Inhibiting Plasma Kallikrein for Hereditary Angioedema Prophylaxis.

BACKGROUND: Hereditary angioedema with C1 inhibitor deficiency is characterized by recurrent, unpredictable swelling episodes caused by uncontrolled plasma kallikrein generation and excessive bradykinin release resulting from cleavage of high-molecular-weight kininogen. Lanadelumab (DX-2930) is a new kallikrein inhibitor with the potential for prophylactic treatment of hereditary angioedema with C1 inhibitor deficiency. METHODS: We conducted a phase 1b, multicenter, double-blind, placebo-controlled, multiple-ascending-dose trial. Patients with hereditary angioedema with C1 inhibitor deficiency were randomly assigned in a 2:1 ratio to receive either lanadelumab (24 patients) or placebo (13 patients), in two administrations 14 days apart. Patients assigned to lanadelumab were enrolled in sequential dose groups: total dose of 30 mg (4 patients), 100 mg (4 patients), 300 mg (5 patients), or 400 mg (11 patients). The pharmacodynamic profile of lanadelumab was assessed by measurement of plasma levels of cleaved high-molecular-weight kininogen, and efficacy was assessed by the rate of attacks of angioedema during a prespecified period (day 8 to day 50) in the 300-mg and 400-mg groups as compared with the placebo group. RESULTS: No discontinuations occurred because of adverse events, serious adverse events, or deaths in patients who received lanadelumab. The most common adverse events that emerged during treatment were attacks of angioedema, injection-site pain, and headache. Dose-proportional increases in serum concentrations of lanadelumab were observed; the mean elimination half-life was approximately 2 weeks. Lanadelumab at a dose of 300 mg or 400 mg reduced cleavage of high-molecular-weight kininogen in plasma from patients with hereditary angioedema with C1 inhibitor deficiency to levels approaching that from patients without the disorder. From day 8 to day 50, the 300-mg and 400-mg groups had 100% and 88% fewer attacks, respectively, than the placebo group. All patients in the 300-mg group and 82% (9 of 11) in the 400-mg group were attack-free, as compared with 27% (3 of 11) in the placebo group. CONCLUSIONS: In this small trial, administration of lanadelumab to patients with hereditary angioedema with C1 inhibitor deficiency reduced cleavage of high-molecular-weight kininogen and attacks of angioedema. (Funded by Dyax; ClinicalTrials.gov number, NCT02093923 .).

Population pharmacokinetics of fusidic acid: rationale for front-loaded dosing regimens due to autoinhibition of clearance.

The objectives of this analysis were to develop a population pharmacokinetic (PK) model to describe the absorption and disposition of fusidic acid after single and multiple doses and to determine the effect of food on the rate and extent of bioavailability. Plasma PK data from three phase 1 studies (n = 75; n = 14 with and without food) in which healthy subjects received sodium fusidate (500 to 2,200 mg) as single or multiple oral doses every 8 h (q8h) or q12h for up to 7 days were modeled using S-ADAPT (MCPEM algorithm). Accumulation of fusidic acid after multiple doses was more than that predicted based on single-dose data. The PK of fusidic acid was best described using a time-dependent mixed-order absorption process, two disposition compartments, and a turnover process to describe the autoinhibition of clearance. The mean total clearance (% coefficient of variation) was 1.28 liters/h (33%) and the maximum extent of autoinhibition was 71.0%, with a 50% inhibitory concentration (IC(50)) of 46.3 mg/liter (36%). Food decreased the extent of bioavailability by 18%. As a result of the autoinhibition of clearance, steady state can be achieved earlier with dosing regimens that contain higher doses (after 8 days for 750 mg q12h and 1 day for 1,500 mg q12h on day 1 followed by 600 mg q12h versus 3 weeks for 500 mg q12h). Given that large initial doses autoinhibit the clearance of fusidic acid, this characteristic provides a basis for the administration of front-loaded dosing regimens of sodium fusidate which would allow for effective concentrations to be achieved early in therapy.

Comparison of plasma, epithelial lining fluid, and alveolar macrophage concentrations of solithromycin (CEM-101) in healthy adult subjects.

The steady-state concentrations of solithromycin in plasma were compared with concomitant concentrations in epithelial lining fluid (ELF) and alveolar macrophages (AM) obtained from intrapulmonary samples during bronchoscopy and bronchoalveolar lavage (BAL) in 30 healthy adult subjects. Subjects received oral solithromycin at 400 mg once daily for five consecutive days. Bronchoscopy and BAL were carried out once in each subject at either 3, 6, 9, 12, or 24 h after the last administered dose of solithromycin. Drug concentrations in plasma, ELF, and AM were assayed by a high-performance liquid chromatography-tandem mass spectrometry method. Solithromycin was concentrated extensively in ELF (range of mean [± standard deviation] concentrations, 1.02 ± 0.83 to 7.58 ± 6.69 mg/liter) and AM (25.9 ± 20.3 to 101.7 ± 52.6 mg/liter) in comparison with simultaneous plasma concentrations (0.086 ± 0.070 to 0.730 ± 0.692 mg/liter). The values for the area under the concentration-time curve from 0 to 24 h (AUC(0-24) values) based on mean and median ELF concentrations were 80.3 and 63.2 mg · h/liter, respectively. The ratio of ELF to plasma concentrations based on the mean and median AUC(0-24) values were 10.3 and 10.0, respectively. The AUC(0-24) values based on mean and median concentrations in AM were 1,498 and 1,282 mg · h/L, respectively. The ratio of AM to plasma concentrations based on the mean and median AUC(0-24) values were 193 and 202, respectively. Once-daily oral dosing of solithromycin at 400 mg produced steady-state concentrations that were significantly (P < 0.05) higher in ELF (2.4 to 28.6 times) and AM (44 to 515 times) than simultaneous plasma concentrations throughout the 24-h period after 5 days of solithromycin administration.

Pharmacokinetics and safety of single, multiple, and loading doses of fusidic acid in healthy subjects.

A phase 1 trial of fusidic acid (CEM-102), an oral fusidane class antibiotic under development for treatment of gram-positive acute bacterial skin and skin structure infections, evaluating pharmacokinetics and safety is described. A randomized, double-blinded, placebo-controlled, dose escalation study was conducted in healthy adult subjects in the fasting state. Plasma exposure after multiple doses was higher than for single doses, indicating accumulation. Loading doses designed to optimize pharmacodynamic effects were well tolerated and achieved near-steady state concentrations of CEM-102 at 24 h. CEM-102 was safe and generally well tolerated at all single, multiple, and loading doses administered.

A randomized, double-blind phase 2 study comparing the efficacy and safety of an oral fusidic acid loading-dose regimen to oral linezolid for the treatment of acute bacterial skin and skin structure infections.

Fusidic acid (CEM-102), an orally bioavailable fusidane antibiotic with a unique mode of action, is under development for treatment of acute gram-positive bacterial skin and skin structure infections, including those caused by methicillin-susceptible and methicillin-resistant Staphylococcus aureus and streptococci. A phase 2, adaptive design, randomized, double-blind, multiple-center study of 198 adult patients with cellulitis or wound infections was conducted to evaluate an oral CEM-102 loading-dose regimen (1500 mg twice per day on day 1 followed by 600 mg twice per day) compared with oral linezolid (600 mg twice per day) administered for 10-14 days. The CEM-102 loading-dose regimen demonstrated efficacy, safety, and tolerability that was comparable to linezolid for the treatment of acute gram-positive bacterial skin and skin structure infections. Clinical Trials registration. NCT00948142.

Pharmacokinetics of solithromycin (CEM-101) after single or multiple oral doses and effects of food on single-dose bioavailability in healthy adult subjects.

The pharmacokinetics of orally administered solithromycin (CEM-101), a novel fluoroketolide, were evaluated in healthy subjects in three phase 1 studies. In two randomized, double-blinded, placebo-controlled studies, escalating single oral doses of solithromycin (50 to 1,600 mg) or seven oral daily doses (200 to 600 mg) of solithromycin were administered. A third study evaluated the effects of food on the bioavailability of single oral doses (400 mg) of solithromycin. Following single doses, the median time to peak concentration (Tmax) ranged from 1.5 h to 6 h. The mean maximum measured plasma concentration (Cmax) ranged from 0.0223 µg/ml to 19.647 µg/ml, and the area under the concentration-versus-time curve from time zero to time t (AUC0-t) ranged from 0.0402 µg·h/ml to 28.599 µg·h/ml. There was no effect of high-fat food on the oral bioavailability of solithromycin. In the multiple-dose study, after 7 days, the mean maximum measured plasma solithromycin concentration at steady-state (Cmax,ss) ranged from 0.248 to 1.50 µg/ml, and the area under the concentration-versus-time curve over the final dosing interval (AUCτ) ranged from 2.310 to 18.41 µg·h/ml. These values indicate a greater than proportional increase in exposure at 200 and 400 mg but a proportional exposure at 600 mg. Median Tmax values remained constant between day 1 and day 7. Moderate accumulation ratios of solithromycin were observed after 7 days of dosing. All dose regimens of solithromycin were well tolerated, and no discontinuations due to an adverse event occurred. The human pharmacokinetic profile and tolerability of solithromycin, combined with its in vitro potency and efficacy in animal models against a broad spectrum of pathogens, support further development of solithromycin.

Control of postprandial plasma glucose by an oral insulin product (HIM2) in patients with type 2 diabetes.

OBJECTIVE: The objectives of this exploratory study were to assess the postprandial glucose-lowering effects and evaluate the safety and tolerability of single, escalating doses of an oral insulin product, hexyl-insulin monoconjugate 2 (HIM2), in patients with type 2 diabetes. Subcutaneous insulin and oral placebo were also administered for comparison. RESEARCH DESIGN AND METHODS: Eighteen patients with type 2 diabetes were enrolled in this randomized, single-blind, placebo-controlled, three-way crossover, dose-escalation study. A single dose of each of the following study drugs was administered to each patient on 3 separate days: oral HIM2 (at one of three dose levels: 0.375, 0.5, or 1.0 mg/kg), subcutaneous regular insulin (8 units Humulin R), and oral placebo. At 30 min after dosing, patients ingested a standardized test meal (16 oz/720 calories of Boost Plus). Serial blood samples were collected for determination of plasma glucose and insulin concentrations during the 4-h postdose period. RESULTS: The mean glucose area under the curve for 0 to 240 min (AUC(0-240)) values were lower following administration of 0.5 and 1.0 mg/kg HIM2 vs. placebo (1,097.1 vs. 1,196.9 and 801.1 vs. 992.1 mg x h(-1) x dl(-1), respectively). This difference was statistically significant at the 1.0-mg/kg HIM2 dose level. Insulin exposure, as measured by insulin AUC(0-240) values, for the 0.375-, 0.5-, and 1.0-mg/kg dose levels of HIM2 were 169.9, 193.1, and 230.8 micro U x h(-1) x ml(-1), respectively; insulin AUC(0-240) values for placebo were 165.8, 196.1, and 169.2 micro U x h(-1) x ml(-1), respectively. The mean glucose AUC(0-240) values were similar following administration of 0.5 and 1.0 mg/kg HIM2 vs. subcutaneous insulin (1,097.1 vs. 1,048.0 and 801.1 vs. 875.2 mg x h(-1) x dl(-1), respectively). For pooled data from the 0.5- and 1.0-mg/kg dose groups, the HIM2/subcutaneous insulin ratios for the 2-h postprandial glucose concentration (0.97, 95% CI 0.90-1.06), maximum postprandial glucose concentration (0.99, 95% CI 0.93-1.06), and glucose AUC(0-240) (0.98, 95% CI 0.9-1.06) were within 10% of unity, implying glucodynamic equivalence. Although HIM2 (0.5 and 1.0 mg/kg) and subcutaneous insulin (8 units) provided comparable control of postprandial plasma glucose concentrations, HIM2 resulted in peripheral insulin concentrations that were lower than subcutaneous insulin (mean insulin AUC(0-240) of 193.1 vs. 233.6 and 230.8 vs. 270.3 micro U x h(-1) x ml(-1), respectively). CONCLUSIONS: Single, oral doses of HIM2 were safe and well tolerated. HIM2 (0.5 and 1.0 mg/kg) was more effective than placebo and as effective as subcutaneous regular insulin (8 units) at controlling postprandial glycemia with respect to the following parameters: 2-h postprandial glucose concentration, maximum glucose concentration, and glucose AUC(0-240). This occurred even though peripheral insulin concentrations were lower following the administration of HIM2 (0.5 and 1.0 mg/kg) than subcutaneous insulin. Thus, HIM2 therapy may control postprandial glycemia without causing peripheral hyperinsulinemia in patients with type 2 diabetes.

Oral modified insulin (HIM2) in patients with type 1 diabetes mellitus: results from a phase I/II clinical trial.

An effective, orally administered insulin product would be of substantial benefit in the treatment of patients with diabetes mellitus. This phase I/II clinical trial was the first to investigate the safety and effectiveness of a single oral dose of a modified human insulin in controlling postprandial plasma glucose levels in patients with type 1 diabetes mellitus who were receiving basal continuous subcutaneous insulin infusion (CSII) therapy. Fourteen patients with type 1 diabetes mellitus were evaluated in an open-label, 2-center, dose-escalation, nonrandomized study of oral hexyl-insulin monoconjugate 2 (HIM2). After an overnight fast and prior to receiving a standardized meal (50% carbohydrates, 30% fat, 20% proteins; 650 calories), the patients received either no additional insulin (day 1), or 0.5 to 1.0 mg/kg of HIM2 (day 2). All patients received a basal insulin regimen by CSII throughout the study. Blood samples were collected for determination of glucose and insulin levels for 240 minutes post-dose. The postprandial glucose excursion versus time curves showed clear reductions in glucose values after both HIM2 doses (day 2) relative to no treatment (day 1), although the differences in the reductions were not statistically significant. When the data for both HIM2 doses were pooled, a statistically significant effect of HIM2 on glucose excursion (as measured by AUCex(30-240)) was observed. Mean +/- SD values for AUCex(30-240) were 501.35 +/- 124.1 mg. h/dL after no treatment and 375.81 +/- 215.5 mg. h/dL after HIM2 (Wilcoxon signed-rank test, P =.042). The results of this study suggest that oral HIM2, when added to a basal insulin regimen, was safe and may prove effective in controlling postprandial hyperglycemia in patients with type 1 diabetes mellitus. Further clinical investigation is necessary.

Pharmacokinetics of modified oral calcitonin product in healthy volunteers.

STUDY OBJECTIVE: To assess the preliminary pharmacokinetics, pharmacodynamics, safety, and tolerability of single oral doses of a chemically modified salmon calcitonin product, CT-025, in healthy volunteers. DESIGN: Phase I, exploratory, five-way, open-label, nonrandomized, crossover study. SETTING: Clinical research center. SUBJECTS: Twelve healthy volunteers aged 22-44 years. INTERVENTION: A single oral dose of CT-025 was administered on 5 separate days with a 72-hour washout period between doses. Each dose consisted of CT-025 160 or 320 microg in varying relative concentrations of a mixture of excipients (formulations A, B, and C). MEASUREMENTS AND MAIN RESULTS: Serial blood samples were collected for determination of plasma CT-025, total serum calcium, and ionized serum calcium concentrations during the 4-hour period after dose administration. The data are the results from four of the five dosing days, when subjects received CT-025 in high and low concentrations of excipients. The data indicate that CT-025 was rapidly absorbed from the gastrointestinal tract. Mean peak plasma concentrations ranging from 51+/-51-110+/-59 pg/ml were observed 36-54 minutes after administration. Mean terminal elimination half-lives ranged from 54-76 minutes. There was a trend for the mean maximum concentration and area under the plasma concentration-time curve (AUC) from time zero to the time of the last quantifiable plasma concentration to increase with dose. Single oral doses of CT-025 160 and 320 microg were pharmacologically active, inducing a statistically significant decrease in total and ionized serum calcium concentrations. The rate of decrease in ionized serum calcium concentration was significantly related to the CT-025 dose. Single ora doses were well tolerated; some subjects experienced mild and transient nausea. CONCLUSION: Single doses of CT-025 were absorbed into the systemic circulation after oral administration and were well tolerated in healthy volunteers at doses up to 320 microg. These data suggest that oral delivery of salmon calcitonin becomes feasible with this product and support further clinical investigation of CT-025 as a treatment for osteoporosis and osteoporotic bone pain.

Oral insulin product hexyl-insulin monoconjugate 2 (HIM2) in type 1 diabetes mellitus: the glucose stabilization effects of HIM2.

This study was designed to determine plasma glucose and insulin levels after administration of three escalating doses of the oral insulin product hexyl-insulin monoconjugate 2 (HIM2) in fasting, insulin-deprived adult patients with type 1 diabetes. The study was also designed to assess the safety of the product. Sixteen patients with daily insulin requirements of 27-60 units and glycosylated hemoglobin levels of 5.8-11.1% completed the study. Patients' regular insulin regimens were discontinued at bedtime, and they fasted overnight. Blood glucose levels were stabilized overnight by intravenous insulin infusion. In the morning, intravenous insulin was discontinued 30 min prior to an oral dose of HIM2 (0.6, 0.8, or 1.0 mg/kg). A second oral dose of HIM2 was administered 120 min later. Plasma glucose and insulin levels were measured during a 240-min evaluation period after the first HIM2 dose. Identical HIM2 dosing and study procedures were repeated 1 week later with the same patients. Stable or declining plasma glucose levels were observed on 31 out of a total of 32 dosing days beginning at 20 min after the initial administration of HIM2. After plasma glucose levels declined or were stable for 30 min to 2 h, increases were observed for some patients. However, for the majority of patients (68.8%), plasma glucose levels were <150% of predose levels throughout the postdose evaluation period. Similar results were observed after repeating the study procedures 1 week later. Also, plasma glucose area under the concentration-time curves (AUCs) were inversely correlated with plasma insulin AUCs. HIM2 appeared to be safe and well-tolerated in this study; no episodes of symptomatic hypoglycemia were observed. Thus, HIM2 prevented the expected rise in plasma glucose concentrations in insulin-deprived adult patients with type 1 diabetes. The lack of hypoglycemic events in this exploratory study is encouraging and suggests that there may be less risk of severe hypoglycemia associated with HIM2 when compared with injectable insulin. The promising data in this study support the hypothesis that oral HIM2 reproduces the physiological pathway of insulin secreted by the pancreas - through the portal vein directly to the liver - suggesting a therapeutic advantage in the management of type 1 diabetes mellitus.

Simulated first-phase insulin release using Humulin or insulin analog HIM2 is associated with prolonged improvement in postprandial glycemia.

We examined the extent to which priming the liver with a pulse of Humulin or the insulin analog hexyl-insulin monoconjugate 2 (HIM2) reduces postprandial hyperglycemia. Somatostatin (0.5 microg.kg(-1).min(-1)) was given with basal intraportal insulin and glucagon for 4.5 h into three groups of 42-h-fasted conscious dogs. From 0-5 min, group 1 (BI, n = 6) received saline, group 2 (HI, n = 6) received a Humulin pulse (10 mU.kg(-1).min(-1)), and group 3 (HIM2, n = 6) received a HIM2 pulse (10 mU.kg(-1).min(-1)). Duodenal glucose was infused (5.0 mg.kg(-1).min(-1)) from 15 to 270 min. Arterial insulin in BI remained basal (6 +/- 1 microU/ml) and peaked at 52 +/- 15 (HI) and 164 +/- 44 microU/ml (HIM2) and returned to baseline by 30 and 60 min, respectively. Arterial plasma glucose plateaued at 265 +/- 20, 214 +/- 15, and 193 +/- 14 mg/dl in BI, HI, and HIM2. Glucose absorption was similar in all groups. Significant net hepatic glucose uptake occurred at 85, 55, and 25 min in BI, HI, and HIM2, respectively. Nonhepatic glucose clearance at 270 min differed among groups (BI, HI, HIM2): 0.62 +/- 0.11, 0.76 +/- 0.26, and 1.61 +/- 0.29 ml.kg(-1).min(-1) (P < 0.05). A brief (5-min) insulin pulse improved postprandial glycemia, stimulating hepatic glucose uptake and prolonging enhancement of nonhepatic glucose clearance. HIM2 was more effective than Humulin, perhaps because its lowered clearance caused higher levels at the liver and periphery and its biological activity was not reduced proportionally to its decreased clearance.