Prospects of focal adhesion kinase inhibitors as a cancer therapy in preclinical and early phase study.

INTRODUCTION: FAK, a nonreceptor cytoplasmic tyrosine kinase, plays a crucial role in tumor metastasis, drug resistance, tumor stem cell maintenance, and regulation of the tumor microenvironment. FAK has emerged as a promising target for tumor therapy based on both preclinical and clinical data. AREAS COVERED: This paper aims to summarize the molecular mechanisms underlying FAK's involvement in tumorigenesis and progression. Encouraging results have emerged from ongoing clinical trials of FAK inhibitors. Additionally, we present an overview of clinical trials for FAK inhibitors, examining their potential as promising treatments. The pertinent studies gathered from databases including PubMed, ClinicalTrials.gov. EXPERT OPINION: Since the first finding in 1990s, targeting FAK has became the focus of interests in many pharmaceutical companies. Through 30 years' discovery, the industry and academy gradually realized the features of FAK target which may not be a driver gene but a solid defense system for the cancer initiation and development. Currently, the ongoing clinical regimens involving FAK inhibition are all the combination strategies in which FAK inhibitors can further strengthen the cancer cell killing effects of other testing agents. The emerging positive signal in clinical trials foresee targeting FAK as class will be an effective mean to fight against cancers.

Targeting of focal adhesion kinase enhances the immunogenic cell death of PEGylated liposome doxorubicin to optimize therapeutic responses of immune checkpoint blockade.

BACKGROUNDS: Immune checkpoint blockade (ICB) is widely considered to exert long-term treatment benefits by activating antitumor immunity. However, many cancer patients show poor clinical responses to ICB due in part to the lack of an immunogenic niche. Focal adhesion kinase (FAK) is frequently amplified and acts as an immune modulator across cancer types. However, evidence illustrates that targeting FAK is most effective in combination therapy rather than in monotherapy. METHODS: Here, we used drug screening, in vitro and in vivo assays to filter out that doxorubicin and its liposomal form pegylated liposome doxorubicin (PLD) showed synergistic anti-tumor effects in combination with FAK inhibitor IN10018. We hypothesized that anti-tumor immunity and immunogenic cell death (ICD) may be involved in the treatment outcomes through the data analysis of our clinical trial testing the combination of IN10018 and PLD. We then performed cell-based assays and animal studies to detect whether FAK inhibition by IN10018 can boost the ICD of PLD/doxorubicin and further established syngeneic models to test the antitumor effect of triplet combination of PLD, IN10018, and ICB. RESULTS: We demonstrated that the combination of FAK inhibitor IN10018, and PLD/doxorubicin exerted effective antitumor activity. Notably, the doublet combination regimen exhibited response latency and long-lasting treatment effects clinically, outcomes frequently observed in immunotherapy. Our preclinical study confirmed that the 2-drug combination can maximize the ICD of cancer cells. This approach primed the tumor microenvironment, supplementing it with sufficient tumor-infiltrating lymphocytes (TILs) to activate antitumor immunity. Finally, different animal studies confirmed that the antitumor effects of ICB can be significantly enhanced by this doublet regimen. CONCLUSIONS: We confirmed that targeting FAK by IN10018 can enhance the ICD of PLD/doxorubicin, further benefiting the anti-tumor effect of ICB. The animal tests of the triplet regimen warrant further discovery in the real world.

Simultaneous inhibition of FAK and ROS1 synergistically repressed triple-negative breast cancer by upregulating p53 signalling.

BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype lacking effective targeted therapies, necessitating innovative treatment approaches. While targeting ROS proto-oncogene 1 (ROS1) with crizotinib has shown promise, resistance remains a limitation. Recent evidence links focal adhesion kinase (FAK) to drug resistance, prompting our study to assess the combined impact of FAK inhibitor IN10018 and crizotinib in TNBC and elucidate the underlying mechanisms. METHODS: We employed the Timer database to analyze FAK and ROS1 mRNA levels in TNBC and adjacent normal tissues. Furthermore, we investigated the correlation between FAK, ROS1, and TNBC clinical prognosis using the GSE database. We conducted various in vitro assays, including cell viability, colony formation, flow cytometry, EdU assays, and western blotting. Additionally, TNBC xenograft and human TNBC organoid models were established to assess the combined therapy's efficacy. To comprehensively understand the synergistic anti-tumor mechanisms, we utilized multiple techniques, such as RNA sequencing, immunofluorescence, cell flow cytometry, C11-BODIPY staining, MDA assay, and GSH assay. RESULTS: The Timer database revealed higher levels of FAK and ROS1 in TNBC tissues compared to normal tissues. Analysis of GEO databases indicated that patients with high FAK and ROS1 expression had the poorest prognosis. Western blotting confirmed increased p-FAK expression in crizotinib-resistant TNBC cells. In vitro experiments showed that the combination therapy down-regulated cyclin B1, p-Cdc2, and Bcl2 while up-regulating BAX, cleaved-Caspase-3, cleaved-Caspase-9, and cleaved PARP. In TNBC xenograft models, the tumor volume in the combination therapy group was 73% smaller compared to the control group (p < 0.0001). Additionally, the combination therapy resulted in a 70% reduction in cell viability in human TNBC organoid models (p < 0.0001). RNA sequencing analysis of TNBC cells and xenograft tumor tissues highlighted enrichment in oxidative stress, glutathione metabolism, and p53 pathways. The combined group displayed a fivefold rise in the reactive oxygen species level, a 69% decrease in the GSH/GSSG ratio, and a sixfold increase in the lipid peroxidation in comparison to the control group. Western blotting demonstrated p53 upregulation and SCL7A11 and GPX4 downregulation in the combination group. The addition of a p53 inhibitor reversed these effects. CONCLUSION: Our study demonstrates that the combination of IN10018 and crizotinib shows synergistic antitumor effects in TNBC. Mechanistically, this combination inhibits cell proliferation, enhances apoptosis, and induces ferroptosis, which is associated with increased p53 levels.

Targeting focal adhesion kinase boosts immune response in KRAS/LKB1 co-mutated lung adenocarcinoma via remodeling the tumor microenvironment.

BACKGROUND: KRAS mutation is one of the most common oncogenic drivers in NSCLC, however, the response to immunotherapy is heterogeneous owing to the distinct co-occurring genomic alterations. KRAS/LKB1 co-mutated lung adenocarcinoma displays poor response to PD-1 blockade whereas the mechanism remains undetermined. METHODS: We explored the specific characteristics of tumor microenvironment (TME) in KL tumors using syngeneic KRASG12DLKB1-/- (KL) and KRASG12DTP53-/- (KP) lung cancer mouse models. The impact of focal adhesion kinase (FAK) inhibitor on KL lung tumors was investigated in vitro and in vivo through evaluation of both KL cell lines and KL lung cancer mouse models. RESULTS: We identified KL tumors as "immune-cold" tumors with excessive extracellular matrix (ECM) collagen deposition that formed a physical barrier to block the infiltration of CD8+T cells. Mechanistically, abundant activated cancer-associated fibroblasts (CAFs) resulted from FAK activation contributed to the formation of the unique TME of KL tumors. FAK inhibition with a small molecular inhibitor could remodel the TME by inhibiting CAFs activation, decreasing collagen deposition and further facilitating the infiltration of anti-tumor immune cells, including CD8+ T cells, DC cells and M1-like macrophages into tumors, hence, converting "immune-cold" KL tumors into "immune-hot" tumors. The combined FAK inhibitor and PD-1 blockade therapy synergistically retarded primary and metastatic tumor growth of KL tumors. CONCLUSIONS: Our study identified FAK as a promising intervention target for KL tumors and provided basis for the combination of FAK inhibitor with PD-1 blockade in the management of KL lung cancers.

Synergism of FAK and ROS1 inhibitors in the treatment of CDH1-deficient cancers mediated by FAK-YAP signaling.

CDH1 deficiency is common in diffuse gastric cancer and triple negative breast cancer patients, both of which still lack effective therapeutics. ROS1 inhibition results in synthetic lethality in CDH1-deficient cancers, but often leads to adaptive resistance. Here, we demonstrate that upregulation of the FAK activity accompanies the emergence of resistance to ROS1 inhibitor therapy in gastric and breast CDH1-deficient cancers. FAK inhibition, either by FAK inhibitors or by knocking down its expression, resulted in higher cytotoxicity potency of the ROS1 inhibitor in CDH1-deficient cancer cell lines. Co-treatment of mice with the FAK inhibitor and ROS1 inhibitors also showed synergistic effects against CDH1-deficient cancers. Mechanistically, ROS1 inhibitors induce the FAK-YAP-TRX signaling, decreasing oxidative stress-related DNA damage and consequently reducing their anti-cancer effects. The FAK inhibitor suppresses the aberrant FAK-YAP-TRX signaling, reinforcing ROS1 inhibitor's cytotoxicity towards cancer cells. These findings support the use of FAK and ROS1 inhibitors as a combination therapeutic strategy in CDH1-deficient triple negative breast cancer and diffuse gastric cancer patients.

A Low-Current and Multi-Channel Chemiresistor Array Sensor Device.

This paper describes the design of a low-current, multichannel, handheld electronic device integrated with nanostructured chemiresistor sensor arrays. A key design feature of the electronic circuit board is its low excitation current for achieving optimal performance with the arrays. The electronics can rapidly acquire the resistances for different sensors, not only spanning several orders of magnitude, but also as high as several hundreds of megaohms. The device tested is designed using a chemiresistor array with nanostructured sensing films prepared by molecularly-mediated assemblies of gold nanoparticles for detection. The low-current, wide-range, and auto-locking capabilities, along with the effective coupling with the nanostructured chemiresistor arrays, meet the desired performances of a low excitation current and low power consumption, and also address the potential instability of the sensors in a complex sensing environment. The results are promising for potential applications of the device as a portable sensor for the point-of-need monitoring of air quality and as a biosensor for point-of-care human breath screening for disease biomarkers.

Focal Adhesion Kinase (FAK) Inhibition Synergizes with KRAS G12C Inhibitors in Treating Cancer through the Regulation of the FAK-YAP Signaling.

KRAS mutation is one of the most prevalent genetic drivers of cancer development, yet KRAS mutations are until very recently considered undruggable. There are ongoing trials of drugs that target the KRAS G12C mutation, yet acquired drug resistance from the extended use has already become a major concern. Here, it is demonstrated that KRAS G12C inhibition induces sustained activation of focal adhesive kinase (FAK) and show that a combination therapy comprising KRAS G12C inhibition and a FAK inhibitor (IN10018) achieves synergistic anticancer effects. It can simultaneously reduce the extent of drug resistance. Diverse CDX and PDX models of KRAS G12C mutant cancer are examined and synergistic benefits from the combination therapy are consistently observed. Mechanistically, it is found that both aberrant FAK-YAP signaling and FAK-related fibrogenesis impact on the development of KRAS G12C inhibitor resistance. This study thus illustrates the mechanism of resistance of cancer to the treatment of KRAS G12C inhibitor, as well as an innovative combination therapy to improve treatment outcomes for KRAS G12C mutant cancers.

Inhibition of focal adhesion kinase enhances antitumor response of radiation therapy in pancreatic cancer through CD8+ T cells.

Objective: Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy, due in large part to its resistance to conventional therapies, including radiotherapy (RT). Despite RT exerting a modest antitumor response, it has also been shown to promote an immunosuppressive tumor microenvironment. Previous studies demonstrated that focal adhesion kinase inhibitors (FAKi) in clinical development inhibit the infiltration of suppressive myeloid cells and T regulatory (T regs) cells, and subsequently enhance effector T cell infiltration. FAK inhibitors in clinical development have not been investigated in combination with RT in preclinical murine models or clinical studies. Thus, we investigated the impact of FAK inhibition on RT, its potential as an RT sensitizer and immunomodulator in a murine model of PDAC. Methods: We used a syngeneic orthotopic murine model to study the effect of FAKi on hypofractionated RT. Results: In this study we showed that IN10018, a small molecular FAKi, enhanced antitumor response to RT. Antitumor activity of the combination of FAKi and RT is T cell dependent. FAKi in combination with RT enhanced CD8+ T cell infiltration significantly in comparison to the radiation or FAKi treatment alone (P < 0.05). FAKi in combination with radiation inhibited the infiltration of granulocytes but enhanced the infiltration of macrophages and T regs in comparison with the radiation or FAKi treatment alone (P < 0.01). Conclusions: These results support the clinical development of FAKi as a radiosensitizer for PDAC and combining FAKi with RT to prime the tumor microenvironment of PDAC for immunotherapy.

Efficacy and safety of elbasvir/grazoprevir in treatment-naive Chinese adults with hepatitis C virus infection: A randomized trial.

BACKGROUND AND AIM: In China, clinical experience with direct-acting antiviral treatments for hepatitis C virus (HCV) infection is still emerging. C-CORAL is a phase 3, multinational, placebo-controlled, double-blind trial of elbasvir/grazoprevir (EBR/GZR) in participants with HCV infection from the Asia-Pacific region and Russia. Here, we report the data from participants enrolled in China. METHODS: Treatment-naive participants with chronic HCV genotype (GT) 1, GT4, or GT6 infection were randomly assigned to receive 50 mg EBR/100 mg GZR for 12 weeks (immediate-treatment group, ITG) or placebo followed by deferred treatment with EBR/GZR (deferred-treatment group, DTG). The primary efficacy end-point was sustained virologic response at 12 weeks after completing treatment (SVR12), and the primary safety end-point was a comparison of safety between participants receiving EBR/GZR and placebo (NCT02251990; Protocol PN-5172-067). RESULTS: A total of 152 participants in China were randomly assigned (ITG, n = 115; DTG, n = 37). SVR12 was achieved in 96.7% (146/151) participants overall and in 97.3% (142/146) of those with GT1b infection. Four participants relapsed (GT1b, n = 3; GT6a, n = 1). Drug-related AEs were reported in 25 (21.7%) and 9 (24.3%) participants receiving EBR/GZR and placebo, respectively; no drug-related serious adverse events (AEs) occurred. Two (1.7%) participants receiving EBR/GZR had late hepatic transaminase elevations. Patient-reported outcomes indicate improved quality of life at follow-up week 4 in participants receiving EBR/GZR compared to placebo. CONCLUSION: EBR/GZR administered for 12 weeks represents a highly effective and safe treatment option for Chinese individuals with HCV GT1 infection.

Efficacy and safety of elbasvir/grazoprevir in participants with hepatitis C virus genotype 1, 4, or 6 infection from the Asia-Pacific region and Russia: Final results from the randomized C-CORAL study.

BACKGROUND AND AIM: Although treatment with direct-acting antivirals has dramatically improved morbidity and mortality attributable to chronic hepatitis C virus infection, universal access to these medicines has been slow in the Asia-Pacific region and Russia. This study evaluated efficacy and safety of elbasvir/grazoprevir in participants with hepatitis C virus infection from Asia-Pacific countries and Russia (C-CORAL). METHODS: C-CORAL was a phase 3, randomized, placebo-controlled study (NCT02251990). Treatment-naive, HIV-negative, cirrhotic and non-cirrhotic participants with chronic hepatitis C genotype 1, 4, or 6 infection were randomized to elbasvir 50 mg/grazoprevir 100 mg once daily for 12 weeks (immediate-treatment group) or placebo followed by deferred treatment with elbasvir/grazoprevir (deferred-treatment group). The primary efficacy outcome was sustained virologic response at 12 weeks, and the primary safety outcome was a comparison between the immediate-treatment group and placebo phase of the deferred-treatment group. RESULTS: A total of 489 participants were randomized (immediate-treatment group, n = 366; deferred-treatment group, n = 123). Sustained virologic response at 12 weeks in the combined immediate/deferred-treatment groups was 94.4% (459/486; 95% confidence interval = 92.4-96.5%). Sustained virologic response at 12 weeks was 98.2% in participants with genotype 1b, 91.9% with genotype 1a, and 66.7% with genotype 6 infection. Similar rates of adverse events and drug-related adverse events were seen in the immediate-treatment group versus placebo phase of the deferred-treatment group (51.0% vs 50.4% and 21.4% vs 21.1%). CONCLUSIONS: Elbasvir/grazoprevir for 12 weeks represents an effective and well-tolerated treatment option for treatment-naive people with genotype 1 infection from Asia-Pacific countries and Russia.

A Phase I, Single- and Multiple-dose Study to Evaluate the Pharmacokinetics of Elbasvir and Grazoprevir in Healthy Chinese Participants.

PURPOSE: This study evaluated the single- and multiple-dose pharmacokinetic (PK) variables of elbasvir and grazoprevir in healthy Chinese individuals. METHODS: This study was a 2-part, parallel-arm, open-label trial. In part 1, single-dose PK variables of elbasvir 10/50/100 mg and grazoprevir 50/100/200 mg were evaluated in 10 participants per drug. In part 2, 10-day multiple-dose PK variables of elbasvir 50 mg and grazoprevir 100 mg administered once daily alone and in combination were evaluated in 12 participants. Summary and inferential statistics of the PK parameters are reported. Elbasvir and grazoprevir PK parameters were also compared between Chinese participants and historical data from white participants. FINDINGS: Single-dose elbasvir and grazoprevir median Tmax were 2.9 to 4.0 and 1.9 to 3.0 hours after administration, respectively. Elbasvir AUC0-∞ and Cmax increased in a dose-proportional manner (slope estimate [90% CI], 0.92 [0.84-1.01] and 0.98 [0.86-1.09], respectively), whereas grazoprevir AUC0-∞ and Cmax increased in a greater-than-dose-proportional manner (slope estimate [90% CI], 1.42 [1.27-1.57] and 1.96 [1.64-2.29]). After repeated administration, the accumulation ratios for AUC0-24, 24-hour concentration, and Cmax were 1.55, 1.57, and 1.38 for elbasvir and 2.03, 1.23, and 2.51 for grazoprevir. Co-administration of elbasvir 50 mg and grazoprevir 100 mg once daily did not have a clinically relevant effect on the PK variables of either drug. Median Tmax after co-administration versus alone was 3.0 hours versus 3.0 hours for elbasvir and 3.1 hours versus 3.0 hours for grazoprevir. Geometric mean ratios (90% CI) for elbasvir and grazoprevir AUC0-24 (Chinese/white participants) were 1.58 (1.03-2.42) and 1.21 (0.76-1.92). Elbasvir and grazoprevir, administered alone or concomitantly, were well tolerated. IMPLICATIONS: In healthy Chinese individuals, administration of elbasvir and grazoprevir, alone or concomitantly, was generally well tolerated, with a thoroughly characterized PK profile. Elbasvir and grazoprevir exposures may trend higher in Chinese healthy participants relative to white healthy participants. Protocol number MK-8742 PN022.

Evaluation of an fMRI USPIO-based assay in healthy human volunteers.

PURPOSE: To present the testretest and contrast dose effect results of cerebral blood volume (CBV) functional MRI (fMRI) in healthy human volunteers using ferumoxytol (Feraheme), an ultrasmall-superparamagnetic iron oxide (USPIO) nanoparticle. MATERIALS AND METHODS: This was an open-label, two-period, fixed-sequence study in healthy young volunteers. In eight subjects, using a 3 Tesla field strength system, blood oxygen level dependent (BOLD) and CBV fMRI were acquired in response to a visual black-and-white checkboard stimulation paradigm using an escalating ferumoxytol dose design (250, 350, and 510 mg iron). Multiple outcome measures were analyzed including absolute percent signal change (|PSC|, primary endpoint), its contrast-to-noise ratio (CNR) and corresponding z-score, percent CBV change (ΔCBV) and respective CNR, concentration of Fe, and baseline CBV. RESULTS: The |PSC| in the visual cortex increased with ferumoxytol dose and was up to 3 × higher than BOLD fMRI. Test-retest reliability was comparable for BOLD and CBV fMRI. Intraclass correlation coefficients (ICCs) for |PSC| were 0.3 (one-sided 95% lower confidence limit = 0.00), 0.81 (0.47), 0.48 (0.00), and 0.3 (0.00) for BOLD and the 250-, 350-, and 510-mg doses of ferumoxytol, respectively. For ΔCBV, ICCs were 0.77 (0.37), 0.48 (0.00), and 0.49 (0.00) for 250 mg, 350 mg, and 510 mg, respectively. CONCLUSION: This work demonstrates that CBV fMRI techniques and endpoints are dose dependent, robust and have good test-retest repeatability. It also confirms previous findings that USPIO enhances sensitivity of fMRI stimulus-response endpoints. LEVEL OF EVIDENCE: 1 J. MAGN. RESON. IMAGING 2017;46:124-133.

Mometasone furoate nasal spray in the treatment of nasal polyposis in Chinese patients: a double-blind, randomized, placebo-controlled trial.

BACKGROUND: Although mometasone furoate nasal spray (MFNS) has demonstrated efficacy in nasal polyposis (NP) in Western populations, data in Asian populations is limited. METHODS: This randomized, double-blind study evaluated MFNS 200 µg twice per day (BID) vs placebo in Chinese adults with bilateral nasal polyps (graded as 1, 2, or 3 by the investigator). A 14-day placebo run-in period was followed by a 16-week treatment period with MFNS 200 µg BID vs placebo (1:1 ratio). The co-primary endpoints were change from baseline in nasal congestion/obstruction averaged over the first 4 weeks of treatment and change from baseline in the total polyp size score (sum of scores from the left and right nasal fossa) at week 16. Secondary endpoints included other sinonasal symptoms scores and safety outcomes such as monitoring laboratory measurements, vital signs, and adverse events (AEs). RESULTS: There were 748 patients randomized, 375 received MFNS 200 µg BID and 373 received placebo. The between-treatment difference in least squares (LS) mean change from baseline in nasal congestion/obstruction over 4 weeks of treatment was -0.14 (95% confidence interval [CI], -0.22 to -0.06) for MFNS vs placebo (p = 0.0007). The between-treatment difference in LS mean change from baseline in total polyp size score at week 16 was -0.30 (95% CI, -0.45 to -0.15) for MFNS vs placebo (p < 0.0001). Serious AEs were rare (0.5% and 0.8% in MFNS and placebo groups, respectively) and considered not drug-related. There were significantly more AEs of epistaxis with MFNS vs placebo (p = 0.009). CONCLUSION: This study demonstrated that MFNS was effective and well tolerated in this population of adult, Chinese patients with NP.

Pharmacokinetics of sugammadex 16 mg/kg in healthy Chinese volunteers.

OBJECTIVE: Elimination of sugammadex occurs predominantly via the kidneys, with the majority of the drug excreted unchanged in the urine. To date, most studies with sugammadex have been performed in non-Asian populations. The objectives of this open-label study were to determine the pharmacokinetics (PK) and safety of single-dose sugammadex (16 mg/kg) in healthy Chinese adult volunteers. METHODS: 12 Chinese subjects (6 male; 6 female) received intravenous sugammadex (16 mg/kg) as a 10-second bolus infusion. Blood samples were collected pre-sugammadex and at regular intervals up to 24 hours post-sugammadex for PK assessment. Safety was assessed via AEs, vital signs, electrocardiogram, and laboratory parameters. RESULTS: Following sugammadex 16 mg/kg infusion, peak sugammadex concentration was 197 µg/mL, clearance was 99.7 mL/min, and apparent volume of distribution at equilibrium was 10.5 L. Plasma sugammadex concentrations showed a polyexponential decline over time, with an overall geometric mean (CV%) terminal half-life of 145 minutes (17.9%) (139 minutes (17.7%) for males; 152 minutes (18.6%) for females). No influence of gender on the PK of sugammadex was observed. Three subjects experienced an adverse events (AE) (dysgeusia of mild intensity), which was considered possibly or probably related to sugammadex. There were no clinically significant changes in vital signs, electrocardiography or laboratory parameters. CONCLUSION: PK of sugammadex (16 mg/kg) was characterized in healthy Chinese subjects. Overall between-subject variability on clearance and apparent volume of distribution was ~ 10%. Sugammadex was generally well tolerated.

Pharmacokinetics of vorapaxar and its metabolite following oral administration in healthy Chinese and American subjects.

AIM: Vorapaxar is a proteaseactivated receptor (PAR)-1 antagonist being developed for the prevention and treatment of thrombotic vascular events. To evaluate race/ethnic differences between Caucasians and Chinese in the pharmacokinetics of vorapaxar and its active metabolite SCH 2046273 (M20) or in the metabolite/parent ratio, we conducted a cross-study comparison on pharmacokinetic data of vorapaxar and M20 obtained from two similarly designed studies: one in healthy Chinese subjects and the other in a healthy Western (United States, [U.S.]) population. METHODS: The pharmacokinetic profiles of vorapaxar and M20 were characterized using open label, two treatment parallel group designs in men and women aged 18 - 45 years. Vorapaxar was administered orally as a single dose of 40 mg in Chinese subjects (n = 14) or 120 mg in U.S. subjects (n = 14), or 2.5 mg QD for 6 weeks in both studies (Chinese, n = 14; U.S., n = 23). RESULTS: Vorapaxar was rapidly absorbed in both Chinese and U.S. subjects. Vorapaxar and M20 had similar elimination half-lives. The range of metabolite/parent ratios after single dose or daily administration was largely overlapped in Chinese and U.S. subjects. Steady state was attained by day 21 for vorapaxar and M20 in both race/ethnic groups. The accumulation ratios for vorapaxar and M20 during daily administration were similar in Chinese and U.S. subjects. Vorapaxar was well-tolerated in Chinese and U.S. subjects. CONCLUSION: The pharmacokinetic profiles of vorapaxar and M20 and the metabolite/parent ratios in healthy Chinese were generally comparable to those in a healthy Western population.

Multiple-dose pharmacokinetics and safety of desloratadine in subjects with moderate hepatic impairment.

Desloratadine, a nonsedating histamine H(1)-receptor antagonist, is metabolized to 3-hydroxy (3-OH) desloratadine. Impaired hepatic function could result in increased exposure to desloratadine. This study assessed possible differences in the pharmacokinetics and safety of desloratadine and 3-OH desloratadine in subjects (N = 21) with moderate hepatic dysfunction or normal liver function. Subjects were given desloratadine 5 mg once daily for 10 days and were assessed in several pharmacokinetic parameters. A similar degree of plasma protein binding to desloratadine and 3-OH desloratadine was observed in healthy volunteers and subjects with moderate hepatic impairment. All subjects with hepatic impairment were normal metabolizers. Three subjects with normal liver function, all African American, were identified as poor metabolizers. Exposure to desloratadine in the poor metabolizers was 2.6- to 6.5-fold greater than in other subjects with normal liver function. Eleven treatment-related adverse events, all mild to moderate in severity, were reported. Results suggest that subjects with moderate hepatic impairment experienced a greater increase in desloratadine exposure than subjects with normal liver function. Poor metabolizers had more exposure to desloratadine than normal metabolizers with or without hepatic impairment. Desloratadine administered at a daily dose of 5 mg was well tolerated.

Retrospective analysis of electrocardiographic changes after administration of oral or intravenous garenoxacin in five phase I, placebo-controlled studies in healthy volunteers.

BACKGROUND: Certain fluoroquinolones and macrolide antibiotics have been associated with prolongation of the corrected QT (QTc) interval or QT dispersion, leading to cardiac arrhythmias. Garenoxacin is a des-F(6)-quinolone with broad-spectrum antimicrobial activity and a favorable pharmacokinetic/pharmacodynamic profile. Its effects on electrocardiographic (ECG) parameters in healthy volunteers have not been reported. OBJECTIVE: The cardiac safety profile of garenoxacin was further examined using data from healthy volunteers enrolled in 5 dose-ranging and comparative Phase I clinical studies. METHODS: This was a retrospective analysis of 5 randomized, double-blind, placebo-controlled studies in which 224 healthy volunteers received oral or intravenous garenoxacin (50-1200 mg/d) for 1 to 28 days' dosing duration (450 milliseconds for men, >470 milliseconds for women) or the PR interval (>250 milliseconds). One subject had a change in QTcB of 67 milliseconds 4 hours after administration of garenoxacin 400 mg PO on day 7, but the actual value was 418 milliseconds (baseline, 351 milliseconds); the corresponding change in QTcF was 49 milliseconds (actual, 408 milliseconds; baseline, 359 milliseconds). The means for other derived ECG parameters were generally similar between garenoxacin-treated volunteers and placebo controls. CONCLUSION: In this retrospective analysis of data from healthy volunteers, garenoxacin had no clinically relevant dose-, route-of-administration-, or concentration-dependent effects on the QTc or PR interval across a dose range from 50 to 1200 mg/d.

Penetration of garenoxacin into lung tissues and bone in subjects undergoing lung biopsy or resection.

OBJECTIVE: Concentrations of garenoxacin in plasma and samples of lung parenchyma, bronchial mucosa, and bone were determined following single-dose administration. RESEARCH DESIGN AND METHODS: Open-label, non-randomized study in which subjects undergoing invasive lung biopsy or resection were given a single 600-mg oral dose of garenoxacin. Lung parenchyma, and, if possible, bronchial mucosa and bone (i.e., flat bone with sinus mucosa or long bone from the lower legs) samples and corresponding plasma samples were obtained 2-4, 4-6, 10-12, or 20-24 h post-dose. Garenoxacin concentrations were measured using validated liquid chromatography with dual mass spectrometry. Safety was also assessed. RESULTS: Twenty-seven subjects enrolled and completed the study. Garenoxacin plasma concentrations (mean +/- standard deviation) during the 24-h period ranged from 1.9 +/- 1 to 7.4 +/- 3 mug/mL. Garenoxacin concentrations in lung tissue (15.2 +/- 9 mug/g) peaked at 4-6 h and decreased to 3.7 +/- 3 mug/g at 20-24 h. Mean ratios between bronchial mucosa and plasma ranged from 0.82 to 0.99 over a 24-h period. At 12 h, the mean ratio between bone and plasma was 0.56. Garenoxacin concentrations in lung tissue exceeded the MIC(90) for common respiratory pathogens by at least 61-fold. Garenoxacin was safe and well tolerated. Forty-five adverse events were reported by 26 subjects; none were determined to be attributable to garenoxacin by the investigators. Most of the adverse events were mild to moderate in severity. CONCLUSIONS: Garenoxacin achieved 24-h concentrations in pulmonary tissues that exceeded the MIC(90) for common respiratory pathogens. A controlled study involving a larger number of lung and bone tissue samples is needed to further confirm these findings.