This study demonstrates feasibility and proof-of-concept of class I PI3K inhibition in patients with advanced cancers. BKM120, at the MTD of 100 mg/d, is safe and well tolerated, with a favorable PK profile, clear evidence of target inhibition, and preliminary antitumor activity.

Pathogenic gain-of-function variants in the genes encoding phosphoinositide 3-kinase δ (PI3Kδ) lead to accumulation of transitional B cells and senescent T cells, lymphadenopathy, and immune deficiency (activated PI3Kδ syndrome [APDS]). Knowing the genetic etiology of APDS afforded us the opportunity to explore PI3Kδ inhibition as a precision-medicine therapy. Here, we report in vitro and in vivo effects of inhibiting PI3Kδ in APDS. Treatment with leniolisib (CDZ173), a selective PI3Kδ inhibitor, caused dose-dependent suppression of PI3Kδ pathway hyperactivation (measured as phosphorylation of AKT/S6) in cell lines ectopically expressing APDS-causative p110δ variants and in T-cell blasts derived from patients. A clinical trial with 6 APDS patients was conducted as a 12-week, open-label, multisite, within-subject, dose-escalation study of oral leniolisib to assess safety, pharmacokinetics, and effects on lymphoproliferation and immune dysregulation. Oral leniolisib led to a dose-dependent reduction in PI3K/AKT pathway activity assessed ex vivo and improved immune dysregulation. We observed normalization of circulating transitional and naive B cells, reduction in PD-1CD4 and senescent CD57CD4 T cells, and decreases in elevated serum immunoglobulin M and inflammatory markers including interferon γ, tumor necrosis factor, CXCL13, and CXCL10 with leniolisib therapy. After 12 weeks of treatment, all patients showed amelioration of lymphoproliferation with lymph node sizes and spleen volumes reduced by 39% (mean; range, 26%-57%) and 40% (mean; range, 13%-65%), respectively. Thus, leniolisib was well tolerated and improved laboratory and clinical parameters in APDS, supporting the specific inhibition of PI3Kδ as a promising new targeted therapy in APDS and other diseases characterized by overactivation of the PI3Kδ pathway. This trial was registered at www.clinicaltrials.gov as #NCT02435173.

ABSTRACT:The aim of this study was to evaluate different physiologically based modeling strategies for the prediction of human pharmacokinetics. Plasma profiles after intravenous and oral dosing were simulated for 26 clinically tested drugs. Two mechanism-based predictions of human tissue-to-plasma partitioning (P tp ) from physicochemical input (method Vd1) were evaluated for their ability to describe human volume of distribution at steady state (V ss ). This method was compared with a strategy that combined predicted and experimentally determined in vivo rat P tp data (method Vd2). Best V ss predictions were obtained using method Vd2, providing that rat P tp input was corrected for interspecies differences in plasma protein binding (84% within 2-fold). V ss predictions from physicochemical input alone were poor (32% within 2-fold). Total body clearance (CL) was predicted as the sum of scaled rat renal clearance and hepatic clearance projected from in vitro metabolism data. Best CL predictions were obtained by disregarding both blood and microsomal or hepatocyte binding (method CL2, 74% within 2-fold), whereas strong bias was seen using both blood and microsomal or hepatocyte binding (method CL1, 53% within 2-fold). The physiologically based pharmacokinetics (PBPK) model, which combined methods Vd2 and CL2 yielded the most accurate predictions of in vivo terminal half-life (69% within 2-fold). The Gastroplus advanced compartmental absorption and transit model was used to construct an absorption-disposition model and provided accurate predictions of area under the plasma concentration-time profile, oral apparent volume of distribution, and maximum plasma concentration after oral dosing, with 74%, 70%, and 65% within 2-fold, respectively. This evaluation demonstrates that PBPK models can lead to reasonable predictions of human pharmacokinetics.In the drug discovery process considerable resources are required to assess the pharmacokinetic (PK) properties of potential drug candidates in vivo in animals. To optimize the use of such in vivo testing, there has been a growing interest in predicting the PK behavior of drug candidates (Theil et al., 2003;van de Waterbeemd and Gifford, 2003). If sufficiently reliable, such simulations could also help to select the most promising candidates for development and reject those with a low probability of success (van de Waterbeemd and Gifford, 2003).The majority of the approaches to predict human PK developed to date typically focus on the drug's behavior in individual processes of absorption, distribution, metabolism and excretion (ADME). The characterization of a drug's PK in a complex biological system is best described by assembling these processes in one global model. In this context, physiologically based pharmacokinetics (PBPK) models have been developed (Bischoff, 1986). PBPK models map the complex drug transport scheme onto a physiologically realistic compartmental structure (Fig. 1). The major structural elements of the PBPK disposition model are derived from the anato...

Purpose: Phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway activation in patients with HER2-positive (HER2 þ ) breast cancer has been implicated in de novo and acquired trastuzumab resistance.The purpose of this study was to determine the clinical activity of the PI3K inhibitor buparlisib (BKM120) in patients with HER2 þ advanced/metastatic breast cancer resistant to trastuzumab-based therapy.Experimental Design: In the dose-escalation portion of this phase I/II study, patients with trastuzumabresistant locally advanced or metastatic HER2 þ breast cancer were treated with daily oral doses of buparlisib and weekly intravenous trastuzumab (2 mg/kg). Dose escalation was guided by a Bayesian logistic regression model with overdose control. Results: Of 18 enrolled patients, 17 received buparlisib. One dose-limiting toxicity of grade 3 general weakness was reported at the 100-mg/day dose level (the single-agent maximum tolerated dose) and this dose level was declared the recommended phase II dose (RP2D) of buparlisib in combination with trastuzumab. Common (>25%) adverse events included rash (39%), hyperglycemia (33%), and diarrhea (28%). The pharmacokinetic profile of buparlisib was not affected by its combination with trastuzumab. At the RP2D, there were two (17%) partial responses, 7 (58%) patients had stable disease (!6 weeks), and the disease control rate was 75%. Pharmacodynamic studies showed inhibition of the PI3K/AKT/mTOR and RAS/MEK/ERK pathways.Conclusions: In this patient population, the combination of buparlisib and trastuzumab was well tolerated, and preliminary signs of clinical activity were observed. The phase II portion of this study will further explore the safety and efficacy of this combination at the RP2D. Clin Cancer Res; 20(7); 1935-45. Ó2014 AACR.

Programmed ribosomal frameshifting (PRF) is a fundamental gene expression event in many viruses, including SARS-CoV-2. It allows production of essential viral, structural and replicative enzymes that are encoded in an alternative reading frame. Despite the importance of PRF for the viral life cycle, it is still largely unknown how and to what extent cellular factors alter mechanical properties of frameshift elements and thereby impact virulence. This prompted us to comprehensively dissect the interplay between the SARS-CoV-2 frameshift element and the host proteome. We reveal that the short isoform of the zinc-finger antiviral protein (ZAP-S) is a direct regulator of PRF in SARS-CoV-2 infected cells. ZAP-S overexpression strongly impairs frameshifting and inhibits viral replication. Using in vitro ensemble and single-molecule techniques, we further demonstrate that ZAP-S directly interacts with the SARS-CoV-2 RNA and interferes with the folding of the frameshift RNA element. Together, these data identify ZAP-S as a host-encoded inhibitor of SARS-CoV-2 frameshifting and expand our understanding of RNA-based gene regulation.

ABSTRACT:The aim of this study was to assess a physiologically based modeling approach for predicting drug metabolism, tissue distribution, and bioavailability in rat for a structurally diverse set of neutral and moderate-to-strong basic compounds (n ‫؍‬ 50). Hepatic blood clearance (CL h ) was projected using microsomal data and shown to be well predicted, irrespective of the type of hepatic extraction model (80% within 2-fold). Best predictions of CL h were obtained disregarding both plasma and microsomal protein binding, whereas strong bias was seen using either blood binding only or both plasma and microsomal protein binding. Two mechanistic tissue composition-based equations were evaluated for predicting volume of distribution (V dss ) and tissue-to-plasma partitioning (P tp ). A first approach, which accounted for ionic interactions with acidic phospholipids, resulted in accurate predictions of V dss (80% within 2-fold). In contrast, a second approach, which disregarded ionic interactions, was a poor predictor of V dss (60% within 2-fold). The first approach also yielded accurate predictions of P tp in muscle, heart, and kidney (80% within 3-fold), whereas in lung, liver, and brain, predictions ranged from 47% to 62% within 3-fold. Using the second approach, P tp prediction accuracy in muscle, heart, and kidney was on average 70% within 3-fold, and ranged from 24% to 54% in all other tissues. Combining all methods for predicting V dss and CL h resulted in accurate predictions of the in vivo half-life (70% within 2-fold). Oral bioavailability was well predicted using CL h data and Gastroplus Software (80% within 2-fold). These results illustrate that physiologically based prediction tools can provide accurate predictions of rat pharmacokinetics.Obtaining rapid information regarding the pharmacokinetics (PK) of new drug candidates can be a bottleneck in early drug discovery. Considerable resources are required to assess the PK properties of potential drug candidates in vivo in animals. To optimize the use of such in vivo testing, there has been a growing interest in predicting the PK behavior of drug candidates as early as possible (Norris et al., 2000;van de Waterbeemd and Gifford, 2003). If sufficiently reliable, such simulations could also help to select the best candidates for development and to reject those with a low probability of success.The characterization of a drug's PK requires elucidation of each of the coincident processes of absorption, distribution, metabolism, and elimination (ADME). A large number of methodologies have been established for this purpose, including empirical and physiologically based methods (Boxenbaum and Ronfeld, 1983;Theil et al., 2003). Until recently, PK prediction has been predominantly descriptive, using empirical methods. Although in some cases these methods give good predictions, their physiological basis is low and inaccurate results can be obtained, in particular when there are large interspecies differences in metabolic clearance (Lave et al., 1995;Zuegge et al., ...

22 23 on July 5, 2020 by guest http://aac.asm.org/ Downloaded from 3 ABSTRACT (250/250 words) 24 Baloxavir marboxil, a prodrug of cap-dependent endonuclease inhibitor, baloxavir acid, 25 reduces the time to improvement of influenza symptoms in patients infected with type A or 26 B influenza virus. To characterize its pharmacokinetics, a population pharmacokinetic 27 model for baloxavir acid was developed using 11846 plasma concentration data items from 28 1827 subjects including 2341 plasma concentration data items from 664 patients at high 29 risk of influenza complications. A three-compartment model with first-order elimination 30 and first-order absorption with lag time well described the plasma concentration data. Body 31 weight and race were found to be the most important factors influencing clearance and 32 volume of distribution. The exposures in high-risk patients were similar to those in 33 otherwise healthy patients, and no pharmacokinetic difference was identified regarding any 34 risk factors for influenza complications.35 Exposure-response analyses were performed regarding the time to improvement of 36 symptoms and the reduction in the influenza virus titer in high-risk patients. The analyses 37 suggested that body weight-based dosage, 40 mg for patients weighing < 80 kg and 80 mg 38 for patients weighing ≥ 80 kg, can shorten the time to improvement of influenza symptoms 39 and reduce virus titer for both type A and B influenza virus regardless of the exposure 40 on July 5, 2020 by guest http://aac.asm.org/ Downloaded from 4 levels of the high-risk patients as well as for the otherwise healthy influenza patients. 41 The results of our population pharmacokinetic and exposure-response analyses in patients 42 with risk factors of influenza complications should provide useful information on the 43 pharmacokinetic and pharmacodynamic characteristics of baloxavir marboxil and also for 44

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