Although the stability of β-lactam antibiotics is a known issue, none of the previously reported bioanalytical methods had an adequate evaluation of the stability of these drugs. In the current study, the stability of cefepime, meropenem, piperacillin, and tazobactam under various conditions was comprehensively evaluated. The evaluated parameters included stock solution stability, short-term stability, long-term stability, freeze-thaw stability, processed sample stability, and whole-blood stability. When stored at -20°C, the stock solution of meropenem in methanol was stable for up to 3 weeks, and the stock solutions of cefepime, piperacillin, and tazobactam were stable for up to 6 weeks. All four antibiotics were stable in human plasma for up to 3 months when stored at -80°C and were stable in whole blood for up to 4 h at room temperature. Short-term stability results indicated that all four β-lactams were stable at room temperature for 2 h, but substantial degradation was observed when the plasma samples were stored at room temperature for 24 h, with the degradation rates for cefepime, meropenem, piperacillin, and tazobactam being 30.1%, 75.6%, 49.0%, and 37.7%, respectively. Because the stability information is method independent, our stability results can be used as a reference by other research groups that work with these antibiotics.

Pooled risk estimates from this meta-analysis showed that polypharmacy was associated with dementia. Although the causality of the relationship cannot be concluded from this analysis, the finding encourages the use of multidimensional assessment tools for dementia that includes the number of medications as a component.

The overexpression of efflux transporters, especially P-glycoprotein (Pgp, MDR1, ABCB1) and breast cancer resistance protein (BCRP, ABCG2), represents an important mechanism of multidrug resistance (MDR). Tyrosine kinase inhibitors (TKIs), a novel group of target-specific anticancer drugs, have recently been found to interact with Pgp and BCRP and to serve as both substrates and inhibitors. Considering their dual role, we anticipate that combination TKI therapy may represent a promising strategy to reverse efflux transporter mediated TKI resistance. Presently, investigations on these interactions are very limited. To fill the literature gap, dasatinib was used as the model drug and the effects of various TKIs on Pgp- and BCRP- mediated dasatinib efflux were evaluated. Cell uptake studies were performed using LLC-PK1 and MDCK-II cells along with their subclones that were transfected with human Pgp and BCRP, respectively. Among the 14 TKIs screened, nine TKIs greatly inhibited Pgp-mediated dasatinib efflux at 50 μm. Further concentration dependent studies showed that imatinib, nilotinib and pazopanib were potent Pgp inhibitors with IC values of 2.42, 6.11 and 8.06 μm, respectively. Additionally, 50 μm of five TKIs greatly increased dasatinib accumulation through BCRP inhibition. Concentration dependent studies revealed that imatinib, erlotinib, nilotinib, axitinib and pazopanib were potent BCRP inhibitors with IC values of 0.94, 2.23, 2.50, 6.89 and 10.4 μm, respectively. Our findings point to potential combinations of TKIs that could enhance intracellular concentrations of the targeted TKI, overcome MDR and improve TKI efficacy. Further in vivo studies are warranted to confirm the efflux transporter-mediated TKI-TKI interaction. Copyright © 2016 John Wiley & Sons, Ltd.

The population pharmacokinetics (PK) of risankizumab and exposure-response relationships for efficacy and safety in patients with Crohn's disease (CD) were characterized using data from phase II and III studies to support dosing regimen selection. A two-compartment model with first-order absorption and first-order elimination adequately described risankizumab PK. Covariates including sex, baseline fecal calprotectin, corticosteroid use, baseline creatinine clearance, body weight, and baseline albumin were statistically correlated with risankizumab clearance, but their impact on exposure was not clinically relevant for efficacy or safety. Exposure-response analyses showed that exposures associated with the 600 mg intravenous (i.v.) induction dose at Weeks 0, 4, and 8 achieved a near maximal response for all efficacy end points evaluated, with negligible added benefit from the 1,200 mg i.v. regimen. By Week 52 of the maintenance treatment, trends of higher responses were observed for the exposure range associated with the 360 mg subcutaneous (s.c.) every-8-weeks (Q8W) regimen for most of the evaluated efficacy end points, particularly for the more stringent end points, such as endoscopic remission and ulcer-free endoscopy. Exposure-response analyses for safety did not identify any apparent relationship between exposure and safety. These results supported the final dose recommendation of 600 mg i.v. at Weeks 0, 4, and 8, followed by 360 mg s.c. at Week 12 and Q8W thereafter in patients with CD.Crohn's disease (CD) is a chronic inflammatory bowel disease that can affect any segment of the gastrointestinal tract, causing symptoms such as abdominal pain, fatigue, prolonged diarrhea with or without serious bleeding, weight loss, and fever. 1 The exact cause of CD is unknown, but it is hypothesized that an interplay of the patient's genetics, microbiome, immune response,

The highly variable pharmacokinetics of β-lactam antibiotics and β-lactamase inhibitors poses a significant challenge to clinicians in ensuring appropriate antibiotic doses in critically ill patients. Therefore, routine monitoring of plasma concentrations is important for individualization of antimicrobial therapy. Accordingly, a simple and robust analytical method for the simultaneous measurement of multiple β-lactam antibiotics and β-lactamase inhibitors is highly desirable to ensure quick decisions on dose adjustments. In this study, a sensitive, simple, and robust method for the simultaneous quantification of cefepime, meropenem, piperacillin, and tazobactam in human plasma was developed and rigorously validated according to FDA guidance. Sample extraction was accomplished by simple protein precipitation. Chromatographic separation of analytes was achieved using stepwise gradient elution. Analytes were monitored using tandem mass spectrometry (MS/MS) with a turbo ion spray source in positive multiple-reaction-monitoring mode. The calibration curve ranged from 0.5 to 150 μg/ml for cefepime, 0.1 to 150 μg/ml for meropenem and piperacillin, and 0.25 to 150 μg/ml for tazobactam. Inter- and intraday precision and accuracy, sensitivity, selectivity, dilution integrity, matrix effect, extraction recovery, and hemolysis effect were investigated for all four analytes, and the results met the acceptance criteria. Compared to other reported methods, our method is more robust because of the combination of the following features: (i) a simple sample extraction procedure, (ii) a short sample run time, (iii) a wide dynamic range, and (iv) the small plasma sample volume needed. Since our method already covers β-lactams and a β-lactamase inhibitor with highly heterogeneous physicochemical properties, further antibiotic candidates may easily be incorporated into this multianalyte method.

Introduction: Risankizumab is an anti-IL23 monoclonal antibody approved for the treatment of moderate to severe plaque psoriasis and active psoriatic arthritis (PsA). This work characterizes the pharmacokinetics of risankizumab in PsA compared with psoriasis and evaluates the efficacy and safety exposure-response relationships in PsA. Methods: The population pharmacokinetic analyses included data from 1527 participants that originated from one phase 1 healthy participant study, one phase 2 dose-ranging study in patients with PsA with an open-label extension study, and two pivotal phase 3 studies in patients with PsA, where the clinical regimen of risankizumab 150 mg administered subcutaneously (SC) at weeks 0, 4, and every 12 weeks thereafter was compared with placebo.

Background:Glucocorticoids (GC) are potent drugs used for treating many inflammatory diseases. While GCs are effective in many immune diseases, dose and duration of administration is limited due to significant side effects. Resting immune cells have very little TNF expression on the cell surface and it is only in an activated state that TNF expression is upregulated. Upon immune cell stimulation, TNF is upregulated and although a significant amount of TNF is cleaved from an activated cell, a portion remains on the cell surface. We have observed that anti-TNF antibodies bind to transmembrane TNF (tmTNF) and undergo endocytosis to the lysosome (1). We have developed a stable antibody drug conjugate (ADC), ABBV-3373, that has a proprietary, highly potent, glucocorticoid receptor modulator (GRM) payload linked to an anti-TNF monoclonal antibody (mAb) that is able to deliver the GC payload to activated immune cells.Objectives:We hypothesized that a TNF ADC with a GRM payload would be able to deliver increased efficacy through both TNF inhibition and targeted GRM payload delivery to activated immune cells while sparing systemic glucocorticoid side effects.Methods:A mouse surrogate TNF GRM ADC was characterized in an acute in vivo contact hypersensitivity model of inflammation (CHS) and in a mouse model of collagen induced arthritis (mCIA). Additionally, the human anti-TNF GRM ADC, ABBV-3373 has been characterized in healthy volunteers.Results:In the CHS model the anti-TNF GRM ADC significantly inhibited the inflammatory response with minimal effect on systemic GC biomarkers. In mCIA a single dose of an anti-TNF GRM ADC, administered at disease onset, was able to completely inhibit arthritis for greater than 30 days while an anti-TNF mAb only partially inhibited disease. ABBV-3373, a human anti-TNF GRM ADC with a GC payload, was evaluated in a Phase 1 study in healthy volunteers. ABBV-3373 demonstrated antibody-like PK profile and ABBV-3373 did not impact cortisol levels at predicted efficacious doses while control subjects that received a single oral dose of 10 mg prednisone demonstrated expected decreases in cortisol levels.Conclusion:These data suggest that an anti-TNF ADC delivering a GRM payload into activated immune cells may provide improved efficacy in immune mediated diseases, while minimizing systemic side effects associated with standard GC treatment.References:[1]Deora, A. et al. MABs. 2017;9(4):680-695.Disclosure of Interests:Bob Stoffel Shareholder of: AbbVie, Grant/research support from: AbbVie, Employee of: AbbVie, Michael McPherson Shareholder of: AbbVie, Grant/research support from: AbbVie, Employee of: AbbVie, Axel Hernandez Shareholder of: AbbVie, Grant/research support from: AbbVie, Employee of: AbbVie, Christian Goess Shareholder of: AbbVie, Grant/research support from: AbbVie, Employee of: AbbVie, Suzanne Mathieu Shareholder of: AbbVie, Grant/research support from: AbbVie, Employee of: AbbVie, Wendy Waegell Shareholder of: AbbVie, Grant/research support from: AbbVie, Employee of: AbbVie, Shaughn Bryant Shareholder of: AbbVie, Grant/research support from: AbbVie, Employee of: AbbVie, Adrian Hobson Shareholder of: AbbVie, Grant/research support from: AbbVie, Employee of: AbbVie, Melanie Ruzek Shareholder of: AbbVie, Grant/research support from: AbbVie, Employee of: AbbVie, Yinuo Pang Shareholder of: AbbVie, Grant/research support from: AbbVie, Employee of: AbbVie, Hartmut Kupper Shareholder of: AbbVie, Grant/research support from: AbbVie, Employee of: AbbVie, Ronilda D’Cunha Shareholder of: AbbVie, Grant/research support from: AbbVie, Employee of: AbbVie, Julie Parmentier Shareholder of: AbbVie, Grant/research support from: AbbVie, Employee of: AbbVie, Timothy Radstake Shareholder of: AbbVie, Grant/research support from: AbbVie, Employee of: AbbVie

Objective. To assess the efficacy and safety of ABBV-3373, a novel antibody-drug conjugate (ADC) composed of the anti-tumor necrosis factor (anti-TNF) monoclonal antibody adalimumab linked to a glucocorticoid receptor modulator (GRM), compared to adalimumab, in patients with rheumatoid arthritis (RA).Methods. In this randomized, double-blind, active-controlled, proof-of-concept trial (ClinicalTrials.gov identifier: NCT03823391), adults with moderate-to-severe RA receiving background methotrexate were administered intravenously (IV) ABBV-3373 100 mg every other week for 12 weeks, followed by placebo for 12 weeks, or subcutaneous adalimumab 80 mg every other week for 24 weeks. The primary end point was change from baseline in the Disease Activity Score in 28 joints using C-reactive protein (DAS28-CRP) at week 12, with 2 prespecified primary comparisons of ABBV-3373 versus historical adalimumab (80 mg every other week or equivalent dose) and versus combined in-trial/historical adalimumab. Secondary end points included change from baseline in the Clinical Disease Activity Index, Simplified Disease Activity Index, and DAS28 using erythrocyte sedimentation rate, as well as the proportion of patients achieving a DAS28-CRP of ≤3.2 and the American College of Rheumatology 50% improvement criteria.Results. Forty-eight patients were randomized to receive either ABBV-3373 (n = 31) or adalimumab (n = 17). At week 12, ABBV-3373 demonstrated a reduction in DAS28-CRP compared to historical adalimumab (−2.65 versus −2.13; P = 0.022) and compared to combined in-trial/historical adalimumab (−2.65 versus −2.29; probability 89.9%), with numerically greater improvement than in-trial adalimumab (−2.51). For secondary end points, greater efficacy was observed with ABBV-3373 compared to historical adalimumab; ABBV-3373 was predicted with 79.3-99.5% probability to be more effective than adalimumab based on combined in-trial/historical adalimumab data. Of the ABBV-3373-treated patients who achieved DAS28-CRP ≤3.2 at week 12, 70.6% maintained this response at week 24 despite switching to placebo. Four serious adverse events (SAEs) were reported with ABBV-3373 (noncardiac chest pain, pneumonia, upper respiratory tract infection, and anaphylactic shock) and 2 SAEs with adalimumab (breast abscess and bronchitis). After increasing the duration of IV ABBV-3373 administration from 3 minutes to 15-30 minutes, no similar events of anaphylactic shock were reported.Conclusion. Data from this proof-of-concept trial support the continued development of a TNF-GRM ADC for the treatment of RA, with the potential to achieve superior outcomes compared to currently available therapies.