Safety, tolerability, pharmacokinetics, pharmacodynamics and food effect of HRS-1893, a cardiac myosin inhibitor, in healthy subjects.

First-in-human clinical trial to assess pharmacokinetics, pharmacodynamics, safety, and tolerability of iscalimab, an anti-CD40 monoclonal antibody.

Phase 1 Single (SAD) and Multiple Ascending Dose (MAD) Studies of the Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of FT-4202, an Allosteric Activator of Pyruvate Kinase-R, in Healthy and Sickle Cell Disease Subjects

Pharmacokinetics and Pharmacodynamics of IPI-145, a Potent Inhibitor of Phosphoinositide-3-Kinase-δ,γ, Following Single- and Multiple-Dose Administration in Healthy Subjects and Patients with Advanced Hematologic Malignancies

e15080 Background: The mTOR inhibitor everolimus is approved for patients (pts) with metastatic renal cell carcinoma after failure of sunitinib or sorafenib, and for pts with subependymal giant-cell astrocytoma associated with tuberous sclerosis who require therapeutic intervention but are not candidates for curative surgery. Studies in healthy subjects suggest that systemic exposure to everolimus is reduced with a high-fat meal. The effect of fasting conditions and food on everolimus PK after an oral 10 mg dose was evaluated. Methods: In this single-center, open-label study, 24 healthy male and female subjects were randomized to single doses of everolimus in a 3-treatment (low-fat vs high-fat meal vs fasting), 3-period, 6-sequence crossover design. Treatment periods were separated by 14-day washout intervals. PK was assessed at baseline and at 0-12, 24, 36, 48, 72, 96, 120, and 144 hours postdose. Results: All 24 subjects were included in the PK analysis. The geometric mean Cmax decreased by 42% after a low-fat meal and by 54% after a high-fat meal compared with fasting conditions. Total exposure (geometric mean AUC0-t and AUC0-∞) decreased by 22% to 33% after intake of a low- or high-fat meal. A meal had no apparent effect on the post-absorption concentration-time profile. The gastrointestinal absorption rate of everolimus was decreased by food intake: median Tmax was 1 hour in the fasted state, 1.75 hours after a low-fat meal, and 2.50 hours after a high-fat meal. The elimination kinetics in whole blood (T1/2 [35.6 to 40.9 hours] and mean residence time [29.2 to 32.2 hours]) did not appear to be affected by food intake regardless of fasting or nonfasting state. No deaths, serious adverse events (AEs), or significant AEs were reported. Conclusions: The systemic availability of a single oral 10 mg dose of everolimus is significantly reduced by coadministration with a meal (low or high fat) compared with fasting conditions; however, food is not expected to have clinically significant effects on predose trough concentration during daily administration of everolimus. All conditions tested were safe and well tolerated.

Purpose: E7050, an orally available c-MET tyrosyne kinase inhibitor is currently under evaluation for the treatment of advanced malignancies. The objectives of this study were to evaluate (1) effects of a standard high-fat and low-fat meal on the pharmacokinetics (PK) of 100 mg E7050; (2) E7050 PK following single doses of 100, 200 and 400 mg of E7050 in under fasted condition and (3) the safety of E7050 in healthy subjects. Methods: This open label study consisted of two parts: Part A (Food Effect) and Part B (Rising dose PK). Part A was a randomized, single-dose, three-way crossover study with a 2-week wash out between treatments. In Part A, 18 subjects received a single dose of E7050 (100 mg) in a fasting state, following a high-fat meal or a low-fat meal. In Part B, 12 and 10 subjects sequentially received 200 and 400 mg E7050 doses, respectively in fasted state. Serial blood samples for E7050 PK analysis were taken up to 196 h post-dosing. Subjects were evaluated for adverse events (AEs). Results: Study results are summarized in Table 1. Based on E7050 Cmax, AUC(0−t) and AUC(0−inf), the presence of food at the time of dosing reduces exposure by 21 to 28%. When administered with food (high-fat or low-fat), the lower 90% CI limit for E7050 is below 80% for Cmax and AUC. Thus the food effect is independent of the type of meal consumed. However, the magnitude of the observed food effect was modest and clinically insignificant. PK of E7050 was found to be linear following single doses of 100 to 400 mg E7050. In this study, a single dose of the 400-mg E7050 tablet was safe and well tolerated when administered under fed and fasted conditions. Most TEAEs were mild in severity; there were no treatment-related severe or serious AEs and no treatment-related AEs leading to study treatment withdrawal. There were no clinically significant changes in vital sign assessments, clinical laboratory analyzes or ECG parameters. Conclusion: Consumption of a low- or high-fat meal had no clinically significant effect on E7050 PK and E7050 can be administered without regards to food. PK of E7050 was found to be linear following single doses of 100 to 400 mg E7050. This study demonstrated an acceptable safety/tolerability profile of E7050 in healthy subjects. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A193.

Sofosbuvir is an NS5B nucleotide inhibitor that was approved for hepatitis C treatment. Generic sofosbuvir has been produced to improve the affordability. The present study investigated the pharmacokinetics (PK) and safety of generic sofosbuvir as well as the effect of food intake on its PK parameters in healthy Chinese subjects. This open-label, randomized, multiple-dose, dose-escalating, and food effect trial enrolled 12 healthy Chinese subjects. The subjects received a single oral dose of 400mg of generic sofosbuvir in fasted state or after a high-fat meal, or 800mg in fasted state, in a three-way crossover design, and then all subjects were administered with 400mg daily for 8days. The PK parameters for sofosbuvir and its metabolites were determined, and the safety was monitored. Sofosbuvir was absorbed rapidly into plasma, with a half-life of 0.46-0.48 hours. Plasma exposure to sofosbuvir and its metabolite GS-566500 was increased in an approximately proportional manner to the increased dose. Repeated dosing did not result in drug accumulation in the blood. Sofosbuvir was mainly excreted as the metabolite GS-331007 in the urine. Drug administration after a high-fat meal increased the plasma sofosbuvir exposure by 1.29-fold, without substantially altering the absorption rate. No serious adverse events were observed, and all subjects tolerated the doses well. This generic sofosbuvir was well absorbed, the plasma concentration was increased with an increased dose, and it was safe in healthy subjects. A high-fat meal appeared to promote the bioavailability of sofosbuvir and the metabolite GS-566500.

Chronic lymphocytic leukemia (CLL) is a B-cell malignancy treated with chemoimmunotherapy. Such treatment results in high response rates but patients may eventually relapse and require alternate therapies. Ibrutinib (PCI-32765), a recently developed novel treatment, is unique in its mechanism as it inhibits Bruton's tyrosine kinase, a key kinase in the B-cell receptor signaling pathway. It's a Biopharmaceutics Classification Systems (BCS) class 2 compound and is metabolized rapidly by CYP3A. Three studies were conducted. The primary objectives were to assess the pharmacokinetics (PK) of ibrutinib under fed and fasted conditions and to assess the impact of food intake timing. Additionally, the safety and tolerability of ibrutinib were assessed. Study 1 was a randomized, open-label, single-center, single-dose, 4-way crossover study in 44 healthy subjects. Study 2 was a multicenter, randomized, repeated-dose crossover study in 16 patients with relapsed or refractory CLL. The ibrutinib dose was 420 mg in both. Study 3 was an open-label, single-center, sequential study to assess absolute bioavailability of ibrutinib 560 mg in 8 healthy subjects. Ibrutinib was well tolerated in these studies. There were no serious adverse events (AEs) or discontinuations due to an AE. There were no clinically significant changes in laboratory safety parameters, electrocardiograms, or vital signs. Administration of ibrutinib to healthy subjects under fasting conditions resulted in approximately 60% of exposure compared to drug intake either 30 min before or 2 h after a high-fat meal. When ibrutinib was taken 30 min after a meal, drug exposure was comparable to the dosing conditions of either 30 min before or 2 h after the meal. Study 2 revealed that under fed conditions, the maximum concentration was 2.24 times greater and the area under the curve was 1.65 times greater compared to the fasted conditions, but similar to uncontrolled food intake conditions. A similar food effect was observed in study 3, in which a standard meal was consumed starting 30 min after dosing. When corrected for repeated dosing in patients, the PK parameters in healthy subjects and patients were comparable. The observed food effect is most likely the result of a decreased (intestinal and hepatic) first-pass effect, rather than an effect on solubilization. Since ibrutinib is a highly permeable compound, residence time in the gut and liver cells could be reduced when mesenteric and portal vein blood flow is increased under fed conditions, making ibrutinib less available to CYP3A clearance. The effect on bioavailability may outweigh the higher clearance due to liver blood flow. In conclusion, food causes no more than a doubling in ibrutinib systemic exposure. Considering the favorable safety profile, ibrutinib can be administered with or without food. Citation Format: Jan de Jong, Juthamas Sukbuntherng, Donna Skee, Joe Murphy, Susan O'Brien, John C. Byrd, Danelle James, Peter Hellemans, Juhui James Jiao, Vijay Chauhan, Italo Poggesi, Erik Mannaert. Evaluation of the pharmacokinetics and food effect of oral ibrutinib in healthy subjects and chronic lymphocytic leukemia patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4637. doi:10.1158/1538-7445.AM2014-4637

2012 American College of Clinical Pharmacology Annual Meeting September 23^rd–25^th San Diego, California

Pharmacokinetic and Pharmacodynamic Assessments of the Dipeptidyl Peptidase-4 Inhibitor PHX1149: Double-Blind, Placebo-Controlled, Single- and Multiple-Dose Studies in Healthy Subjects

Single Oral Doses of a Novel Thrombopoietin Mimetic ONO-7746 Increase Platelet Counts In Healthy Subjects

Sarizotan is a 5-HTIA receptor agonist with high affinity for D3 and D4 receptors. Here we report the pharmacokinetic and tolerability results from four Phase 1 studies. Two single-dose (5 -25 mg, n = 25, 0.5 - 5 mg, n = 16) and two multiple-dose (10 and 20 mg b.i.d., n = 30, 5 mg b.i.d., n = 12) studies with orally administered sarizotan HCl were carried out in healthy subjects. Plasma sarizotan HCl concentrations were measured using a validated HPLC method and fluorescence or MS/MS detection. Pharmacokinetic parameters were obtained using standard non-compartmental methods. Sarizotan was rapidly absorbed, group-median times to reach maximum concentration (tmax) ranged from 0.5 -2.25 h after single doses and during steady state. Maximum plasma concentration (Cmax) and tmax were slightly dependent on formulation and food intake, whereas area under the curve (AUC) was unaffected by these factors. AUC and Cmax increased dose-proportionally over the tested dose range. Independently of dose and time, sarizotan HCl plasma concentrations declined polyexponentially with a terminal elimination half-life (t1/2) of 5 - 7 h. Accumulation factors corresponded to t1/2 values, and steady state was reached within 24 h. Plasma metabolite concentrations were considerably lower than those of the parent drug. The ratio metabolite AUC : parent drug AUC was time- and dose-independent for all three metabolites suggesting that the metabolism of sarizotan is non-saturable in the tested dose range. The pharmacokinetics of sarizotan were dose-proportional and time-independent for the dose range 0.5 -25 mg). The drug was well-tolerated by healthy subjects up to a single dose of 20 mg.

766-P: DA-1241, a Novel GPR119 Agonist: Data on Safety, Tolerability, and Pharmacokinetics (PK) from Part 1 of a Phase 1b Multiple Ascending Dose (MAD) Study in Healthy Volunteers (HV)

This research aimed to compare the bioequivalence of a test formulation (regorafenib produced by Beijing SL Pharmaceutical Co., Ltd.) with a reference formulation (the original drug Stivarga®) in Chinese healthy subjects under fasting conditions and two postprandial states: after low-fat and high-fat meals. The research design was a randomized, open-label, two-period crossover trial involving a single 40mg oral dose. Three separate studies were conducted. Study 1 enrolled 64 subjects who were dosed under fasting conditions; Study 2 involved 76 subjects dosed after a low-fat breakfast; and Study 3 also involved 76 subjects dosed after a high-fat breakfast. Plasma concentrations of regorafenib and M-2 were determined using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The primary endpoints were the peak plasma concentration (Cmax), the area under the concentration-time curve from time 0 to 168h (AUC0-168h), and the extrapolated area under the curve from time zero to infinity (AUC0-∞) of regorafenib, with pharmacokinetics (PK) parameters of the metabolite M-2 serving as reference data. The results showed that, under fasting, post-low-fat meal, and post-high-fat meal conditions, the 90% confidence intervals (CIs) of geometric mean ratios (GMRs) for Cmax of test to reference regorafenib were 96.39%-114.94%, 93.81%-106.67% and 94.23%-107.21%, respectively. For AUC0-168h were 88.40%-102.04%, 92.40%-102.97% and 92.50%-102.60%. For AUC0-∞ were 85.86%-100.01%, 90.26%-101.79% and 90.15%-101.36%. All of these fell within the 80.00%-125.00% range, meeting the equivalence criteria. Food intake had some impact on the PK parameters of regorafenib, but the effect was minor. Administration of a single 40mg dose of regorafenib to healthy subjects demonstrated good safety and tolerability. Under different dietary conditions, a single oral dose of 40mg of generic drug regorafenib was bioequivalent to the original drug Stivarga® in healthy Chinese subjects, and the food effect was limited. http://www.chinadrugtrials.org.cn/, identifier CTR20210575, CTR20210576, CTR20223278.

The pharmacokinetic parameters of a single 400-mg oral dose of posaconazole suspension, administered under fasting and fed conditions, were compared in healthy male Taiwanese volunteers. After an overnight fast, 16 subjects received a single oral dose of posaconazole suspension (400 mg) under fasting conditions or immediately after a normal-fat (700-800 calories, 30% fat) or high-fat breakfast meal (800-1000 calories, 50% fat). The treatments were administered as per the 3 × 6 Williams square design, with a 1-week washout phase between treatments. Blood samples were drawn at predetermined time points (0, 1, 2, 3, 4, 4.5, 5, 5.5, 6, 8, 10, 12, 24, 48, 72, 96, and 120 hours). All plasma concentrations of posaconazole were measured by high-performance liquid chromatography. The observed maximum plasma concentration (C max), area under the plasma concentration-time curve (AUC 0-t and AUC 0-∞), time to reach C max (t max), and plasma half-life (t 1/2) were assessed. Fourteen subjects completed the study; 2 subjects withdrew because of adverse events. Thirteen subjects were included in the pharmacokinetic analysis. Sixteen subjects were included in the safety analysis. The mean posaconazole C max, AUC 0-t, and AUC 0-∞ values were significantly lower under fasting conditions than after a normal- or a high-fat meal. The mean C max values under fasting, normal-fat, and high-fat conditions were 279.00 ± 123.32 ng/mL, 662.46 ± 251.02 ng/mL, and 608.38 ± 183.22 ng/mL, respectively (P < 0.0001); the mean AUC 0-t values under each condition were 6828.56 ± 3349.12 ng · mL(-1) · h(-1), 20,629.84 ± 8346.45 ng · mL(-1) · h(-1), and 20,741.09 ± 7681.02 ng · mL(-1) · h(-1), respectively (P < 0.0001); and the mean AUC 0-∞ values under each condition were 7304.72 ± 3444.54 ng · mL(-1) · h(-1), 21,326.65 ± 8495.01 ng · mL(-1) · h(-1), and 21,626.08 ± 8193.31 ng · mL · h(-1), respectively (P < 0.0001). The mean t max value was significantly shorter at 3.15 hours under fasting conditions than at 4.88 hours after normal- or high-fat meals (P = 0.0176). The mean t 1/2 values were 22.0, 20.8, and 22.0 hours, respectively. The posaconazole AUC increased by approximately 3-fold, C max by 2.2-fold, and t max by 1.5-fold when healthy Taiwanese subjects were administered the drug with food compared with under fasting conditions. These parameters were similar when the drug was administered with either a normal- or high-fat meal.

Velufenacin (DA-8010) is a new muscarinic receptor antagonist under development for the treatment of overactive bladder. This study aimed to evaluate the effect of food on the pharmacokinetics (PK) and safety of velufenacin in healthy subjects. A randomized, open-label, single-dose, 4-sequence, 4-treatment, 4-period crossover study was conducted. Subjects received a single oral dose of velufenacin 2.5 or 5 mg in a fasted or fed (high-fat meal) state in each period with a 7-day washout. PK parameters including maximum plasma concentration (Cmax ) and area under the concentration-time curve from time 0 to the last measurable point were compared between the fed and fasted states. Twenty-seven subjects completed the study. The mean area under the concentration-time curve from time 0 to the last measurable point of the velufenacin 2.5 and 5 mg doses under the fed condition showed a 1.5- and 1.3-fold increase, respectively, compared to the fasted condition. The corresponding values for Cmax were a 2.3- and 2.0-fold increase, respectively. The time to reach Cmax was comparable regardless of the dose or food intake, showing median values of 4.5-5.0 hours. These results suggest a modest increase of velufenacin absorption by food intake. Velufenacin was generally safe and well tolerated at the 2.5 and 5 mg doses regardless of food.