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.

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.

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.

Putative coiled-coil structural elements of the BBA68 protein of Lyme disease spirochetes are required for formation of its factor H binding site.

Factor H and factor H like-protein 1 (FHL-1) are complement regulatory proteins that serve as cofactors for the factor I-mediated cleavage of C3b. Some Lyme disease and relapsing fever spirochete species bind factor H to their surface to facilitate immune evasion. The Lyme disease spirochetes produce several factor H binding proteins (FHBPs) that form two distinct classes. Class I FHBPs (OspE orthologs and paralogs) bind only factor H, while class II FHBPs (BBA68) bind both factor H and FHL-1. BBA68 belongs to a large paralogous protein family, and of these paralogs, BBA69 is the member most closely related to BBA68. To determine if BBA69 can also bind factor H, recombinant protein was generated and tested for factor H binding. BBA69 did not exhibit factor H binding ability, suggesting that among family 54 paralogs, factor H binding is unique to BBA68. To identify the determinants of BBA68 that are involved in factor H binding, truncation and site-directed mutational analyses were performed. These analyses revealed that the factor H binding site is discontinuous and provide strong evidence that coiled-coil structural elements are involved in the formation of the binding site.