Phase I Trial to Evaluate the Tolerance, Pharmacokinetics and Efficacy of the Broad-Spectrum ErbB Family Inhibitor Larotinib Mesylate in Patients With Advanced Solid Tumors

Background: The presented phase I, first-in-human study evaluated the tolerance, pharmacokinetics, and preliminary efficacy of larotinib mesylate in patients with advanced solid tumors.Methods: Cancer patients were assigned to receive larotinib mesylate at 50–400 mg dose levels until disease progression or intolerance. Dose-limiting toxicities were assessed during Cycles 0 and 1. Pharmacokinetic evaluations were performed after the first dose and at steady-state.Results: Twenty-five patients with solid tumors were enrolled in the dose-escalation study. No DLTs were observed. Acne-like rash (68.0%), diarrhea (48.0%), paronychia (48.0%), and anemia (48.0%) were the most reported treatment-related adverse events. No clear linear pharmacokinetic characteristic could be drawn, and obvious accumulation was observed. Two patients with non-small cell lung cancer experienced a partial response, and 15 patients had stable disease after treatment.Conclusion: Continuous oral administration of larotinib mesylate at 50–400 mg daily demonstrated a favorable safety profile, and anti-tumor activity was observed in patients with advanced solid tumors.

Safety, tolerability and pharmacokinetic characterisation of DACRA KBP-042 in healthy male subjects

There is a need for anti-diabetic agents successfully targeting insulin sensitivity and treating obesity control at the same time. The aim of this first-in-human study was 1) to evaluate safety and tolerability; 2) to evaluate pharmacokinetics and 3) to assess indications of receptor engagement of single ascending doses of KBP-042, a Dual Amylin and Calcitonin Receptor Agonists (DACRA) that has shown promising preclinical data, with superior activity in terms of typical amylin-induced responses including reduction of food intake, weight loss and gluco-regulatory capacities. A randomised double-blind placebo-controlled single ascending dose study was performed with six dose levels of KBP-042 (5, 7.5, 10, 20, 20 evening and 40µg) in healthy male adults. KBP-042 or placebo was administered as a single dose after an overnight fast, followed by a standardized lunch after four hours. KBP-042 was associated with dose-dependent complaints of nausea and vomiting, with a lack of tolerability at doses of 20µg and above. Doses of 5 to 40 μg KBP-042 were behaved according to a linear pharmacokinetic profile. Indications of target receptor engagement were observed at the level of glucose control and lowering of bone resorption, compared to placebo. The results of this study showed that doses up to 40 μg were safe, although tolerability was not present at the highest doses. The study confirmed target receptor engagement at the studied doses.

Kochiae Fructus, the Fruit of Common Potherb Kochia scoparia (L.) Schrad: A Review on Phytochemistry, Pharmacology, Toxicology, Quality Control, and Pharmacokinetics

Kochiae Fructus (KF) is the fruit of an annual potherb Kochia scoparia (Linn.) Schrad and has been traditionally used for the treatment of diseases in the skin, eyes, and urinary tract for thousands of years in China. Recent studies have showed its anti-inflammatory, antifungal, antiallergic, and antipruritogenic effects to clarify the mechanisms of these actions. Meanwhile, its other effects, such as anticancer, hypoglycemic, and hepatoprotective effects, also have been reported. The achievement of these therapeutic effects is contributed by its chemical constituents. A total of 153 compounds have been identified in KF, mainly including triterpenoids, flavonoids, carbohydrates, amino acids, organic acids, and essential oils. Momordin Ic is the representative triterpene glycoside compound, which is used as a phytochemical marker for the quality control of Kochiae Fructus. The research on toxicity is insufficient, and only one article reported that the LD50 was 7.15 ± 0.03 g/kg for water extract of KF after oral administration in KM mice. In addition, the pharmacokinetic study was carried out on momordin Ic with linear pharmacokinetic characteristics. Above all, this review provides comprehensive information about Kochiae Fructus and may provide the theoretic foundation of its clinical application and further development.

Preparation and Evaluation of Amino Acid Conjugates of Celecoxib as Prodrugs to Improve the Pharmacokinetic and Therapeutic Properties of Celecoxib

Although celecoxib is quite effective in the management of inflammation-related diseases, especially arthritis, its use is limited by concerns including low bioavailability (BA), non-linear pharmacokinetic (PK) profile, and peak concentration-related toxicity. To overcome these issues, we designed and prepared hydrophilic celecoxib prodrugs, namely N-glycyl-aspart-1yl celecoxib (N-GA1C), glutam-1-yl celecoxib (G1C), and aspart-1yl celecoxib (A1C), for the sustained release of celecoxib in the intestine with limited systemic absorption. The celecoxib derivatives were converted to celecoxib in the intestinal contents. The conversion rates were in order of N-GA1C > G1C > A1C. Oral administration of the celecoxib derivatives (oral celecoxib derivatives) sustained the plasma concentration of celecoxib for 24 h, improving the BA and linearity of the PK profile of celecoxib. The peak concentrations (Cmax) of celecoxib after oral celecoxib derivatives were lower than that after oral celecoxib. In a carrageenan-induced rat paw edema model, oral N-GA1C exhibited greater anti-inflammatory activity for a longer duration compared with oral celecoxib. The order of efficacy of the celecoxib derivatives was N-GA1C > G1C > A1C. Taken together, the prodrug approach is a feasible strategy to improve the PK and therapeutic properties of celecoxib, and among the celecoxib derivatives, N-GA1C may be the most promising prodrug of celecoxib.

Phase I Trial to Evaluate the Tolerance, Pharmacokinetics and Efficacy of the Broad-Spectrum ErbB Family Inhibitor Larotinib Mesylate in Patients with Advanced Solid Tumors

Background: The presented phase I, first-in-human study evaluated the tolerance, pharmacokinetics, and preliminary efficacy of larotinib mesylate in patients with advanced solid tumors.Methods: Cancer patients were assigned to receive larotinib mesylate at 50–400 mg dose levels until disease progression or intolerance. Dose-limiting toxicities were assessed during Cycles 0 and 1. Pharmacokinetic evaluations were performed after the first dose and at steady-state. Results: Twenty-five patients with solid tumors were enrolled in the dose-escalation study. No DLTs were observed. Acne-like rash (68.0%), diarrhea (48.0%), paronychia (48.0%), and anemia (48.0%) were the most reported treatment-related adverse events. No clear linear pharmacokinetic characteristic could be drawn, and obvious accumulation was observed. Two patients with non-small cell lung cancer experienced a partial response, and 15 patients had stable disease after treatment. Conclusion: Continuous oral administration of larotinib mesylate at 50–400 mg daily demonstrated a favorable safety profile, and anti-tumor activity was observed in patients with advanced solid tumors.Trial registration: registration no.ChiCTR-OPC-15007153, registered 28 September 2015 at http://www.chictr.org.cn

Prevention of Adrenal Crisis: Cortisol Responses to Major Stress Compared to Stress Dose Hydrocortisone Delivery

Context Patients with adrenal insufficiency require increased hydrocortisone cover during major stress to avoid a life-threatening adrenal crisis. However, current treatment recommendations are not evidence-based. Objective To identify the most appropriate mode of hydrocortisone delivery in patients with adrenal insufficiency who are exposed to major stress. Design and Participants Cross-sectional study: 122 unstressed healthy subjects and 288 subjects exposed to different stressors (major trauma [N = 83], sepsis [N = 100], and combat stress [N = 105]). Longitudinal study: 22 patients with preserved adrenal function undergoing elective surgery. Pharmacokinetic study: 10 patients with primary adrenal insufficiency undergoing administration of 200 mg hydrocortisone over 24 hours in 4 different delivery modes (continuous intravenous infusion; 6-hourly oral, intramuscular or intravenous bolus administration). Main Outcome Measure We measured total serum cortisol and cortisone, free serum cortisol, and urinary glucocorticoid metabolite excretion by mass spectrometry. Linear pharmacokinetic modeling was used to determine the most appropriate mode and dose of hydrocortisone administration in patients with adrenal insufficiency exposed to major stress. Results Serum cortisol was increased in all stress conditions, with the highest values observed in surgery and sepsis. Continuous intravenous hydrocortisone was the only administration mode persistently achieving median cortisol concentrations in the range observed during major stress. Linear pharmacokinetic modeling identified continuous intravenous infusion of 200 mg hydrocortisone over 24 hours, preceded by an initial bolus of 50–100 mg hydrocortisone, as best suited for maintaining cortisol concentrations in the required range. Conclusions Continuous intravenous hydrocortisone infusion should be favored over intermittent bolus administration in the prevention and treatment of adrenal crisis during major stress.

Prevention of adrenal crisis: cortisol responses to major stress compared to stress dose hydrocortisone delivery in adrenal insufficiency

ABSTRACTContextPatients with adrenal insufficiency require increased hydrocortisone cover during major stress to avoid life-threatening adrenal crisis. However, current treatment recommendations are not evidence-based.ObjectiveTo identify the most appropriate mode of hydrocortisone delivery in patients with adrenal insufficiency exposed to major stress.Design and ParticipantsCross-sectional study: 122 unstressed healthy subjects and 288 subjects exposed to different stressors (major trauma [N=83], sepsis [N=100], and combat stress [N=105]). Longitudinal study: 22 patients with preserved adrenal function undergoing elective surgery. Pharmacokinetic study: 10 patients with primary adrenal insufficiency undergoing administration of 200mg hydrocortisone over 24 hours in four different delivery modes (continuous intravenous infusion; six-hourly oral, intramuscular or intravenous bolus administration).Main Outcome MeasureWe measured total serum cortisol and cortisone, free serum cortisol and urinary glucocorticoid metabolite excretion by mass spectrometry. Linear pharmacokinetic modelling was used to determine the most appropriate mode and dose of hydrocortisone administration in patients with adrenal insufficiency exposed to major stress.ResultsSerum cortisol was increased in all stress conditions, with the highest values observed in surgery and sepsis. Continuous intravenous hydrocortisone was the only administration mode persistently achieving median cortisol concentrations in the range observed during major stress. Linear pharmacokinetic modelling identified continuous intravenous infusion of 200mg hydrocortisone over 24 hours, preceded by an initial bolus of 50-100mg hydrocortisone, as best suited for maintaining cortisol concentrations in the required range.ConclusionsContinuous intravenous hydrocortisone infusion should be favored over intermittent bolus administration in the prevention and treatment of adrenal crisis during major stress.