamazepine (200 mg) alone and a dose after pretreatment with daily dosing of armodafinil (titrated to 250 mg/d). Subjects assigned to group 2 received a dose of armodafinil (250 mg) alone and a dose after pretreatment with carbamazepine BID (titrated to 400 mg/d). Pharmacokinetic parameters for carbamazepine, armodafinil, and their major circulating metabolites were determined when dosed alone and after pretreatment with the other drug. The safety and tolerability of armodafinil and carbamazepine were also assessed throughout the study. FINDINGS: Eighty-one subjects enrolled in the study (group 1 = 40; group 2 = 41), of whom 79 (group 1 = 40; group 2 = 39) were evaluable for pharmacokinetic analysis and 80 (group 1 = 40; group 2 = 40) were evaluable for safety analysis. In group 1, pretreatment with armodafinil reduced systemic exposure to carbamazepine by 12% for Cmax and 25% for AUC (based on comparison of geometric means). Similarly, in group 2, pretreatment with carbamazepine reduced systemic exposure to armodafinil by 11% for Cmax and 37% for AUC. Systemic exposure to the metabolites of these agents that are formed via CYP3A4 were increased after pretreatment in each group. There were no new or unexpected adverse events. IMPLICATIONS: Systemic exposure to both carbamazepine and armodafinil was reduced after pretreatment with the other drug; systemic exposure to the metabolites of each drug, which are formed via CYP3A4, was increased. These changes were consistent with the induction of CYP3A4. Both drugs were generally safe and well tolerated alone and in combination under the conditions studied. Dose adjustment may be required when initiating or discontinuing armodafinil and carbamazepine cotherapy.

Population pharmacokinetics and pharmacokinetics/pharmacodynamics of bendamustine in pediatric patients with relapsed/refractory acute leukemia.

OBJECTIVE: The pharmacokinetic (PK) profile of bendamustine has been characterized in adults with indolent non-Hodgkin lymphoma (NHL), but remains to be elucidated in pediatric patients with hematologic malignancies. This analysis used data from a nonrandomized pediatric study in patients with relapsed/refractory acute lymphocytic leukemia or acute myeloid leukemia. METHODS: Bendamustine 90 or 120 mg/m(2) (60-minute infusion) was administered on days 1 and 2 of 21 day cycles. The population PK base model was adjusted for body surface area (BSA), and the appropriateness of the final model was evaluated by visual predictive check. A covariate analysis explored PK variability. Bayesian PK parameter estimates and concentration-time profiles for each patient were generated. Bendamustine PK in pediatric patients was compared with that of adults with indolent NHL. PK/pharmacodynamic analyses were conducted for fatigue, nausea, vomiting, and infection. RESULTS: Thirty-eight patients (median age: 7 years; range: 1-19 years) receiving bendamustine 120 mg/m(2) and an additional five patients receiving bendamustine 90 mg/m(2) (median age: 12 years; range: 8-14 years) were included in the population PK analysis. Peak plasma concentrations of bendamustine (Cmax) occurred at the end of infusion (about 1 h). Decline from peak showed a rapid distribution phase (t½α = 0.308 h) and a slower elimination phase (t½ß = 1.47 h). Model-predicted mean Cmax and area under the curve values from time 0-24 h were 6806 ng/mL and 8240 ng*h/mL, respectively. When dosed based upon BSA, it appeared that age, body weight, race, mild renal (n = 3) or hepatic (n = 2) dysfunction, cancer type, and cytochrome P450 1A2 inhibitors (n = 17) or inducers (n = 3) did not affect systemic exposure, which was comparable between pediatric and adult patients. Infection was the only adverse event associated with bendamustine Cmax. However, due to the small sample size for some subgroups, the observed trends should be interpreted with caution. CONCLUSIONS: At the recommended dose (120 mg/m(2)), bendamustine systemic exposure was similar across the pediatric population and comparable to adults. The similarity in exposure despite the large range of BSA across pediatric and adult populations confirms the appropriateness of BSA-based dosing, which was utilized to attain systemic exposures in pediatric patients reflective of the therapeutic range in adults. Probability of occurrence of infection increased with higher bendamustine Cmax.

Evaluation of the potential for a pharmacokinetic drug-drug interaction between armodafinil and ziprasidone in healthy adults.

BACKGROUND: Armodafinil has been studied as adjunctive therapy for major depressive episodes associated with bipolar I disorder. This open-label, single-centre, 2-period study evaluated the effect of armodafinil, a moderate inducer of cytochrome-P450 (CYP) isoenzyme CYP3A4, on the pharmacokinetics and safety of ziprasidone, an atypical antipsychotic used to treat bipolar I disorder and metabolized in part by CYP3A4. METHODS: Thirty-five healthy subjects received ziprasidone (20 mg) alone and after armodafinil pretreatment (titrated to 250 mg/day); of those, 25 were evaluable for pharmacokinetics. Pharmacokinetic parameters were derived from plasma concentrations of ziprasidone collected prior to and over the 48 h after each ziprasidone administration. Plasma concentrations of armodafinil and its circulating metabolites, R-modafinil acid and modafinil sulfone, were also obtained after repeated daily dosing of armodafinil alone. Safety and tolerability were assessed. RESULTS: Systemic exposure to ziprasidone was similar following administration alone or after pretreatment with armodafinil, as assessed by mean peak plasma concentration (C max, 52.1 vs 50.4 ng/mL) and area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞, 544.6 vs 469.1 ng·h/mL). Geometric mean ratios of systemic exposure (ziprasidone alone: ziprasidone after pretreatment with armodafinil) were close to unity, with associated 90 % confidence intervals (CIs) within the range of 0.80-1.25 (C max, 0.97; 90 % CI, 0.87-1.08; AUC0-∞, 0.86; 90 % CI, 0.82-0.91). Adverse events were consistent with the known safety profiles of each agent. CONCLUSION: Systemic exposure to ziprasidone was not affected by pretreatment with armodafinil. Both drugs were generally safe and well tolerated under the conditions studied.

An evaluation of the potential for drug-drug interactions between bendamustine and rituximab in indolent non-Hodgkin lymphoma and mantle cell lymphoma.

PURPOSE: Bendamustine plus rituximab has been reported to be effective in treating lymphoid malignancies. This analysis investigated the potential for drug-drug interactions between the drugs in patients with indolent non-Hodgkin lymphoma or mantle cell lymphoma. METHODS: Data were derived from a bendamustine-rituximab combination therapy study, a bendamustine monotherapy study, and published literature on rituximab monotherapy and combination therapy. Analysis of the potential for rituximab to affect bendamustine systemic exposure included comparing bendamustine concentration-time profile following monotherapy to that following combination therapy and comparing model-predicted Bayesian bendamustine clearance in the presence and absence of rituximab. Analysis of the potential for bendamustine to affect rituximab systemic exposure included plotting observed minimum, median, and maximum serum rituximab concentrations at the end of rituximab infusion (EOI) and 24 h and 7 days post-infusion in patients receiving combination therapy versus concentrations reported in literature following rituximab monotherapy. RESULTS: The established population pharmacokinetic model following bendamustine monotherapy was evaluated to determine its applicability to combination therapy for the purpose of confirming lack of pharmacokinetic interaction. The model adequately described the bendamustine concentration-time profile following monotherapy and combination therapy in adults. There was no statistically significant difference in estimated bendamustine clearance either alone or in combination. Also, rituximab concentrations from EOI to 24 h and 7 days demonstrated a pattern of decline similar to that seen in rituximab studies without bendamustine, suggesting that bendamustine does not affect the rituximab clearance rate. CONCLUSIONS: Neither bendamustine nor rituximab appears to affect systemic exposure of the other drug when coadministered.

Pharmacokinetics and excretion of 14C-bendamustine in patients with relapsed or refractory malignancy.

BACKGROUND: Bendamustine is an alkylating agent with clinical activity against a variety of hematologic malignancies and solid tumors. To assess the roles of renal and hepatic drug elimination pathways in the excretion and metabolism of bendamustine, a mass balance study was performed in patients with relapsed or refractory malignancies. METHODS: A single 60-minute intravenous dose of 120 mg/m(2), 80-95 µCi (14)C-bendamustine hydrochloride was administered to six patients, followed by collection of blood, urine, and fecal samples at specified time points up to day 8 or until the radioactivity of the 24-hour urine and fecal collections was below 1% of the administered dose (whichever was longer). Total radioactivity (TRA) was measured in all samples, and concentrations of unchanged bendamustine and its metabolites γ-hydroxy-bendamustine (M3), N-desmethyl-bendamustine (M4), and dihydroxy bendamustine (HP2) were determined in plasma and urine, using validated liquid chromatography-tandem mass spectrometry methods. RESULTS: The mean recovery of TRA in excreta was 76% of the radiochemical dose. Approximately half of the administered dose was recovered in urine and a quarter in feces. Less than 5% of the administered dose was recovered in urine as unchanged bendamustine. Bendamustine clearance from plasma was rapid, with a half-life of ~40 minutes. Plasma concentrations of M3, M4, and HP2 were very low relative to bendamustine concentrations. Plasma levels of TRA were higher and more sustained as compared with plasma concentrations of bendamustine, M3, M4, and HP2, suggesting the presence of one or more longer-lived (14)C-bendamustine-derived compounds. Fatigue (50%) and vomiting (50%) were the most frequent treatment-related adverse events. A grade 3/4 absolute lymphocyte count decrease occurred in all patients at some point during the study. CONCLUSION: Bendamustine is extensively metabolized, with subsequent excretion in both urine and feces. Accumulation of bendamustine is not anticipated in cancer patients with renal or hepatic impairment, because of the dose administration schedule and short half-life.