In Vivo Evaluation of the Oral Toxicity of the Chlorobutanol

Chlorobutanol (CB) is used as a preservative in cosmetics and has antibacterial activity. This study investigated the single- and repeated-dose 28-day oral toxicity of a CB solvent in Sprague Dawley (SD) rats. For the single-dose oral toxicity study, a dose of 62.5, 125, or 250 mg per kg of body weight (mg/kg b.w.) of CB was given once orally via gavage. For the repeated-dose 28-day toxicity study, the high dose was set as 100 mg/kg b.w./day, and the middle, middle-low, and low doses were set to 50, 25, and 12.5 mg/kg b.w./day, respectively. Body weight was not significantly changed in the repeated-dose toxicity study. Relative liver and kidney weights were significantly increased in both sexes of the 100 mg/kg b.w./day treatment group. However, there were histopathological changes in liver and kidney for females and males, respectively. These data suggested that the approximate lethal dose (ALD) of CB was over 250 mg/kg b.w./day in the single-dose study, and the no adverse effect level (NOAEL) for CB was over 50 and 12.5 mg/kg b.w./day for female and male rats in the repeated-dose toxicity study.

Pharmacokinetic Characterisation and Comparison of Bioavailability of Intranasal Fentanyl, Transmucosal, and Intravenous Administration through a Three-Way Crossover Study in 24 Healthy Volunteers

Background. For more than 60 years, the synthetic opioid fentanyl has been widely used in anaesthesia and analgesia. While the intravenous formulation is primarily used for general anaesthesia and intensive care settings, the drug’s high lipophilic properties also allow various noninvasive routes of administration. Published data suggest that intranasal administration is also attractive for use as intranasal patient-controlled analgesia (PCA). A newly developed intranasal fentanyl formulation containing 47 μg fentanyl, intravenous fentanyl, and oral transmucosal fentanyl citrate were characterised, and bioavailability was compared to assess the suitability of the intranasal formulation for an intranasal PCA product. Methods. 27 healthy volunteers were enrolled in a single-centre, open-label, randomised (order of treatments), single-dose study in a three-period crossover design. The pharmacokinetics of one intranasal puff of fentanyl formulation (47 μg, 140 mL per puff), one short intravenous infusion of 50 μg fentanyl, and one lozenge with an integrated applicator (200 μg fentanyl) were studied, and bioavailability was calculated. Blood samples were collected over 12 hours, and plasma concentrations of fentanyl were determined by HPLC with MS/MS detection. Results. 24 volunteers completed the study. The geometric mean of AUC0-tlast was the highest with oral transmucosal administration (1106 h ∗ pg/ml, CV% = 32.86), followed by intravenous (672 h ∗ pg/ml, CV% = 32.18) and intranasal administration (515 h ∗ pg/ml, CV% = 30.10). Cmax was 886 pg/ml (CV% = 59.38) for intravenous, 338 pg/ml (CV% = 45.61) for intranasal, and 310 pg/ml (CV% = 29.58) for oral transmucosal administration. tmax was shortest for intravenous administration (0.06 h, SD = 0.056), followed by intranasal (0.21 h, SD = 0.078) and oral transmucosal administration (1.20 h, SD = 0.763). Dose-adjusted relative bioavailability was determined to be 74.70% for the intranasal formulation and 41.25% for the oral transmucosal product. In total, 38 adverse events (AEs) occurred. Fourteen AEs were potentially related to the investigational items. No serious AE occurred. Conclusion. Pharmacokinetic parameters and bioavailability of the investigated intranasal fentanyl indicated suitability for its intended use as an intranasal PCA option.

982. Effect of Hepatic Impairment on the Safety and Pharmacokinetics of Rezafungin

Background Rezafungin (RZF) is a novel echinocandin antifungal being developed for treatment of candidemia and invasive candidiasis, and for prevention of invasive fungal diseases among immunosuppressed patients. In the Phase 2 and Phase 3 treatment trials of rezafungin compared with caspofungin (STRIVE [NCT02734862] and ReSTORE [NCT03667690], respectively), patients with severe hepatic impairment (HI) were not included due to lack of caspofungin data in this population. Rezafungin was previously evaluated in patients with moderate hepatic impairment. Here we report an open-label, single-dose study on rezafungin in patients with HI (Child-Pugh class C). Methods To investigate the safety, tolerability, and pharmacokinetics (PK) of RZF in subjects with HI and healthy subjects (HS), 8 subjects with HI and 8 HS matched for age, sex, and body mass index (BMI) were enrolled and received a single 400-mg intravenous 1-hour infusion of RZF. Plasma PK sampling was performed at various time points through 336 hours postdose. RZF PK parameters were derived using non-compartmental analysis. Safety was assessed throughout the study. Results The majority of the HI subjects were White (87.5%) and male (75%) while equal distribution between White and Black or African American was observed among HS (50%) and 75% were male. The mean age of HI subjects was 58 years (range, 41–68 years) and 56.6 years (range, 50–61 years) for the HS. Mean BMI was 29.7 kg/m2 (range, 24.5–34.3 kg/m2) for HI subjects and 29.7 kg/m2 (range, 25.4–34.2 kg/m2) for the HS. RZF exposure (Cmax and AUC) in subjects with HI was ~30% lower than that in HS (Table 1), while half-life was generally similar (HI: 121 h, HS:124 h; Figure 1). Three HI subjects had one adverse event (AE) each (bronchitis, worsening hepatic encephalopathy, hyponatremia), all moderate in severity; one HS had 1 AE of infusion site infiltration mild in severity. No AEs were considered related to RZF, and all were resolved or resolving by the end of the study. Table 1. Plasma Rezafungin PK Parameter Estimates in Subjects with Severe Hepatic Impairment or Normal Hepatic Function After a Single 400 mg IV Infusion of Rezafungin Figure 1. Mean (+SD) Plasma Rezafungin Concentration-Time Profiles in Subjects with Severe Hepatic Impairment or Normal Hepatic Function After a Single 400-mg IV Infusion of Rezafungin (Semi-Logarithmic Scale) Conclusion RZF was well tolerated in HI subjects and showed modestly reduced exposure that was within the range observed in matched HS. These findings support no RZF dose adjustment in subjects with severe hepatic impairment. Disclosures Voon Ong, PhD, Cidara Therapeutics (Employee, Shareholder) Taylor Sandison, MD, MPH, Cidara Therapeutics (Employee, Shareholder) Rebeca M. Melara, M.S., Altasciences (contract research organization) (Employee) Thomas C. Marbury, MD, Orlando Clinical Research Center (Employee, Other Financial or Material Support, Equity owner of Orlando Clinical Research Center) Alena Jandourek, MD, Cidara therapeutics (Consultant) Shawn Flanagan, PhD, Cidara Therapeutics (Employee, Shareholder)

1120. Absorption, Metabolism, and Excretion of [14C]-Tebipenem Pivoxil Hydrobromide (TBP-PI-HBr) Following a Single Oral Dose in Healthy Male Subjects

Background Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral prodrug that is converted to tebipenem (TBP), the active moiety, with activity against multidrug-resistant gram-negative pathogens, including extended-spectrum-β-lactamase (ESBL)-producing Enterobacterales. TBP-PI-HBr is the first oral carbapenem intended for treating complicated urinary tract infections and acute pyelonephritis. This study evaluated the absorption, metabolism, and excretion (AME) of TBP-PI-HBr following a single oral dose of [14C]-TBP-PI-HBr to healthy males and characterized metabolites in plasma, urine, and feces. Methods This was a Phase 1, open-label, single-dose study in healthy subjects. Study drug was provided as radiolabeled and non-radiolabeled active pharmaceutical ingredient containing approximately 150 μCi of [14C]-TBP-PI-HBr. On Day 1, each subject received a 600 mg dose of TBP-PI-HBr. administered with 240 mL of water and fasted overnight for at least 10 hours. Blood samples were collected to determine TBP concentrations (whole blood), total radioactivity (whole blood and plasma), and metabolite profiling and identification were determined from plasma, urine, and feces. For mass balance, total radioactivity derived from urine and feces collections were determined. PK parameters were calculated using noncompartmental methods. Results Total radioactivity in plasma and whole blood decreased rapidly with geometric mean t½ values of 6.0 hours and 3.5 hours, respectively and Tmax of 1 hour. The cumulative mean recovery of radioactivity was 38.7% in urine and 44.6% in feces. Most of the administered radioactivity was recovered in the first 144 hours post dose in urine and feces (80.0%). Six of 8 subjects achieved a mass balance recovery ranging from 80.1% to 85.0%. The TBP plasma to total radioactivity ratio of 0.536 indicated that other metabolites contribute to the total radioactivity AUC in plasma. Metabolite profiling and identification results indicated that TBP was the major component in plasma and urine. The inactive ring open metabolite of TBP (LJC 11,562) was also found in plasma ( >10%), urine (5.27%), and feces ( >10%) as a secondary metabolite. Conclusion This study adequately characterized the AME of TBP-PI-HBr in humans. Disclosures Vipul K. Gupta, Ph.D., Spero Therapeutics (Employee, Shareholder) Gary Maier, PhD, Spero Therapeutics, Inc. (Consultant) Leanne Gasink, MD, Spero Therapeutics, Inc. (Consultant) Amanda Ek, MS, Spero Therapeutics, Inc. (Employee) Mary Fudeman, BA, MBA, Spero Therapeutics, Inc. (Employee) Praveen Srivastava, MS, BS, Spero Therapeutics, Inc. (Employee) Angela Talley, MD, Spero Therapeutics, Inc. (Employee)

Association between HbA1c and dyslipidemia among sample of Iraqi Patients with Type2 DM

Background: Diabetic Mellitus is considered as a public health concern. More than 8 percent of the United States has diabetes. Diabetes is a serious risk factor for Atherosclerotic cardiovascular disease (ASCVD) and an important cause of mortality. ASCVD is the commonest cause of death in the Western world. Diabetes was defined as a high risk condition for ASCVD. In adults with diabetes with ASCVD or multiple ASCVD risk factors it is important to prescribe high intensity statin to reduce LDL at least to 50%. Objective: To investigate association between dyslipidemia and HbA1c and to detect benefit of using some statins in decreases the risk of CVD. Material and method: A prospective randomized single dose study was carried out at a private clinic in Wasit governorate-Iraq; included patients with type 2 diabetes. Clinical biochemical lab assessment and re assessment was carried out before and after 3 months of receiving Rosuvastatin 20 mg/ day. A questionnaire paper was used, including sociodemographic and clinical features (age, gender, measuring weight, height, and waist circumference; biochemical markers [total cholesterol, HDL, LDL, TG and HbA1c]). Results: A total of 256 type 2 DM patients were included; receiving 20 mg of rosuvastatin as a single dose for 3 consecutive months. 83 (32.4%) of them were males and 173 (67.6%) were females. Mean age of male (52.0710.486) and that of female (53.1110.410). the mean difference of (BMI, WC, HbA1c, LDL, TG, and cholesterol) among all studied sample after treatment was significantly lower than mean difference that measured before treatment, except that for HDL; where it was significantly higher after treatment, P <0.001. Mean differences of HbA1c and total cholesterol were reduced significantly after treatment among males, females, age <45 yrs., and age 45 yrs., P<0.01; without significant differences in between groups, P>0.05. Conclusions: HbA1c value associated with level of lipid profile in diabetic patients. All age groups and both gender have had benefit of rosuvastatin treatment in reduction of lipid cholesterol as well as HbA1c. Rosuvastatin can be used by type 2 diabetics’ regardless age and gender. HbA1c can be used as a predictor of dyslipidemia in type 2 diabetes.

Activity of preclinical and phase I clinical trial of a novel androgen receptor antagonist GT0918 in metastatic breast cancer

Purpose To evaluate GT0918, a 2nd-generation AR antagonist, for its AR down-regulation activity among breast cancer patients. Methods The effect of GT0918 on AR protein expression was evaluated in AR expression breast cancer cells and in breast cancer xenograft model. A 3 + 3 phase I dose-escalation study was launched in Peking University Cancer Hospital. The endpoints included dose finding, safety, pharmacokinetics, and antitumor activity. Results GT0918 was demonstrated to effectively suppress the expression of AR protein and the growth of AR-positive breast cancer tumors in mouse xenograft tumor models. All patients treated with GT0918 were at a QD dose-escalation of five dose levels from 100 to 500 mg. The most common treatment-related AEs of any grade were asthenia, anemia, decreased appetite, increased blood cholesterol, increased blood triglycerides, decreased white blood cell count, and increased low-density lipoprotein. Grade 3 AEs were fatigue (2 of 18, 11.1%), aspartate aminotransferase increase (1 of 18, 5.6%), alanine aminotransferase increase (1 of 18, 5.6%), and neutrophil count decrease (1 of 18, 5.6%). Clinical benefit rate (CBR) in 16 weeks was 23.1% (3/13). Among 7 AR-positive patients, 6 can evaluate efficacy, and 2 completed 23.5- and 25-cycle treatment, respectively (as of 2020/1/20). PK parameters showed a fast absorption profile of GT0918 in the single-dose study. GT0918 and its major metabolite reached steady-state serum concentration levels at day 21 after multiple dosing. Conclusion GT0918 can effectively inhibit AR-positive breast cancer tumor growth. GT0918 was demonstrated well tolerated with a favorable PK profile. The suitable dose of GT0918 was 500 mg QD and may provide clinical benefits for AR-positive mBC.

Hypoglycemic Activity of Methanol Fraction of Tectona grandis (Linn) Bark in Experimental Rat Models

Diabetes mellitus (DM) is a now a major global health problem and its incidence is increasing day by day in whole world. There are various medicinal plants in India those possess antidiabetic property which are traditionally used in management of diabetes. Tectona grandis Linn. (TG) plant belonging to family Verbenaceae is medicinally reported and claims to cure various diseases in Indian traditional system of medicine (Ayurveda) and also in folklore. The purpose of this present study is to examine the hypoglycemic potential of methanol fractions (50, 100 and 200mg/kg body weight) of Tectona grandis bark (MFTG) from defatted hydro-alcoholic extract in normoglycemic, streptozotocin induced (45mg.kg‒1) diabetic and glucose loaded hyperglycemic rats by single and multiple oral administration in comparison to standard drug Glibenclamide (2.5 mg/kg body weight). Initially acute oral toxicity study of MFTG was carried out in rats to estimate the dose for animal study. The study report showed that the MFTG (200mg/kg) significantly (p<0.05 to p<0.01) reduces blood glucose level both in normoglycemic and diabetic rats induced by Streptozotocin and oral glucose loaded methods till the end of 8 hour and 3hour respectively during the single dose study and from the 15th day to 30th day in multi dose study. Hence the present study reveals that MFTG possess significant hypoglycemic activity which inspires the traditional use of the plant for the treatment of diabetes mellitus.

A randomized, double-blind, single-dose study (LAVENDER) to assess the safety, tolerability, pharmacokinetics, and immunogenicity of a combined infusion of ABP 980 and pertuzumab in healthy subjects

Purpose ABP 980 (KANJINTI™) is a biosimilar to reference product HERCEPTIN® (trastuzumab RP). The goal of this study was to characterize the safety, tolerability, and immunogenicity of ABP 980 plus pertuzumab (PERJETA®) when co-administered in a single infusion bag in healthy subjects. Methods This randomized, double-blind, single-dose, 2-arm, parallel-group study (LAVENDER Study) evaluated an intravenous (IV) infusion of ABP 980 (6 mg/kg) plus pertuzumab (420 mg) combined in a single infusion bag relative to an IV infusion of trastuzumab RP (6 mg/kg) plus pertuzumab (420 mg) combined in a single infusion bag given over 60 min. The subjects were followed for 92 days post dosing. Results A total of 42 subjects were enrolled in the study and treated with investigational product. Due to an operational issue during dosing, the first 6 subjects enrolled in the study were replaced. A total of 36 randomized subjects, n = 18 for ABP 980 plus pertuzumab and n = 18 for trastuzumab RP plus pertuzumab, were treated. Resulting serum concentrations of ABP 980 and trastuzumab RP were similar. There were no serious adverse events, no deaths, and no cardiac disorders during the study. No subject developed anti-drug antibodies throughout the study. Conclusions This study demonstrated the safety and tolerability of ABP 980 and pertuzumab admixture in a single infusion bag. The safety profiles and pharmacokinetic parameters of ABP 980 and pertuzumab were consistent with what is known for trastuzumab RP and pertuzumab. Clinical trial listing EudraCT 2018-002903-33.