A First-in-Human Phase 1 Study of a Tumor-Directed RNA-Interference Drug against HIF2α in Patients with Advanced Clear Cell Renal Cell Carcinoma.

PURPOSE: ARO-HIF2 is an siRNA drug designed to selectively target hypoxia-inducible factor-2α (HIF2α) interrupting downstream pro-oncogenic signaling in clear cell renal cell carcinoma (ccRCC). The aims of this Phase 1 study (AROHIF21001) were to evaluate safety, tolerability, pharmacokinetics, and establish a recommended Phase 2 dose. PATIENTS AND METHODS: Subjects with ccRCC and progressive disease after at least 2 prior therapies that included VEGF and immune checkpoint inhibitors were progressively enrolled into dose-escalation cohorts of ARO-HIF2 administered intravenously at 225, 525, or 1,050 mg weekly. RESULTS: Twenty-six subjects received ARO-HIF2. The most common treatment emergent adverse events (AE) irrespective of causality were fatigue (50.0%), dizziness (26.9%), dyspnea (23.1%), and nausea (23.1%). Four subjects (15.4%) had treatment-related serious AEs. AEs of special interest included neuropathy, hypoxia, and dyspnea. ARO-HIF2 was almost completely cleared from plasma circulation within 48 hours with minimal renal clearance. Reductions in HIF2α were observed between pre- and post-dosing tumor biopsies, but the magnitude was quite variable. The objective response rate was 7.7% and the disease control rate was 38.5%. Responses were accompanied by ARO-HIF2 uptake in tumor cells, HIF2α downregulation, as well as rapid suppression of tumor produced erythropoietin (EPO) in a patient with paraneoplastic polycythemia. CONCLUSIONS: ARO-HIF2 downregulated HIF2α in advanced ccRCC-inhibiting tumor growth in a subset of subjects. Further development was hampered by off-target neurotoxicity and low response rate. This study provides proof of concept that siRNA can target tumors in a specific manner.

Dose-Response Analysis of the Effect of Carbidopa-Levodopa Extended-Release Capsules (IPX066) in Levodopa-Naive Patients With Parkinson Disease.

Parkinson disease is an age-related disorder of the central nervous system principally due to loss of dopamine-producing cells in the midbrain. Levodopa, in combination with carbidopa, is widely regarded as an effective treatment for the symptoms of Parkinson disease. A dose-response relationship is established for carbidopa-levodopa extended-release capsules (IPX066) in levodopa-naive Parkinson disease patients using a disease progression model. Unified Parkinson Disease Rating Scale (UPDRS) part II plus part III scores from 171 North American patients treated with placebo or IPX066 for approximately 30 weeks from a double-blind, parallel-group, dose-ranging study were used to develop the pharmacodynamic model. The model comprised 3 components: a linear function describing disease progression, a component describing placebo (or nonlevodopa) effects, and a component to describe the effect of levodopa. Natural disease progression in early Parkinson disease as measured by UPDRS was 11.6 units/year and faster in patients with more severe disease (Hoehn-Yahr stage 3). Maximum placebo/nonlevodopa response was 23.0% of baseline UPDRS. Maximum levodopa effect from IPX066 was 76.7% of baseline UPDRS, and the ED50 was 450 mg levodopa. Equilibration half-life for the effect compartment was 62.8 days. Increasing age increased and being female decreased equilibration half-life. The quantitative model allowed description of the entire time course of response to clinical trial intervention.

Population pharmacokinetics of vernakalant hydrochloride injection (RSD1235) in patients with atrial fibrillation or atrial flutter.

Vernakalant hydrochloride is a novel, predominantly atrial-selective antiarrhythmic drug that effectively and rapidly terminates atrial fibrillation (AF). Plasma vernakalant concentration data from 5 phase 2 and 3 clinical trials of vernakalant in patients with AF or atrial flutter and a phase 1 study in healthy volunteers were used to construct a population pharmacokinetic model. Plasma vernakalant concentration-time data were best fit by a 2-compartment mammillary model, with rapid first-order elimination from the central compartment. Median systemic clearance was 0.35 L/h/kg (or 28 L/h for an 80-kg patient), with intersubject variability estimated to be 40%. Clearance was significantly influenced by CYP2D6 genotype, age, serum creatinine concentration, and subject status (patient vs volunteer). The intercompartmental clearance was also influenced by subject status, whereas the volumes of the central compartment and peripheral compartment were unaffected by any covariates. Based on the final pharmacokinetic model, the area under the plasma vernakalant concentration-time curve from 0 to 90 minutes was estimated to be 15% higher in CYP2D6 poor metabolizers than extensive metabolizers, with age and serum creatinine having much smaller influences on exposure. These data suggest that dose adjustments based on patient characteristics, including use of concomitant drugs, are unnecessary for intravenous vernakalant.

Pharmacokinetics of conivaptan hydrochloride, a vasopressin V(1A)/V(2)-receptor antagonist, in patients with euvolemic or hypervolemic hyponatremia and with or without congestive heart failure from a prospective, 4-day open-label study.

BACKGROUND: Conivaptan is a nonpeptide vasopressin V(1A)/V(2)-receptor antagonist that produces a controlled increase in serum sodium concentration in hospitalized patients with euvolemic or hyper-volemic hyponatremia. OBJECTIVE: This study evaluated the pharmacokinetics of conivaptan in patients with euvolemic or hypervolemic hyponatremia and with or without underlying congestive heart failure who were participating in an efficacy and tolerability clinical trial. METHODS: Data from an open-label, multicenter study were used to evaluate the pharmacokinetics of conivaptan in hyponatremic patients. Patients received a 20-mg loading dose intravenously over 30 minutes, followed by a continuous 4-day infusion of 20 or 40 mg/d. In the entire cohort, plasma conivaptan concentrations were determined at baseline, at the end of the loading dose (0.5 hour), at 24 hours, on days 3 and 4, and at the follow-up visit on day 11. A subset of patients at 2 study sites (the "pharmacokineticrich" subset) provided additional samples for pharmacokinetic analysis on day 1 at 1, 4, and 24 hours; on day 2 at 24 hours; and on day 5 at 1, 2, 7, 12, and 24 hours. RESULTS: Plasma conivaptan concentrations were evaluated in 31 patients who received conivaptan 20 mg/d (mean [SD] age, 73.1 [14.3] years; weight, 68.1 [17.2] kg; 71.0% female; 87.1% white, 9.7% black, 3.2% other) and 172 patients who received co-nivaptan 40 mg/d (mean [SD] age, 71.5 [14.4] years; weight, 65.6 [15.9] kg; 64.0% female; 90.1% white, 6.4% black, 3.5% other). The pharmacokinetic-rich subset included 8 patients who received conivap-tan 20 mg/d (mean [SD] age, 76.3 [12.4] years; weight, 71.5 [14.7] kg; 87.5% female; 100% white) and 8 who received conivaptan 40 mg/d (mean [SD] age, 78.3 [7.9] years; weight, 71.3 [15.6] kg; 37.5% female; 100% white). In the overall patient group, plasma conivaptan concentrations were the highest after the 30-minute (C(0.5h)) loading dose (mean [SD] C(0.5h) = 733 [323] and 701 [343] ng/mL with conivap-tan 20 and 40 mg/d, respectively) and then declined during day 1 to concentrations (C(24h)) (mean [SD] C(24h) = 84 [78] and 215 [129] ng/mL with conivaptan 20 and 40 mg/d, respectively) that were maintained by the continuous infusion of 20 or 40 mg/d. At the end of infusion (96 hours), the mean (SD) plasma conivaptan concentrations were 176 (196) and 308 (321) ng/mL for conivaptan 20 and 40 mg/d, respectively. A ratio of 1.75 indicated near dose proportionality; however, interpatient variability was evident. No apparent differences in plasma conivaptan concentrations measured at 0.5 or 96 hours were observed between patients with euvolemic or hypervolemic hypona-tremia or between patients with or without congestive heart failure. In the pharmacokinetic-rich subset, for conivaptan 20 and 40 mg/d, respectively, conivaptan clearance was 18.7 and 9.5 L/h, the elimination t1/2 was 5.3 and 10.2 hours, and exposure to conivaptan in terms of AUC(infinity) was 6996 and 30,771 ng . h/mL. CONCLUSION: The results of this study suggest that the pharmacokinetics of conivaptan 20 and 40 mg/d do not differ by volume status or the presence or absence of congestive heart failure.