Wolfgang Uhl

Safety of Hydroxocobalamin in Healthy Volunteers in a Randomized, Placebo-Controlled Study

Introduction. This randomized, double-blind, placebo-controlled, ascending-dose study was conducted in healthy volunteers to evaluate the safety of the investigational cyanide antidote hydroxocobalamin. Methods. Four ascending dosing groups received intravenous doses of 2.5, 5, 7.5 or 10 g hydroxocobalamin over 7.5 to 30 minutes at a constant infusion rate. Volunteers (n = 136) randomized 3:1 to receive hydroxocobalamin or placebo underwent a 4-day in-house observation after infusion on Day 1 and follow‐up visits on Days 8, 15, and 28. Results. The most common drug-related adverse events were asymptomatic and self-limiting chromaturia and reddening of the skin, which are attributed to the red color of hydroxocobalamin. Other adverse events included pustular/papular rash, headache, erythema at the injection site, decrease in lymphocyte percentage, nausea, pruritus, chest discomfort, and dysphagia. Hydroxocobalamin was associated with an increase in blood pressure in some volunteers. Blood pressure changes peaked toward the end of hydroxocobalamin infusion and typically returned to baseline levels by 4 hours postinfusion. Maximum mean changes from baseline in systolic blood pressure ranged from 22.6 to 27.0 mmHg across hydroxocobalamin doses compared with 0.2 to 6.7 mmHg in the corresponding placebo groups. Maximum mean change from baseline in diastolic blood pressure ranged from 14.3 to 25.4 mmHg across hydroxocobalamin doses compared with −3.0 to 3.8 mmHg in the corresponding placebo groups. Two allergic reactions that occurred within minutes after start of the 5- and 10-g hydroxocobalamin infusions were successfully managed with dexamethasone and/or dimethindene maleate. Conclusion. Timely intervention for acute cyanide poisoning could entail administration of an antidote in the prehospital setting based on a presumptive diagnosis. Results of this placebo-controlled study in healthy volunteers corroborate previous studies and French postmarketing experience in cyanide-exposed patients in suggesting that the safety profile of hydroxocobalamin is consistent with prehospital or hospital use.

A Multicenter Phase 1 Study of EMD 525797 (DI17E6), a Novel Humanized Monoclonal Antibody Targeting αv Integrins, in Progressive Castration-resistant Prostate Cancer with Bone Metastases After Chemotherapy

BACKGROUND EMD 525797 (DI17E6) is a deimmunized, humanized monoclonal immunoglobulin G2 antibody against the αv subunit of human integrins. Blocking αv integrins may be an effective strategy for inhibiting prostate cancer (PCa) metastasis. OBJECTIVE Evaluate EMD 525797 safety/tolerability and pharmacokinetics (PK) in castration-resistant PCa patients. Secondary objectives included antitumor activity assessments. DESIGN, SETTING, AND PARTICIPANTS A phase 1 open-label study in 26 patients (four European centers). Eligible patients (≥ 18 yr) had histologically proven PCa with bone metastases after prior chemotherapy and evidence of progressive disease (PD) based on prostate-specific antigen (PSA) values. INTERVENTION Patients received three intravenous EMD 525797 infusions (250, 500, 1000, or 1500 mg every 2 wk). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Treatment-emergent adverse events (TEAEs) and dose-limiting toxicities (DLTs) were assessed. PK parameters were calculated according to noncompartmental standard methods. Antitumor activity measures were response after 6 wk, changes in PSA levels, and pain interference total score. Descriptive statistics were used. RESULTS AND LIMITATIONS Patients were treated for a mean of 16.8 ± 16.7 wk. No DLTs were reported in any of the cohorts. All patients experienced TEAEs, which were considered drug-related in 11 patients. Four deaths occurred during the trial and were considered not related to EMD 525797. EMD 525797 showed dose-dependent, nonlinear PK. Eighteen of 26 patients did not show PD for ≥ 18 wk. Two patients (500-mg cohort), treated for 42.4 and 76.3 wk, had clinically significant PSA reductions and pain relief, including one patient with confirmed partial response. This trial was not specifically designed to assess clinical activity, and further investigations are needed in randomized controlled trials. CONCLUSIONS No DLTs were reported in any of the evaluated cohorts. There was evidence of clinical activity. For the currently ongoing phase 2 trial, EMD 525797 doses of 750 and 1500 mg every 3 wk were chosen. TRIAL REGISTRATION NCT00958477 (EMR 62242-002).

Changes in blood pressure after administration of hydroxocobalamin: Relationship to changes in plasma cobalamins-(III) concentrations in healthy volunteers

Objective. To assess the relationship between blood pressure changes following infusion of antidotal doses of hydroxocobalamin and plasma concentrations of total and free cobalamins-(III). Methods. Independent groups of healthy volunteers received single intravenous doses of 2.5, 5, 7.5, or 10 g hydroxocobalamin over 7.5 to 30 minutes. Results. In the pharmacokinetic population (n = 41), hydroxocobalamin caused short-lived mean blood pressure increases. Blood pressure increased shortly after initiation of infusion and returned nearly to baseline by 4 hours post-infusion. The time course of blood pressure changes coincided with that of changes in plasma total and free cobalamins-(III). Change in mean arterial pressure (MAP) was strongly correlated with plasma area-under-the-concentration-time curves (AUCs) of total and free cobalamins-(III) during infusion (r > 0.7) but not through 24 hours post-infusion (r ≤ 0.36). Conclusion. The short-lived increase in mean blood pressure during administration of antidotal doses of hydroxocobalamin is closely linked to initial exposure to total and free cobalamins-(III).

Final analysis: A multicenter phase I study of EMD 525797 (DI17E6), a novel humanized monoclonal antibody to human αv integrins, in progressive castrate-resistant prostate cancer with bone metastases after chemotherapy.

231 Background: EMD 525797 is a humanized monoclonal IgG2 antibody specifically targeting αv integrins involved in tumor progression. METHODS The safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of EMD 525797 were assessed in metastatic castrate-resistant prostate cancer (mCRPC) patients (pts). 24 pts (43-80 years) were treated with IV infusions of 250, 500, 1000, or 1500 mg EMD 525797 given over 1 h and received 3 doses (weeks 1, 3, and 5) before response assessment at the end of week 6. Pts without progressive disease could receive further doses every 2 weeks. Dose-limiting toxicities (DLTs) were assessed over the first 6 weeks and safety was monitored until 4 weeks after the last administration of EMD 525797. RESULTS Final analysis showed that 13 of 24 pts had a longer exposure time than expected (≥84 d): 7 pts had exposure times ≥126 d, 3 pts ≥280 d and 1 pt received EMD 525797 for 534 d (Table). All pts experienced adverse events (AEs), and in 11 pts AEs were considered related to EMD 525797. 4 pts had generalized pruritus, erythema, or rash and 3 pts experienced fatigue, mucosal inflammation, or peripheral edema, but no pt had administration site reactions. Changes in clinical lab values were consistent with basic disease. No DLTs occurred. EMD 525797 showed a dose-dependent, nonlinear PK profile in line with a target-mediated drug disposition. Pt 1 and 2 of the 500 mg cohort had a marked decrease in prostate specific antigen. Pt 1 also had primary tumor shrinkage and normalization of lymph node size. These pts had long-term anti-integrin treatment (297 and 534 d, respectively). Both patients showed additional pain relief. CONCLUSIONS EMD 525797 showed clinical activity in mCPRC pts in salvage setting, pain relief, and tumor regression. EMD 525797 is well tolerated without any premedication and did not show clinically relevant dose-related changes in the safety parameters assessed. [Table: see text].

Single-dose pharmacokinetic study comparing the pharmacokinetics of recombinant human chorionic gonadotropin in healthy Japanese and Caucasian women and recombinant human chorionic gonadotropin and urinary human chorionic gonadotropin in healthy Japanese women

Recombinant hCG (r‐hCG) was approved in Japan in 2016. As a prerequisite for a Phase III study in Japan related to this approval, the pharmacokinetic (PK) profile of r‐hCG was investigated.

New levothyroxine formulation meeting 95–105% specification over the whole shelf-life: results from two pharmacokinetic trials

Abstract Objective: Small levothyroxine (L-T4) dose changes can lead to significant clinical effects. To ensure thyroid hormone levels are safely maintained, authorities are increasingly adopting stricter potency specifications for L-T4, the most stringent of these being 95–105% of the labeled dose over the whole shelf-life. Levothyroxine sodium (Euthyrox, Eutirox, Lévothyrox) has been reformulated, and two studies performed, to ensure bioequivalence to the currently marketed formulation and dosage form proportionality of the new formulation. Methods: The bioequivalence study was an open-label, randomized, single-dose, two-period, two-sequence crossover comparing the highest dosage strengths of the currently marketed and the new L-T4 formulation at a total dose of 600 μg. The dosage form proportionality study was an open-label, randomized, three-period, six-sequence crossover, comparing 50 μg, 100 μg, and 200 μg L-T4 tablets, at a total dose of 600 μg. Blood samples were taken at predefined time intervals. Primary outcomes were area under the curve (AUC) and maximum concentration (Cmax) of thyroxine (T4) in plasma. Results: In the bioequivalence study, comparing the T4 profiles for the new and current formulation of L-T4, the geometric least square mean ratio of the baseline-adjusted AUC0–72,adj was 99.3% (90% confidence interval [CI]: 95.6–103.2) and the Cmax,adj was 101.7% (90% CI: 98.8–104.6). Bioequivalence was established if the 90% CI lay within the predefined 0.9–1.11 limits. In the dosage form proportionality study, pairwise comparisons ranged from 99.3% to 104.8%, and all 95% CIs were within the predefined CI range (0.8–1.25): the three dose strengths were dosage form proportional. Conclusions: The new formulation of L-T4 meets the most stringent potency specification guidelines, and has been demonstrated to be bioequivalent to the current formulation and to show dosage form proportionality. The new formulation will enable patients to receive a dose fine tuned to their medical needs, contributing to improved safety in the use of L-T4.

Abstract 1296: Safety, tolerability, and pharmacokinetics of the novel αv-integrin antibody DI17E6 in healthy subjects after ascending single intravenous doses

Introduction: Integrins play an important role in cancer. They are highly expressed in angiogenic, proliferating tumor blood vessels and on certain tumor cells. Apart from their classical role in mediating cell attachment and migration, αv-integrins play a direct role in tumor progression, angiogenesis, and metastasis. DI17E6 (EMD 525797) is a deimmunized monoclonal antibody against αv-integrins, with clinical potential in a range of cancers. This study assessed the safety, tolerability, and pharmacokinetics (PK) of single iv doses of DI17E6 in healthy subjects. Methods: In this first-in-man, single-center, randomized, double-blind, placebo-controlled study, DI17E6 was infused as single doses of 35, 100, 250, 500, 1000, or 1500 mg in 6 consecutive groups. Within each dose-group, 6 subjects were randomized to receive DI17E6 and 3 to receive placebo. Each subject was followed-up for 42 days. Safety, tolerability, and PK were assessed, and plasma parameters and urine biomarkers (including those related to cytokine activation and inflammatory response) were analyzed. Results: In total, 55 healthy male subjects (age 18-45 years) received infusions of DI17E6 or placebo. Of the 37 subjects receiving any dose of DI17E6, 73% reported at least one adverse event (AE) compared to 77.8% in the placebo group. AEs were mainly general or gastrointestinal disorders and injection site reactions. Most of the AEs were reported to a similar extent for DI17E6 and placebo. No serious AEs occurred and all AEs had resolved at the end of the study. Hematology, biochemistry, markers of coagulation and inflammation, and urinalysis showed no clinically relevant changes over time. No influence of DI17E6 on vital signs, physical and ophthalmologic examination, ECG, and spirometry was observed. The DI17E6 Cmax increased nearly dose-proportionally, whereas the increase in the DI17E6 AUC was more than dose-proportional. The clearance (CL) decreased with increasing doses. This dose dependency was more pronounced in lower dose groups; at doses above 250 mg CL started to level off. In 18.9% of the subjects who received DI17E6, anti-DI17E6 antibodies were detected. This was not associated with any clinical signs or symptoms and did not influence the PK of DI17E6. In healthy subjects, DI17E6 did not induce changes in pharmacodynamic parameters (endogenous thrombin potential, D-dimer, platelet activation, CRP, TNFα, IL-8, and CH50) nor in circulating endothelial cells and progenitors. Conclusion: In this healthy subject study, DI17E6 was safe and well tolerated. There were no clinically relevant dose-related changes in any of the safety parameters assessed. PK of DI17E6 are driven by nonlinear elimination, as already described for other antibodies targeting cell surface antigens. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1296. doi:10.1158/1538-7445.AM2011-1296