Population Pharmacokinetics and Dosing Simulations for Aripiprazole 2-Month Ready-to-Use Long-Acting Injectable in Adult Patients With Schizophrenia or Bipolar I Disorder.

A ready-to-use (RTU) long-acting injectable (LAI) formulation of aripiprazole monohydrate for administration once every 2 months, available in 960 mg (Ari 2MRTU 960) or 720 mg doses, has been developed for the treatment of schizophrenia or bipolar I disorder. A previously developed and validated population pharmacokinetic model for characterizing aripiprazole plasma concentrations following administration of oral aripiprazole or aripiprazole once-monthly (AOM) intramuscular injection was expanded to include the RTU LAI formulation of aripiprazole (Ari RTU LAI). Overall, 8899 aripiprazole pharmacokinetic samples from 1191 adults from 10 clinical trials were included in the final combined analysis data set. Aripiprazole plasma concentration-time profiles were simulated for various Ari RTU LAI initiation and maintenance scenarios in 1000 virtual patients. Diagnostic plots demonstrated that the final population pharmacokinetic model, which incorporated data for oral aripiprazole, AOM, and Ari RTU LAI, adequately described aripiprazole concentrations following Ari RTU LAI administration. Absorption of Ari RTU LAI was modeled by a parallel zero-order and lagged first-order process. Simulations across multiple scenarios were performed to inform dosing recommendations, including various treatment initiation regimens for a 2-monthly formulation of Ari RTU LAI in patients with or without prior stabilization on oral aripiprazole, and for patients switching from AOM. Additional simulations accounted for missed/delayed doses, cytochrome (CYP) 2D6 metabolizer status, and concomitant use of CYP2D6 or CYP3A4 inhibitors. Overall, simulations across a variety of scenarios demonstrated an Ari RTU LAI pharmacokinetic exposure profile that was comparable to AOM, with a longer dosing interval.

Randomized Phase I Trial of the α-Synuclein Antibody Lu AF82422.

BACKGROUND: Immunotherapy targeting pathological α-synuclein (α-syn) species is a promising strategy for slowing disease progression in neurodegenerative synucleinopathies, including Parkinson's disease (PD). OBJECTIVE: The aim was to evaluate the safety, tolerability, pharmacokinetics, and target engagement of ascending doses of Lu AF82422. METHODS: In this first-in-human study (NCT03611569), healthy participants (18-55 years, cohort A) and patients with PD (40-80 years, Hoehn and Yahr stage ≤3, cohort B) were enrolled in ascending-dose cohorts and randomly assigned to receive single intravenous infusions of Lu AF82422 (cohorts A1-A6: 75, 225, 750, 2250 4500, and 9000 mg, respectively; cohorts B1 and B2: 2250 and 9000 mg, respectively) or placebo. Participants were monitored during a 12-week observational period. RESULTS: Overall, single intravenous infusions of Lu AF82422 were safe and well tolerated, and no serious adverse events (AE) were observed; the most common AEs were related to the study on lumbar punctures, headache, and common infections. Lu AF82422 concentrations (in plasma and cerebrospinal fluid [CSF]) increased in a dose-proportional manner with no observable differences between cohorts; mean plasma half-life was 700 h. Plasma concentrations of Lu AF82422 had an immediate, concentration-dependent lowering effect on the plasma concentration of free α-syn and on the ratio of free to total α-syn in all cohorts and lowered the free-to-total α-syn ratio in CSF in the high-dose PD cohort. CONCLUSIONS: The safety and pharmacokinetic profile of Lu AF82422 were appropriate for further clinical development, and results indicated peripheral target engagement. The central target engagement observed in participants with PD indicates that the doses of Lu AF82422 tested may provide CSF concentrations sufficient to target aggregated forms of α-syn. © 2024 H. Lundbeck A/S. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Pharmacokinetics and Safety of Eptinezumab in Healthy Chinese Participants: A Randomized Clinical Trial.

BACKGROUND AND OBJECTIVE: Most evidence suggests that the pharmacokinetics of monoclonal antibodies (mAbs) are not meaningfully altered by patient characteristics, including racial/ethnic differences. Nevertheless, the pharmacokinetic profile of eptinezumab has not been evaluated in a Chinese population. This study was designed to confirm the hypothesis that the pharmacokinetic profile of the anti-calcitonin gene-related peptide mAb, eptinezumab, is similar in healthy Chinese individuals to that of healthy non-Asian individuals and non-Asian patients with migraine. METHODS: Over a study period of 12 weeks, healthy adult Chinese participants (N = 20) were randomized (1:1) to receive a single intravenous dose of eptinezumab 100 mg (n = 10) or 300 mg (n = 10) in a prospective, single-site, open-label parallel-group trial. Blood samples for the evaluation of plasma eptinezumab concentrations were obtained over 84 days, and standard pharmacokinetic parameters were derived. RESULTS: Mean maximum plasma concentrations (Cmax) of eptinezumab occurred 1.0-1.5 h post start of infusion, were similar between the 100 mg and 300 mg dose groups, and slowly declined in a biphasic manner. Cmax and area under the drug concentration-time curve (AUC) increased in a dose-proportional manner. Volume of distribution and clearance were similar between the 100 mg and 300 mg dose groups, and half-life was 22.5-28.1 days. Eptinezumab was generally well tolerated with no new safety signals identified. Only one participant, randomized to the 100 mg dose group, was positive for eptinezumab anti-drug antibodies, but negative for neutralizing antibodies, with no impact on pharmacokinetics. CONCLUSION: The pharmacokinetic profile of eptinezumab in healthy Chinese individuals was generally similar to that reported for non-Asian populations with migraine, and eptinezumab was generally well tolerated. Evaluation of immunogenicity showed no evidence of an impact of anti-drug antibodies or neutralizing antibodies on safety profiles. This supports the globally approved doses of 100 mg and 300 mg as being appropriate for Chinese patients with episodic migraine or chronic migraine.

Safety and Efficacy of Aripiprazole 2-Month Ready-to-Use 960 mg: Secondary Analysis of Outcomes in Adult Patients With Schizophrenia in a Randomized, Open-label, Parallel-Arm, Pivotal Study.

Objective: Aripiprazole 2-month ready-to-use 960 mg (Ari 2MRTU 960) is a new long-acting injectable antipsychotic formulation for administration every 2 months. A randomized, open-label, 32-week trial evaluated the safety, tolerability, and pharmacokinetics of Ari 2MRTU 960 in clinically stable adults with schizophrenia or bipolar I disorder (per DSM-5 criteria). This secondary analysis evaluated the safety and efficacy of Ari 2MRTU 960 in the subpopulation of patients with schizophrenia.Methods: Patients were randomized to receive Ari 2MRTU 960 every 56 ± 2 days (4 injections scheduled) or aripiprazole once-monthly 400 mg (AOM 400) every 28 ± 2 days (8 injections scheduled). Data were collected during August 2019-July 2020 across 16 US sites. Primary endpoints included safety and tolerability, evaluated throughout. Secondary endpoints for efficacy in patients with schizophrenia included change from baseline at week 32 in Positive and Negative Syndrome Scale, Clinical Global Impression - Severity, and Subjective Well-being under Neuroleptic Treatment - Short Form scores, along with Clinical Global Impression - Improvement at week 32.Results: Patients with schizophrenia were randomized to Ari 2MRTU 960 (n = 92) or AOM 400 (n = 93). The incidence of treatment-emergent adverse events (TEAEs) was similar between Ari 2MRTU 960 (66.3%) and AOM 400 (63.4%). The most frequently reported TEAE was increased weight (Ari 2MRTU 960: 21.7%; AOM 400: 18.3%). Patients in both treatment groups remained clinically stable throughout, with minimal change from baseline observed in efficacy parameters at week 32.Conclusions: Ari 2MRTU 960 was well tolerated in clinically stable patients with schizophrenia, with efficacy similar to AOM 400.Trial Registration: ClinicalTrials.gov identifier: NCT04030143.

Population Pharmacokinetic Analysis of Brexpiprazole to Support its Indication and Dose Selection in Adolescents With Schizophrenia.

Due to the customary delay between medication approvals in adult and adolescent populations, adolescents with schizophrenia may receive off-label antipsychotic treatment, without empirically justified dosing recommendations. In order to accelerate pediatric drug development, the US Food and Drug Administration (FDA) released a general advice letter to sponsors permitting the effectiveness of atypical antipsychotics for the treatment of schizophrenia in adults to be extrapolated to adolescents based on a pharmacokinetic (PK) analysis to support dose selection, plus a safety study. The aim of the present article is to describe the population PK analysis that was submitted to the FDA to inform brexpiprazole dose selection in adolescents with schizophrenia. Using a population PK model with brexpiprazole clearance and volume of distribution allometrically scaled by body weight, PK simulations showed comparable brexpiprazole dose-exposure between adults and adolescents aged 13-17 years following oral daily doses of brexpiprazole 1-4 mg, indicating that the target brexpiprazole dose of 2-4 mg/day in adults with schizophrenia is also suitable for adolescents. Based on this population PK analysis, together with a safety study in adolescents, the FDA approved brexpiprazole for the treatment of schizophrenia in adolescents aged 13-17 years, via extrapolation of the efficacy of brexpiprazole from adults to adolescents.

Safety and efficacy of aripiprazole 2-month ready-to-use 960 mg: secondary analysis of outcomes in adult patients with bipolar I disorder in a randomized, open-label, parallel-arm, pivotal study.

OBJECTIVE: Aripiprazole 2-month ready-to-use 960 mg (Ari 2MRTU 960) is a new long-acting injectable antipsychotic formulation for administration every 2 months. A 32-week trial evaluated the safety, tolerability, and pharmacokinetics of Ari 2MRTU 960 in clinically stable adults with schizophrenia or bipolar I disorder (BP-I) (per DSM-5 criteria). This secondary analysis evaluated the safety and efficacy of Ari 2MRTU 960 in the subpopulation of patients with BP-I. METHODS: Patients with BP-I were randomized to receive Ari 2MRTU 960 (n = 40) every 56 ± 2 days (4 injections scheduled) or aripiprazole once-monthly 400 mg (AOM 400; n = 41) every 28 ± 2 days (8 injections scheduled). Data were collected during August 2019-July 2020 across 16 US sites. Primary safety endpoints included reported adverse events (coded by the Medical Dictionary for Regulatory Activities preferred term), injection site reactions (assessments included a Visual Analog Scale [VAS] to evaluate patient-reported injection-site pain), and motoric symptoms. Secondary endpoints for efficacy included change from baseline at Week 32 in the Young Mania Rating Scale (YMRS), Montgomery-Åsberg Depression Rating Scale (MADRS), Clinical Global Impression - Bipolar Version (CGI-BP), and Subjective Well-being under Neuroleptic Treatment - Short Form (SWN-S) scores, and Clinical Global Impression - Improvement (CGI-I) at Week 32. RESULTS: The incidence of treatment-emergent adverse events (TEAEs) was similar between Ari 2MRTU 960 (82.5% [33/40]) and AOM 400 (87.8% [36/41]; p = .5468). The most frequently reported TEAE was increased weight (Ari 2MRTU 960: 25.0% [10/40]; AOM 400: 26.8% [11/41]; p = 1). Injection-site pain was experienced by more patients in the Ari 2MRTU 960 group (25% [10/40]) versus the AOM 400 group (7.3% [3/41]; p = .0622). Mean (standard deviation [SD]) VAS scores for patient-reported injection-site pain following the last injection were 1.2 (2.07) for Ari 2MRTU 960 group and 1.3 (2.19) for AOM 400 (p = .9479) (VAS scale range 0-100 [no pain-extreme pain]). No notable improvement or decline from baseline was observed in motoric symptoms in either treatment group. Patients in both treatment groups remained clinically stable for the entire 32-week trial duration, with minimal difference between treatment groups in the least squares (LS) mean change from baseline at Week 32 in the YMRS Total (p = .8995), MADRS Total (p = .3185), and CGI-BP scores (p = .8485), and in mean CGI-I score (p = .7960). LS mean change from baseline in SWN-S score was greater for Ari 2MRTU 960 than for AOM 400 at Week 32 (p = .0169). CONCLUSIONS: Ari 2MRTU 960 was well tolerated in patients with BP-I, with efficacy similar to AOM 400. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04030143.

Aripiprazole Plasma Concentrations Delivered from Two 2-Month Long-Acting Injectable Formulations: An Indirect Comparison.

Aripiprazole 2-month ready-to-use 960 mg (Ari 2MRTU 960) is a novel long-acting injectable (LAI) formulation of aripiprazole monohydrate for administration once every 2 months, developed for the treatment of schizophrenia or maintenance monotherapy treatment of bipolar I disorder in adults (indication will vary by country). Aripiprazole lauroxil 1064 mg (AL 1064) is an LAI formulation of aripiprazole lauroxil, an aripiprazole prodrug, for administration once every 2 months, indicated for the treatment of schizophrenia in adults. This analysis provides an indirect comparison of aripiprazole plasma concentrations following multiple doses of either formulation. Clinical trial data were used to determine average steady-state aripiprazole plasma concentration (Cavg,ss), maximum aripiprazole plasma concentration (Cmax), and other pharmacokinetic parameters of either formulation following four administrations (96 patients received Ari 2MRTU 960; 28 patients received AL 1064). All pharmacokinetic parameters were considered in the context of a minimum aripiprazole therapeutic concentration (Cmin) of ≥95 ng/mL. An exposure-response analysis using data from two Phase III trials of aripiprazole once-monthly (an aripiprazole monohydrate LAI, administered monthly), showed that patients with a Cmin ≥95 ng/mL are 4.41 times less likely to relapse than patients with a Cmin <95 ng/mL. A similar analysis has not been performed for AL 1064. However, consensus guidelines for therapeutic drug monitoring recommend a range of 100-350 ng/mL for aripiprazole. Following four administrations, mean (standard deviation [SD]) Cavg,ss over the 2-month dosing interval was 263 (133) ng/mL for Ari 2MRTU 960 and 140.7 (57.3) ng/mL for AL 1064. Mean (SD) Cmax during the fourth dosing interval was 342 (157) ng/mL for Ari 2MRTU 960 and 188.8 (79.8) ng/mL for AL 1064. This indirect comparison showed that, following four administrations, Ari 2MRTU 960 and AL 1064 delivered mean aripiprazole plasma concentrations that remained above the minimum therapeutic concentration of aripiprazole over the 2-month dosing interval.

A Randomized, Open-Label, Multiple-Dose, Parallel-Arm, Pivotal Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Aripiprazole 2-Month Long-Acting Injectable in Adults With Schizophrenia or Bipolar I Disorder.

BACKGROUND: Aripiprazole 2-month ready-to-use 960 mg (Ari 2MRTU 960) is a new long-acting injectable antipsychotic formulation for gluteal administration every 2 months, currently being investigated for the treatment of schizophrenia and bipolar I disorder (BP-I). The objectives of this trial were to evaluate the safety and tolerability of Ari 2MRTU 960, and the similarity of aripiprazole plasma concentrations following administration of Ari 2MRTU 960 or aripiprazole once-monthly 400 mg (AOM 400), in adults with schizophrenia or BP-I. METHODS: This was a 32-week open-label study. Eligible participants were randomized 1:1 to receive Ari 2MRTU 960 every 56 ± 2 days (four injections scheduled) or AOM 400 every 28 ± 2 days (eight injections scheduled). Participants received overlapping oral antipsychotic treatment with the first administration of study drug (there was no oral overlap for participants stabilized on AOM 400). Safety, tolerability, and pharmacokinetics (PK) were evaluated throughout the study. Primary safety endpoints included reported adverse events, injection site reactions, and extrapyramidal symptoms. Primary PK endpoints were plasma concentration of aripiprazole 56 days after the fourth dose of Ari 2MRTU 960 and 28 days after the eighth dose of AOM 400, and area under the concentration-time curve (AUC) from Day 0 to 56 postdose after the fourth dose of Ari 2MRTU 960, or AUC from Day 0 to 28 after the seventh and eighth doses of AOM 400. RESULTS: Of the 266 participants enrolled (schizophrenia, n = 185; BP-I, n = 81), 132 were randomized to receive Ari 2MRTU 960 and 134 were randomized to receive AOM 400. The majority (66.2%) of participants were male; 72.9% were Black or African American, and mean age was 47.3 years; demographic characteristics and baseline disease characteristics were generally well balanced between groups. Study completion rate was 77.3% in the Ari 2MRTU 960 group and 68.7% in the AOM 400 group. The incidence of treatment-emergent adverse events (TEAEs) was similar between Ari 2MRTU 960 (71.2%) and AOM 400 (70.9%). The most frequently reported TEAEs were increased weight (Ari 2MRTU 960: 22.7%; AOM 400: 20.9%) and injection-site pain (Ari 2MRTU 960: 18.2%; AOM 400: 9.0%). The geometric means ratio (GMR) of aripiprazole plasma concentrations on the last day following the final dosing for Ari 2MRTU 960 versus AOM 400 was 1.011 (90% confidence interval [CI] 0.893-1.145), and the GMR of aripiprazole plasma exposure (area under the concentration-time curve) over the fourth Ari 2MRTU 960 dosing interval versus the seventh and eighth AOM 400 dosing intervals was 1.006 (90% CI 0.851-1.190). CONCLUSIONS: Ari 2MRTU 960 was generally well tolerated in adults with schizophrenia or BP-I, with a safety profile comparable with that of AOM 400, and aripiprazole exposure equivalent to that with AOM 400 (ClinicalTrials.gov identifier: NCT04030143, registered on 23 July 2019).

Aripiprazole is a medication used to treat psychotic symptoms in schizophrenia or bipolar I disorder (BP-I) that can be taken orally or injected into the muscle. Aripiprazole once-monthly 400 mg (AOM 400) is a long-acting injectable formulation administered every 28 days, used in the treatment of schizophrenia or BP-I. A new 2-month ready-to-use formulation containing 960 mg of aripiprazole (Ari 2MRTU 960) is currently being investigated for the treatment of schizophrenia or BP-I. This 32-week study compared Ari 2MRTU 960 with AOM 400 in adults with schizophrenia or BP-I stabilized on their current medication. Study participants were randomly assigned to receive either Ari 2MRTU 960 every 56 ± 2 days (four injections scheduled in total) or AOM 400 every 28 ± 2 days (eight injections scheduled in total). Safety, tolerability, and concentration of aripiprazole in the blood were evaluated throughout the study. The incidence of adverse events emerging during the treatment period was similar between Ari 2MRTU 960 and AOM 400 (71.2% and 70.9%, respectively), with the most frequently reported events being increased weight (Ari 2MRTU 960: 22.7%; AOM 400: 20.9%) and injection-site pain (Ari 2MRTU 960: 18.2%; AOM 400: 9.0%). At the end of the study, aripiprazole concentrations were similar between treatment groups, based on the reported pharmacokinetic parameters. Participants remained clinically stable throughout the study. Ari 2MRTU 960 was generally well tolerated in adults with schizophrenia or BP-I.

Nonclinical safety evaluation, pharmacokinetics, and target engagement of Lu AF82422, a monoclonal IgG1 antibody against alpha-synuclein in development for treatment of synucleinopathies.

Alpha-synuclein is a 15 kDa protein associated with neurodegenerative diseases such as Parkinson disease and multiple-system atrophy where pathological forms of alpha-synuclein aggregate and become neurotoxic. Here we describe the nonclinical program to support a first-in-human (FIH) single ascending dose (SAD) study for Lu AF82422, a human recombinant, anti-alpha-synuclein monoclonal antibody (mAb) in development for treatment of synucleinopathies. Alpha-synuclein is primarily expressed in brain, peripheral nerves and in blood cells. A tissue cross-reactivity assessment showed that Lu AF82422 binding was generally restricted to nervous tissues. Flow cytometry analysis did not show extracellular surface binding of Lu AF82422 to human platelets, erythrocytes, granulocytes, or lymphocytes, but to a low fraction of monocytes, without any functional consequences on activation or phagocytic capacity. A single dose pharmacokinetic (PK) study in cynomolgus monkeys with dose levels of 1-30 mg/kg confirmed PK properties in the expected range for a mAb with a soluble target, and target engagement was shown as a decrease in free alpha-synuclein in plasma. Four-week repeat-dose toxicity studies were conducted in rats and cynomolgus monkeys at doses up to 600 mg/kg administered intravenously every 10 days. Results showed no treatment-related adverse findings and the no-observed-adverse-effect-level was the highest dose tested. Target engagement was shown in plasma and cerebrospinal fluid. Taken together, the nonclinical data indicated no safety signal of concern and provided adequate safety margins between observed safe doses in animals and the planned dose levels in the FIH SAD study.

An alternative start regimen with aripiprazole once-monthly in patients with schizophrenia: population pharmacokinetic analysis of a single-day, two-injection start with gluteal and/or deltoid intramuscular injection.

BACKGROUND: The single-injection start regimen for aripiprazole once-monthly 400 mg (AOM 400) in patients with schizophrenia requires a single intramuscular injection in the gluteal or deltoid site and 14 days of concurrent oral therapy. A simplified, single-day regimen of two injections at separate gluteal and/or deltoid injection sites, together with a single 20-mg dose of oral aripiprazole on the 1st day, was assessed. PATIENTS AND METHODS: A previously developed population-pharmacokinetic (popPK) model for characterizing aripiprazole PK following oral administration and gluteal intramuscular depot injection was expanded to include deltoid injection. Simulations were conducted to assess PK profiles following various (including two-injection) start regimens. Postmarketing data on patients who received higher-than-recommended AOM doses were used to assess overall safety/tolerability. RESULTS: The two-injection start regimen with a single concurrent oral dose displayed a comparable PK profile to the single-injection start regimen with concurrent 14-day oral administration in simulations. The safety assessment indicated the two-injection start regimen was unlikely to be associated with safety concerns beyond those expected with a single-injection start regimen. CONCLUSION: These data support use of the two-injection start regimen in clinical practice to reduce reliance on daily oral administration and optimize the therapeutic benefits of AOM 400 in patients with schizophrenia.

A Comprehensive Overview of the Clinical Pharmacokinetics of Clobazam.

Clobazam (CLB) is a 1,5-benzodiazepine that has been widely used as an anxiolytic and antiseizure drug (ASD) since it was first synthesized over 50 years ago. CLB was approved in the United States in 2011 as adjunctive therapy for seizures in patients ≥2 years old with Lennox-Gastaut syndrome. CLB pharmacokinetics (PK) have been studied in single- and multiple-dose administrations in healthy subjects. Salient features include high bioavailability, linear PK, and negligible effects from coadministration of other ASDs. CLB is highly and extensively absorbed, with little effect from food; time to maximum plasma concentration is 0.5 to 4 hours following the dose. After CLB doses of 20 to 40 mg/day, the volume of distribution is 99 to 120 L, with oral clearance ranging from 1.9 to 2.3 L/h. CLB is lipophilic and distributes throughout the body after oral administration. It is metabolized in the liver by cytochrome P450 (CYP) isoenzymes CYP3A, CYP2C19, and CYP2B6, and its main active metabolite is N-desmethylclobazam. The half-life of CLB after a single oral dose ranges from 36 to 42 hours; the half-life of N-desmethylclobazam ranges from 59 to 74 hours. The metabolites of CLB are primarily excreted renally. Population PK modeling using data from healthy subjects and patients with Lennox-Gastaut syndrome indicates that race, sex, age, weight, and renal function do not influence CLB PK. As CLB has been extensively studied since the 1970s, this review is meant to provide a consolidated and comprehensive resource on CLB PK for both prescribers and scientists alike.

Aripiprazole Once-Monthly 400 mg: Comparison of Pharmacokinetics, Tolerability, and Safety of Deltoid Versus Gluteal Administration.

Background: Two open-label, randomized, parallel-arm studies compared pharmacokinetics, safety, and tolerability of aripiprazole once-monthly 400 mg following deltoid vs gluteal injection in patients with schizophrenia. Methods: In the single-dose study, 1 injection of aripiprazole once-monthly 400 mg in the deltoid (n=17) or gluteal (n=18) muscle (NCT01646827) was administered. In the multiple-dose study, the first aripiprazole once-monthly 400 mg injection was administered in either the deltoid (n=71) or gluteal (n=67) muscle followed by 4 once-monthly deltoid injections (NCT01909466). Results: After single-dose administration, aripiprazole exposure (area under the concentration-time curve) was similar between deltoid and gluteal administrations, whereas median time to maximum plasma concentration was shorter (7.1 [deltoid] vs 24.1 days [gluteal]) and maximum concentration was 31% higher after deltoid administration. In the multiple-dose study, median time to maximum plasma concentration for deltoid administration was shorter (3.95 vs 7.1 days), whereas aripiprazole mean trough concentrations, maximum concentration, and area under the concentration-time curve were comparable between deltoid and gluteal muscles (historical data comparison). Multiple-dose pharmacokinetic results for the major metabolite, dehydro-aripiprazole, followed a similar pattern to that of the parent drug for both deltoid and gluteal injection sites. Safety and tolerability profiles were similar after gluteal or deltoid injections. Based on observed data, minimum aripiprazole concentrations achieved by aripiprazole once-monthly 400 mg are comparable with those of oral aripiprazole 15 to 20 mg/d. Conclusions: The deltoid muscle is a safe alternative injection site for aripiprazole once-monthly 400 mg in patients with schizophrenia.

A systematic review of the characteristics and validity of monitoring technologies to assess Parkinson's disease.

BACKGROUND: There is growing interest in having objective assessment of health-related outcomes using technology-based devices that provide unbiased measurements which can be used in clinical practice and scientific research. Many studies have investigated the clinical manifestations of Parkinson's disease using such devices. However, clinimetric properties and clinical validation vary among the different devices. METHODS: Given such heterogeneity, we sought to perform a systematic review in order to (i) list, (ii) compare and (iii) classify technological-based devices used to measure motor function in individuals with Parkinson's disease into three groups, namely wearable, non-wearable and hybrid devices. A systematic literature search of the PubMed database resulted in the inclusion of 168 studies. These studies were grouped based on the type of device used. For each device we reviewed availability, use, reliability, validity, and sensitivity to change. The devices were then classified as (i) 'recommended', (ii) 'suggested' or (iii) 'listed' based on the following criteria: (1) used in the assessment of Parkinson's disease (yes/no), (2) used in published studies by people other than the developers (yes/no), and (3) successful clinimetric testing (yes/no). RESULTS: Seventy-three devices were identified, 22 were wearable, 38 were non-wearable, and 13 were hybrid devices. In accordance with our classification method, 9 devices were 'recommended', 34 devices were 'suggested', and 30 devices were classified as 'listed'. Within the wearable devices group, the Mobility Lab sensors from Ambulatory Parkinson's Disease Monitoring (APDM), Physilog®, StepWatch 3, TriTrac RT3 Triaxial accelerometer, McRoberts DynaPort, and Axivity (AX3) were classified as 'recommended'. Within the non-wearable devices group, the Nintendo Wii Balance Board and GAITRite® gait analysis system were classified as 'recommended'. Within the hybrid devices group only the Kinesia® system was classified as 'recommended'.

Population pharmacokinetics of nalmefene in healthy subjects and its relation to µ-opioid receptor occupancy.

AIMS: The aims of this study were to develop a population pharmacokinetic (PK) model to describe the PK of nalmefene in healthy subjects and to relate the exposure of nalmefene to the µ-opioid receptor occupancy by simulations in the target population. METHODS: Data from nine phase I studies (243 subjects) with extensive blood sampling were pooled and used for the population PK model building. Data from four other phase I studies (85 subjects) were pooled and used as an external validation dataset. Eight subjects from an imaging study contributed occupancy data and the pharmacokinetic/pharmacodynamic (PK/PD) relationship was modelled. Combining the population PK model and the PK/PD relationship enabled simulations to predict µ-opioid occupancy. RESULTS: A two compartment model with first order absorption best described the nalmefene PK data. The typical subject in the population was estimated to have a systemic clearance of 60.4 l h(-1) and a central volume of distribution of 266 l. Absolute oral bioavailability was estimated to 41% without food intake and with food about 53%. Simulation of the µ-opioid receptor occupancy shows that the 95% confidence bound is within or above 60-90% occupancy for up to 22-24 h after a single dose of 20 mg nalmefene. CONCLUSIONS: A robust population PK model for nalmefene was developed. Based on the concentration-occupancy model the µ-opioid receptor occupancy after a single 20 mg dose of nalmefene is predicted to be above the target therapeutic occupancy for about 24 h in about 95% of the target population.

Quantitative home-based assessment of Parkinson's symptoms: the SENSE-PARK feasibility and usability study.

BACKGROUND: Currently, assessment of symptoms associated with Parkinson's disease is mainly performed in the clinic. However, these assessments have limitations because they provide only a snapshot of the condition. METHODS: The feasibility and usability of an objective, continuous and relatively unobtrusive system (SENSE-PARK System), which consists of wearable sensors (three worn during the day and one worn at night), a smartphone-based App, a balance board and computer software, was tested 24/7 over 12 weeks in a study including 22 PD patients. During the first four weeks of the study, patients did not get feedback about their performance, during the last eight weeks they did. The study included seven clinical visits with standardized interviews, and regular phone contact. The primary outcome was the number of drop-outs during the study. As secondary outcomes, the Post-Study System Usability Questionnaire (PSSUQ), score and information obtained from the standardized interviews were used to evaluate the usability of the system. RESULTS: All patients completed the study. The participants rated the usability of the SENSE-PARK System with a mean score of 2.67 (±0.49) on the PSSUQ. The interviews revealed that most participants liked using the system and appreciated that it signaled changes in their health condition. CONCLUSIONS: This 12 week controlled study demonstrates that the acceptance level of PD patients using the SENSE-PARK System as a home-based 24/7 assessment is very good. Particular emphasis should be given to a user-friendly design. Motivation to wear such a system can be increased by providing direct feedback about the individual health condition.

Internet-based remote consultations - general practitioner experience and attitudes in Norway and Germany.

UNLABELLED: The objective of the study was to identify experiences and attitudes of German and Norwegian general practitioners (GPs) towards Internet-based remote consultation solutions supporting communication between GPs and patients in the context of the German and Norwegian healthcare systems. METHODS: Interviews with four German and five Norwegian GPs were conducted. The results were qualitatively analyzed. RESULTS: All interviewed GPs stated they would like to make use of Internet-based remote consultations in the future. Current experiences with remote consultations are existent to a limited degree. No GP reported to use a comprehensive remote consultation solution. The main features GPs would like to see in a remote consultation solution include asynchronous exchange of text messages, video conferencing with text chat, scheduling of remote consultation appointments, secure login and data transfer and the integration of the remote consultation solution into the GP's EHR system.

Clinical Parameters and Tools for Home-Based Assessment of Parkinson's Disease: Results from a Delphi study.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder with fluctuating symptoms. To aid the development of a system to evaluate people with PD (PwP) at home (SENSE-PARK system) there was a need to define parameters and tools to be applied in the assessment of 6 domains: gait, bradykinesia/hypokinesia, tremor, sleep, balance and cognition. OBJECTIVE: To identify relevant parameters and assessment tools of the 6 domains, from the perspective of PwP, caregivers and movement disorders specialists. METHODS: A 2-round Delphi study was conducted to select a core of parameters and assessment tools to be applied. This process included PwP, caregivers and movement disorders specialists. RESULTS: Two hundred and thirty-three PwP, caregivers and physicians completed the first round questionnaire, and 50 the second. Results allowed the identification of parameters and assessment tools to be added to the SENSE-PARK system. The most consensual parameters were: Falls and Near Falls; Capability to Perform Activities of Daily Living; Interference with Activities of Daily Living; Capability to Process Tasks; and Capability to Recall and Retrieve Information. The most cited assessment strategies included Walkers; the Evaluation of Performance Doing Fine Motor Movements; Capability to Eat; Assessment of Sleep Quality; Identification of Circumstances and Triggers for Loose of Balance and Memory Assessment. CONCLUSIONS: An agreed set of measuring parameters, tests, tools and devices was achieved to be part of a system to evaluate PwP at home. A pattern of different perspectives was identified for each stakeholder.

Participatory design in Parkinson's research with focus on the symptomatic domains to be measured.

BACKGROUND: There is a growing interest in the objective assessment of health related outcomes using technology providing quality measurements to be applied not only in daily clinical practice, but also in scientific research. Differences in the understandings of the condition and the terminology used between people with Parkinson's (PwPs), clinicians and technical developers may influence the progress of a participatory design process. OBJECTIVE: This paper reports on a participatory design process to achieve a consensus among PwPs, clinicians and technologists over the selection of a set of symptomatic domains to be continuously assessed, in order to provide results relevant to both PwPs and clinicians. METHODS: The methods used were a Web based user survey, end-user focus groups, ranking by combined methods, a Delphi process performed among clinicians and scientists, and prioritization of the results in a concertation workshop for PwPs, clinicians and technologists. RESULTS: The following symptomatic domains were commonly agreed by PwPs and clinicians to be of central importance in a system of continuous assessment: hypokinesia/bradykinesia, tremor, sway, gait, sleep and cognition. This list satisfied both the needs of the PwPs and the concerns of the clinicians regarding the means of advancing new strategies in assessment and interventions in PD. CONCLUSIONS: A participatory design strategy allowed the definition of a consensual list of symptomatic domains. Both the strategy and the achieved results may be of relevance for similar interdisciplinary approaches in the field of PD using a participatory design involving patients, clinicians and technologists.