Model-based comparisons of post-treatment free IgE and FEV1 between omalizumab asthma dosing tables in the United States and European Union.

AIMS: Omalizumab is an anti-immunoglobulin E (IgE) monoclonal antibody that was first approved by the United States (US) Food and Drug Administration (FDA) for the treatment of allergic asthma in 2003. The pivotal trials supporting the initial approval of omalizumab used dosing determined by patient's baseline IgE and body weight, with the goal of reducing the mean free IgE level to approximately 25 ng/mL or less. While the underlying parameters supporting the dosing table remained the same, subsequent studies and analyses have resulted in approved alternative versions of the dosing table, including the European Union (EU) asthma dosing table, which differs in weight bands and maximum allowable baseline IgE and omalizumab dose. In this study, we leveraged modelling and simulation approaches to predict and compare the free IgE reduction and forced expiratory volume in 1 second (FEV1) improvement with omalizumab dosing based on the US and EU asthma dosing tables. METHODS: Previously established population pharmacokinetic-IgE and IgE-FEV1 models were used to predict and compare post-treatment free IgE and FEV1 based on the US and EU dosing tables. Clinical trial simulations (with virtual asthma populations) and Monte Carlo simulations were performed to provide both breadth and depth in the comparisons. RESULTS: The US and EU asthma dosing tables were predicted to result in generally comparable free IgE suppression and FEV1 improvement. CONCLUSIONS: Despite the similar free IgE and FEV1 outcomes from simulations, this has not been clinically validated with respect to the registrational endpoint of reduction in annualized asthma exacerbations.

Bioequivalence Between a New Omalizumab Prefilled Syringe With an Autoinjector or with a Needle Safety Device Compared with the Current Prefilled Syringe: A Randomized Controlled Trial in Healthy Volunteers.

Omalizumab is an anti-IgE monoclonal antibody currently approved for the treatment of asthma, nasal polyps/chronic rhinosinusitis with nasal polyps, and chronic spontaneous urticaria. Omalizumab is available as an injection in a prefilled syringe (PFS) with a needle safety device (NSD). New product configurations were developed to reduce the number of injections per dose administration, improve patient convenience and treatment compliance. The objective of this randomized open-label 12-week study was to demonstrate pharmacokinetic bioequivalence between (1) new PFS with autoinjector (PFS-AI), (2) new PFS-NSD configuration, and (3) current PFS-NSD configuration. Each new configuration was considered bioequivalent to the current configuration if the confidence intervals (CIs) for the geometric mean ratios (GMR) were contained in the 0.80-1.25 range for maximum concentration (Cmax), area under the concentration-time curve until the last quantifiable measurement (AUClast), and AUC extrapolated to infinity (AUCinf). Safety was assessed throughout the study. In total, 193 healthy volunteers were randomized at 1:1:1 ratio to omalizumab 1×300 mg/2 mL via new PFS-AI (n = 66), omalizumab 1×300 mg/2 mL via new PFS-NSD (n = 64), or omalizumab 2×150 mg/1 mL via current PFS-NSD (n = 63). Comparing new PFS-AI versus current PFS-NSD, the GMRs were: Cmax, 1.085; AUClast, 1.093; AUCinf, 1.100. Comparing new PFS-NSD versus current PFS-NSD, the GMRs were: Cmax, 1.006; AUClast, 1.016; AUCinf, 1.027. The 95% CIs for all GMR parameters were contained within the 0.80-1.25 range. Safety findings were consistent with the known safety profile of omalizumab. Single-dose omalizumab administered as the new PFS-AI or new PFS-NSD was bioequivalent to the current PFS-NSD.

In vivo functional immunoprotection correlates for vaccines against invasive bacteria.

Vaccination has significantly reduced the incidence of invasive infections caused by several bacterial pathogens, including Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis. However, no vaccines are available for many other invasive pathogens. A major hurdle in vaccine development is the lack of functional markers to quantify vaccine immunity in eliminating pathogens during the process of infection. Based on our recent discovery of the liver as the major organ of vaccine-induced clearance of blood-borne virulent bacteria, we here describe a new vaccine evaluation system that quantitatively characterizes the key features of effective vaccines in shuffling virulent bacteria from the blood circulation to the liver resident macrophage Kupffer cells (KCs) and sinusoidal endothelial cells (LSECs) in mouse septic infection model. This system consists of three related correlates or assays: pathogen clearance from the bloodstream, pathogen trapping in the liver, and pathogen capture by KCs/LSECs. These readouts were consistently associated with the serotype-specific immunoprotection levels of the 13-valent pneumococcal polysaccharide conjugate vaccine (PCV13) against lethal infection of S. pneumoniae, a major invasive Gram-positive pathogen of community-acquired infections in humans. Furthermore, the reliability and sensitivity of these correlates in reflecting vaccine efficacy were verified with whole cell vaccines of Klebsiella pneumoniae and Escherichia coli, two major Gram-negative pathogens in hospital-acquired invasive infections. This system may be used as effective readouts to evaluate the immunoprotective potential of vaccine candidates in the preclinical phase by filling the current technical gap in vaccine evaluation between the conventional in vitro approaches (e.g. antibody production and pathogen neutralization/opsonophagocytosis) and survival of immunized animals.

Liver macrophages and sinusoidal endothelial cells execute vaccine-elicited capture of invasive bacteria.

Vaccination has substantially reduced the morbidity and mortality of bacterial diseases, but mechanisms of vaccine-elicited pathogen clearance remain largely undefined. We report that vaccine-elicited immunity against invasive bacteria mainly operates in the liver. In contrast to the current paradigm that migrating phagocytes execute vaccine-elicited immunity against blood-borne pathogens, we found that invasive bacteria are captured and killed in the liver of vaccinated host via various immune mechanisms that depend on the protective potency of the vaccine. Vaccines with relatively lower degrees of protection only activated liver-resident macrophage Kupffer cells (KCs) by inducing pathogen-binding immunoglobulin M (IgM) or low amounts of IgG. IgG-coated pathogens were directly captured by KCs via multiple IgG receptors FcγRs, whereas IgM-opsonized bacteria were indirectly bound to KCs via complement receptors of immunoglobulin superfamily (CRIg) and complement receptor 3 (CR3) after complement C3 activation at the bacterial surface. Conversely, the more potent vaccines engaged both KCs and liver sinusoidal endothelial cells by inducing higher titers of functional IgG antibodies. Endothelial cells (ECs) captured densely IgG-opsonized pathogens by the low-affinity IgG receptor FcγRIIB in a "zipper-like" manner and achieved bacterial killing predominantly in the extracellular milieu via an undefined mechanism. KC- and endothelial cell-based capture of antibody-opsonized bacteria also occurred in FcγR-humanized mice. These vaccine protection mechanisms in the liver not only provide a comprehensive explanation for vaccine-/antibody-boosted immunity against invasive bacteria but also may serve as in vivo functional readouts of vaccine efficacy.

Identification of the mouse Kupffer cell receptors recognizing pneumococcal capsules by affinity screening.

Kupffer cells (KCs) are the major sentinels to guard the bloodstream by recognizing diverse microbial ligands of blood-borne pathogens. Here, we establish a protocol for identifying the KC receptors recognizing the capsular polysaccharides (CPSs) of low-virulence Streptococcus pneumoniae in a mouse model. This protocol includes preparation of CPS-coated microspheres and KC membrane proteins, affinity pulldown of CPS-binding proteins, and functional validation of the CPS receptors. This protocol provides a platform to investigate the receptor-ligand interactions between KCs and encapsulated bacteria. For complete details on the use and execution of this protocol, please refer to An et al. (2022).1.

Functional vulnerability of liver macrophages to capsules defines virulence of blood-borne bacteria.

Many encapsulated bacteria use capsules to cause invasive diseases. However, it remains largely unknown how the capsules enhance bacterial virulence under in vivo infection conditions. Here we show that the capsules primarily target the liver to enhance bacterial survival at the onset of blood-borne infections. In a mouse sepsis model, the capsules enabled human pathogens Streptococcus pneumoniae and Escherichia coli to circumvent the recognition of liver-resident macrophage Kupffer cells (KCs) in a capsular serotype-dependent manner. In contrast to effective capture of acapsular bacteria by KCs, the encapsulated bacteria are partially (low-virulence types) or completely (high-virulence types) "untouchable" for KCs. We finally identified the asialoglycoprotein receptor (ASGR) as the first known capsule receptor on KCs to recognize the low-virulence serotype-7F and -14 pneumococcal capsules. Our data identify the molecular interplay between the capsules and KCs as a master controller of the fate and virulence of encapsulated bacteria, and suggest that the interplay is targetable for therapeutic control of septic infections.

Pharmacokinetics and exposure-efficacy relationships of omalizumab in patients with nasal polyps.

The anti-immunoglobulin E (IgE) antibody, omalizumab (Xolair), is approved in the United States for the treatment of allergic asthma and chronic spontaneous urticaria, and has recently been studied for the treatment of nasal polyposis following completion of the two replicate phase 3 studies (POLYP 1 and POLYP 2). The dosing of omalizumab used in the phase 3 studies is based on a combination of patients' pre-treatment IgE level and body weight, similar to the approach used in allergic asthma. The objectives of the current analyses were to evaluate whether the pharmacokinetics (PK) of omalizumab and its pharmacodynamic (PD) effect on free and total IgE level in chronic rhinosinusitis with nasal polyps (CRSwNP) are consistent with those in allergic asthma via population PK/PD modeling and simulation, and to graphically explore exposure-response relationships and free IgE-response relationships in CRSwNP. Omalizumab PK and PD effect of total and free IgE in CRSwNP are generally consistent with those in asthma. Observed post-treatment free IgE suppressions were generally within the target range of the baseline IgE- and body weight-based omalizumab dosing table, with 74.2% and 93.0% of patients achieving a serum free IgE level below 25 ng/mL and 50 ng/mL, respectively at Week 24. Exposure-response analyses indicated that there was no clear correlation between omalizumab or free IgE concentration and key efficacy endpoints within the POLYP studies. Overall, these results indicate that the body weight and IgE-based dosing regimen of omalizumab was appropriate for use in CRSwNP patients.

Structural basis of NF-κB signaling by the p75 neurotrophin receptor interaction with adaptor protein TRADD through their respective death domains.

The p75 neurotrophin receptor (p75NTR) is a critical mediator of neuronal death and tissue remodeling and has been implicated in various neurodegenerative diseases and cancers. The death domain (DD) of p75NTR is an intracellular signaling hub and has been shown to interact with diverse adaptor proteins. In breast cancer cells, binding of the adaptor protein TRADD to p75NTR depends on nerve growth factor and promotes cell survival. However, the structural mechanism and functional significance of TRADD recruitment in neuronal p75NTR signaling remain poorly understood. Here we report an NMR structure of the p75NTR-DD and TRADD-DD complex and reveal the mechanism of specific recognition of the TRADD-DD by the p75NTR-DD mainly through electrostatic interactions. Furthermore, we identified spatiotemporal overlap of p75NTR and TRADD expression in developing cerebellar granule neurons (CGNs) at early postnatal stages and discover the physiological relevance of the interaction between TRADD and p75NTR in the regulation of canonical NF-κB signaling and cell survival in CGNs. Our results provide a new structural framework for understanding how the recruitment of TRADD to p75NTR through DD interactions creates a membrane-proximal platform, which can be efficiently regulated by various neurotrophic factors through extracellular domains of p75NTR, to propagate downstream signaling in developing neurons.

Pharmacokinetics of Nilotinib in Pediatric Patients with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia or Acute Lymphoblastic Leukemia.

PURPOSE: We investigated nilotinib exposure in pediatric patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) resistant to, relapsed on, refractory to, or intolerant of previous treatment. PATIENTS AND METHODS: Fifteen patients (aged 1-<18 years) with CML resistant to or intolerant of imatinib and/or dasatinib (n = 11) or Ph+ ALL relapsed on or refractory to standard therapy (n = 4) enrolled in this phase I study. Nilotinib (230 mg/m2 twice daily; equivalent to the adult 400-mg twice-daily dose) was administered orally in 12 or 24 cycles of 28 days. The primary objective was to characterize the pharmacokinetics of nilotinib in pediatric patients. RESULTS: The area under the concentration-time curve at steady state was slightly lower in pediatric patients versus adults (14,751.4 vs. 17,102.9 ng/h/mL); the geometric mean ratio (GMR; pediatric:adult) was 0.86 [90% confidence interval (CI), 0.70-1.06]. Body surface area-adjusted systemic clearance was slightly higher in pediatric versus adult patients (GMR, 1.30; 90% CI, 1.04-1.62). Nilotinib was generally well tolerated. The most common adverse events were headache, vomiting, increased blood bilirubin, and rash. Three patients with CML achieved major molecular response, and three with Ph+ ALL achieved complete remission. CONCLUSIONS: Nilotinib 230 mg/m2 twice daily in pediatric patients provided a pharmacokinetics and safety profile comparable with the adult reference dose; clinical activity was demonstrated in both CML and Ph+ ALL. This dose is recommended for further evaluation in pediatric patients. The safety profile was consistent with that in adults.

Disposition of asciminib, a potent BCR-ABL1 tyrosine kinase inhibitor, in healthy male subjects.

Asciminib is a potent, specific BCR-ABL1 inhibitor being developed for the treatment of patients with chronic myelogenous leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph + ALL).Here, we present the results of human oral absorption, distribution, metabolism, excretion (ADME) and in vitro studies that together provide an overall understanding of the metabolism, distribution and clearance of asciminib in humans.Asciminib was rapidly absorbed with a maximum plasma concentration at two hours post-dose. Total radioactivity and asciminib showed similar terminal half-lives in plasma.Oral asciminib absorption ranged between a minimum of 33%, and a maximum of 57% based on the metabolite profiles of late time-point feces collections.Asciminib was eliminated mainly through feces via unchanged asciminib excretion and metabolism.Direct glucuronidation and oxidation were major metabolic pathways in human that were catalyzed predominantly by UDP-glucuronosyltransferase (UGT)2B7 and cytochrome P450 (CYP)3A4, respectively.The relative contribution of the glucuronidation pathway to the total clearance of asciminib via metabolism is estimated to range ∼28-58%, whereas the relative contribution of the oxidative pathway is estimated to range ∼37-64%, based upon the maximum oral absorption in humans.

Physiologically Based Pharmacokinetic Modeling to Supplement Nilotinib Pharmacokinetics and Confirm Dose Selection in Pediatric Patients.

In adult patients, nilotinib is indicated for chronic myeloid leukemia at an approved oral dose of 300 or 400 mg BID. Physiologically based pharmacokinetic (PBPK) model was developed to describe and supplement limited PK data in the pediatric population ranging from 2 to less than 6 years of age and ultimately inform dosing regimen. An adult Simcyp PBPK model was established and verified with clinical pharmacokinetic data after a single or multiple oral doses of 400 mg nilotinib (230 mg/m2). The model was then applied to a pediatric PBPK model, taking account of ontogeny profiles of metabolizing enzymes and pediatric physiological parameters. The model was further verified using observed pediatric PK data in 12- to <18-year-old and from 6- to <12-year-old patients. The PBPK models were able to recover, describe, and supplement the limited nilotinib concentration-time data profile in 2- to <6-year-old patients after a single dose and Cmin,ss after BID dosing. The exposure (Cmax,ss, Cmin,ss, and AUCtau,ss) was predicted to be similar across age groups. PBPK model simulations confirmed that body surface area-normalized dosing regimen of 230 mg/m2 is considered appropriate for pediatric patients >2 to <18 years of age.

Relative Bioavailability and Food Effect Evaluation for 2 Tablet Formulations of Asciminib in a 2-Arm, Crossover, Randomized, Open-Label Study in Healthy Volunteers.

Asciminib (ABL001) is an orally administered allosteric inhibitor of the BCR-ABL tyrosine kinase. The current study evaluated the relative bioavailability of its 2 tablet variants, AAA and NXA, compared with the capsule CSF and assessed the impact of food in healthy participants in a 2-arm, randomized, open-label, 4-way crossover design. The primary pharmacokinetic parameters analyzed were area under the plasma concentration-time curve (AUC) from time 0 to the time of last measurable concentration (AUClast ), AUC from time 0 to infinity (AUCinf ), and peak concentration (Cmax ). Forty-five healthy volunteers were enrolled, 22 in the AAA arm and 23 in the NXA arm. Under fasting conditions, the AUCinf , AUClast , and Cmax of the AAA tablet were similar to those of the capsule, but slightly higher (∼20%) for NXA and decreased with a high-fat meal (∼65%) and a low-fat meal (∼30%) for both tablet formulations. Overall, 20 participants (9 in the AAA arm; 11 in the NXA arm) experienced at least 1 adverse event, the most common in both arms being headache. The study showed that under fasting conditions, tablet AAA had bioavailability similar to that in the capsule CSF. The bioavailability of both tablet formulations decreased with food, with a more pronounced effect observed with a high-fat meal.

Clinical Pharmacokinetic and Pharmacodynamic Overview of Nilotinib, a Selective Tyrosine Kinase Inhibitor.

Nilotinib, an oral inhibitor of the tyrosine kinase activity of Abelson protein, is approved for the treatment of patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase and patients with CML in chronic phase or accelerated phase resistant or intolerant to prior therapies. This review describes the pharmacokinetic and pharmacodynamic data of nilotinib in patients with CML and in healthy volunteers. Nilotinib is rapidly absorbed, with a peak serum concentration approximately 3 hours after dosing. The area under the plasma drug concentration-time curve over 24 hours and the peak serum concentration of nilotinib were dose proportional from 50-400 mg once daily. The metabolism of nilotinib is primarily via hepatic cytochrome P450 (CYP) 3A4 according to in vitro studies. In the clinical setting, exposure to nilotinib was significantly reduced by the induction of CYP3A4 with rifampicin and significantly increased by the inhibition of CYP3A with ketoconazole. Additionally, nilotinib is a competitive inhibitor of CYP3A4/5, CYP2C8, CYP2C9, CYP2D6, and uridine diphosphate glucuronosyltransferase 1A1. The bioavailability of nilotinib is increased by up to 82% when given with a high-fat meal compared with fasted state. There is a positive correlation between the occurrences of all-grade total bilirubin elevations and the steady-state nilotinib trough concentrations. Fredericia method corrected QT interval change from baseline was observed to have a correlation with nilotinib exposure. No significant relationship between nilotinib exposure and major molecular response at 12 months was seen at therapeutic doses of nilotinib 300-400 mg, probably due to the narrow range of the doses investigated.

A phase I open-label dose-escalation study of the anti-HER3 monoclonal antibody LJM716 in patients with advanced squamous cell carcinoma of the esophagus or head and neck and HER2-overexpressing breast or gastric cancer.

BACKGROUND: Human epidermal growth factor receptor 3 (HER3) is important in maintaining epidermal growth factor receptor-driven cancers and mediating resistance to targeted therapy. A phase I study of anti-HER3 monoclonal antibody LJM716 was conducted with the primary objective to identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE), and dosing schedule. Secondary objectives were to characterize safety/tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity. METHODS: This open-label, dose-finding study comprised dose escalation, followed by expansion in patients with squamous cell carcinoma of the head and neck or esophagus, and HER2-overexpressing metastatic breast cancer or gastric cancer. During dose escalation, patients received LJM716 intravenous once weekly (QW) or every two weeks (Q2W), in 28-day cycles. An adaptive Bayesian logistic regression model was used to guide dose escalation and establish the RDE. Exploratory pharmacodynamic tumor studies evaluated modulation of HER3 signaling. RESULTS: Patients received LJM716 3-40 mg/kg QW and 20 mg/kg Q2W (54 patients; 36 patients at 40 mg/kg QW). No dose-limiting toxicities (DLTs) were reported during dose-escalation. One patient experienced two DLTs (diarrhea, hypokalemia [both grade 3]) in the expansion phase. The RDE was 40 mg/kg QW, providing drug levels above the preclinical minimum effective concentration. One patient with gastric cancer had an unconfirmed partial response; 17/54 patients had stable disease, two lasting >30 weeks. Down-modulation of phospho-HER3 was observed in paired tumor samples. CONCLUSIONS: LJM716 was well tolerated; the MTD was not reached, and the RDE was 40 mg/kg QW. Further development of LJM716 is ongoing. TRIAL REGISTRATION: Clinicaltrials.gov registry number NCT01598077 (registered on 4 May, 2012).

Discovery of HSD-621 as a Potential Agent for the Treatment of Type 2 Diabetes.

11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) catalyzes the conversion of inactive glucocorticoid cortisone to its active form, cortisol. The glucocorticoid receptor (GR) signaling pathway has been linked to the pathophysiology of diabetes and metabolic syndrome. Herein, the structure-activity relationship of a series of piperazine sulfonamide-based 11ß-HSD1 inhibitors is described. (R)-3,3,3-Trifluoro-2-(5-(((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-yl)sulfonyl)thiophen-2-yl)-2-hydroxypropanamide 18a (HSD-621) was identified as a potent and selective 11ß-HSD1 inhibitor and was ultimately selected as a clinical development candidate. HSD-621 has an attractive overall pharmaceutical profile and demonstrates good oral bioavailability in mouse, rat, and dog. When orally dosed in C57/BL6 diet-induced obesity (DIO) mice, HSD-621 was efficacious and showed a significant reduction in both fed and fasting glucose and insulin levels. Furthermore, HSD-621 was well tolerated in drug safety assessment studies.

ARC15105 is a potent antagonist of von Willebrand factor mediated platelet activation and adhesion.

OBJECTIVE: We investigated the stability, pharmacokinetic, and pharmacodynamic profile of the 2(nd) generation anti-von Willeband factor aptamer ARC15105. METHODS AND RESULTS: Platelet plug formation was measured by collagen/adenosine diphosphate-induced closure time with the platelet function analyzer-100 and platelet aggregation by multiple electrode aggregometry. Platelet adhesion was measured on denuded porcine aortas and in a flow chamber. Aptamer stability was assessed by incubation in nuclease rich human, monkey, and rat serum for up to 72 hours. Pharmacokinetic and pharmacodynamic profiles were tested in cynomolgus monkeys after IV and SC administration. The median IC(100) and IC(50) to prolong collagen/adenosine diphosphate-induced closure timewere 27 nmol/L and 12 nmol/L, respectively. ARC15105 (1.3 µmol/L) completely inhibited ristocetin-induced platelet aggregation in whole blood (P<0.001), but also diminished collagen, ADP, arachidonic acid, and thrombin receptor activating peptide-induced platelet aggregation to some extent (P<0.05). ARC15105 (40 nmol/L) decreased platelet adhesion by >90% on denuded porcine aortas (P<0.001), which was comparable to the degree of inhibition obtained with abciximab. ARC15105 (100 nmol/L) also inhibited platelet adhesion to collagen under arterial shear in a flow chamber by >90% (P<0.001). The IV and SC terminal half-lives in cynomolgus monkeys were 67 and 65 hours, respectively, and the SC bioavailability was ≈98%. Allometric scaling estimates the human T(1/2) would be ≈217 hours. Pharmacodynamic analysis confirms that ARC15105 inhibits von Willeband factor activity >90% in blood samples taken 300 hours after a 20 mg/kg IV or SC dose in monkeys. CONCLUSIONS: The potency, pharmacokinetic profile, and SC bioavailability of ARC15105 support its clinical investigation for chronic inhibition of von Willeband factor -mediated platelet activation.

Comparative pharmacokinetics and metabolism studies in lean and diet- induced obese mice: an animal efficacy model for 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibitors.

Diet-induced obese (DIO) mice have been commonly used as an animal model in the efficacy assessment for new drug candidates. Although high-fat feeding has been reported to cause profound physiological changes, including the expression of drug-metabolizing enzymes, limited studies have been reported regarding the effect of obesity/diabetes on pharmacokinetics (PK) in animals. In this study, we investigated PK profiles of three 11 -HSD-1 inhibitors in the DIO mice and compared them to the normal lean mice. After oral administration, the in vivo exposure (AUC) of all three compounds was higher in DIO mice, which was consistent with the observed lower systemic clearance (CL) in DIO mice compared to lean mice. As illustrated by Compound E, a compound metabolized predominantly by CYP3A and 2C, the metabolic profiles for Compound E were qualitatively similar between DIO and lean mice, but quantitatively lower in the DIO mice. Indeed, P-450 activities for CYP3A and 2C as well as 2D were found to be lower in liver microsomes prepared from DIO mice. The calculated hepatic clearance (CLH) from in vitro studies with liver microsomes correlated well with the observed in vivo clearance for both DIO and lean mice. The calculated oral bioavailability (F%) based on intrinsic hepatic clearance (C(LH, int)) predicted ~3 fold increase in F% for the DIO mice, which was comparable to the observed value. Collectively, these data suggest that the higher F% is most likely due to the lower first-pass effect in DIO mice. This study highlights the needs to take caution when extrapolating PK and exposure data from healthy animals to diseased animals in designing pharmacological studies.

Efficacious 11beta-hydroxysteroid dehydrogenase type I inhibitors in the diet-induced obesity mouse model.

Cortisol and the glucocorticoid receptor signaling pathway have been implicated in the development of diabetes and obesity. The reduction of cortisone to cortisol is catalyzed by 11beta-hydroxysteroid dehydrogenase type I (11beta-HSD1). 2,4-Disubsituted benzenesulfonamides were identified as potent inhibitors of both the human and mouse enzymes. The lead compounds displayed good pharmacokinetics and ex vivo inhibition of the target in mice. Cocrystal structures of compounds 1 and 20 bound to human 11beta-HSD1 were obtained. Compound 20 was found to achieve high concentrations in target tissues, resulting in 95% inhibition in the ex vivo assay when dosed with a food mix (0.5 mg of drug per g of food) after 4 days. Compound 20 was efficacious in a mouse diet-induced obesity model and significantly reduced fed glucose and fasted insulin levels. Our findings suggest that 11beta-HSD1 inhibition may be a valid target for the treatment of diabetes.

Integration of preclinical and clinical data with pharmacokinetic modeling and simulation to evaluate fexofenadine as a probe for hepatobiliary transport function.

PURPOSE: The suitability of fexofenadine as a probe substrate to assess hepatobiliary transport function in humans was evaluated by pharmacokinetic modeling/simulation and in vitro/in situ studies using chemical modulators. METHODS: Simulations based on a pharmacokinetic model developed to describe fexofenadine disposition in humans were conducted to examine the impact of altered hepatobiliary transport on fexofenadine disposition. The effect of GF120918 on fexofenadine disposition was evaluated in human sandwich-cultured hepatocytes (SCH). Additionally, the effect of GF120918, bosentan, and taurocholate on fexofenadine disposition in perfused livers from TR(-) Wistar rats was examined. RESULTS: Based on modeling/simulation, fexofenadine systemic exposure was most sensitive to changes in the hepatic uptake rate constant, and did not reflect changes in hepatic exposure due to altered hepatic efflux. GF120918 did not impair fexofenadine biliary excretion in human SCH. GF120918 coadministration significantly decreased Cl'(biliary) to 27.5% of control in perfused rat livers. CONCLUSIONS: Simulations were in agreement with perfused liver data which predicted changes in fexofenadine systemic exposure primarily due to altered hepatic uptake. Fexofenadine is not a suitable probe to assess hepatic efflux function based on systemic concentrations. GF120918-sensitive protein(s) mediate fexofenadine biliary excretion in rat liver, whereas in human hepatocytes multiple efflux proteins are involved in fexofenadine hepatobiliary disposition.