Vanessa Zann

On the Colonic Bacterial Metabolism of Azo-Bonded Prodrugsof 5-Aminosalicylic Acid

Azo-bonded prodrugs of 5-aminosalicylic acid (mesalazine)-sulfasalazine, balsalazide, and olsalazine, which are used in the treatment of ulcerative colitis, rely on colonic bacteria to cleave the azo bond and liberate the active drug in the large intestine. The aim of this study was to use an in vitro colonic simulator to determine the rates of metabolism of these three prodrugs in the presence of colonic bacteria, and to link the data to results obtained previously in humans. In individual fecal slurries prepared from five different donors, sulfasalazine degradation was rapid and virtually complete within 4 h, confirming the ubiquitous nature of azo-reduction between individuals. In pooled fecal slurry, the rate of degradation of sulfasalazine was faster (t1/2 , 32.8 min) than balsalazide (t1/2 , 80.9 min) and olsalazine (t1/2 , 145.1 min). These results are in agreement with data in humans, where it was found that sulfasalazine was more extensively metabolized on passage through the human colon than the other two drugs. These findings indicate that other than the azo bond itself, the broader chemical structure of the molecules play a role in the degradation of this class of compound, and highlight the utility of this in vitro model to evaluate the metabolism of drugs in the presence of colonic microbiota.

Chain length affects pancreatic lipase activity and the extent and pH-time profile of triglyceride lipolysis.

Triglycerides (TG) are one of the most common excipients used in oral lipid-based formulations. The chain length of the TG plays an important role in the oral bioavailability of the co-administered drug. Fatty acid (FA) chain-length specificity of porcine pancreatic lipase was studied by means of an in vitro lipolysis model under bio-relevant conditions at pH 6.80. In order to determine the total extent of lipolysis, back-titration experiments at pH 11.50 were performed. Results suggest that there is a specific chain length range (C2-C8) for which pancreatic lipase shows higher activity. This specificity could result from a combination of physicochemical properties of TGs, 2-monoglycerides (2-MGs) and FAs, namely the droplet size of the TGs, the solubility of 2-MGs within mixed micelles, and the relative stability of the FAs as leaving groups in the hydrolysis reaction. During experimentation, it was evident that an optimisation of lipolysis conditions was needed for tighter control over pH levels so as to better mimic in vivo conditions. 1M NaOH, 3.5 mL/min maximum dosing rate, and 3 μL/min minimum dosing rate were the optimised set of conditions that allowed better pH control, as well as the differentiation of the lipolysis of different lipid loads.

Assessment of Safety, Tolerability, Pharmacokinetics, and Pharmacological Effect of Orally Administered CORT125134: An Adaptive, Double‐Blind, Randomized, Placebo‐Controlled Phase 1 Clinical Study

CORT125134 is an orally active, high‐affinity, selective antagonist of the glucocorticoid receptor that is being developed for indications that may benefit from the modulation of cortisol activity. This first‐in‐human study was conducted to evaluate the dose‐related safety, tolerability, pharmacokinetics and pharmacological effects of CORT125134 and its active metabolite CORT125201. Eighty‐one healthy male or female subjects received a single dose of 5 to 500 mg CORT125134 or matching placebo across 9 cohorts; 1 cohort received 150 mg CORT125134 after a high‐fat breakfast; and 46 subjects received 50 to 500 mg CORT125134 or matching placebo once daily for up to 14 days across 4 cohorts. CORT125134 was well tolerated at doses up to 250 mg per day for 14 days. CORT125134 was absorbed rapidly and eliminated with a mean half‐life ranging from 11 to 19 hours. Steady state was achieved by day 7. Exposure increased in a greater than proportional manner, particularly at lower doses. Exposure to CORT125201 at steady state was less than 5% that of parent CORT125134. Evidence for the desired pharmacological effect (glucocorticoid receptor antagonism) was demonstrated by the ability of CORT125134 to prevent several effects of the glucocorticoid receptor agonist prednisone.

Palatability and physical properties of potassium-binding resin RDX7675: comparison with sodium polystyrene sulfonate

Background Hyperkalemia is a potentially life-threatening condition that patients with heart failure or chronic kidney disease, especially those taking renin–angiotensin–aldosterone system inhibitors, are at high risk of developing. Sodium polystyrene sulfonate (SPS), a current treatment, binds potassium within the gastrointestinal tract to reduce potassium absorption. However, poor palatability limits its long-term use. RDX7675, a novel potassium binder in development for the treatment of hyperkalemia, is a calcium salt of a reengineered polystyrene sulfonate-based resin designed to have enhanced palatability. Here, the physical properties and palatability of RDX7675 and SPS are compared. Methods RDX7675 and SPS particle sizes were measured using wet dispersion laser diffraction. Palatability was assessed in a randomized, crossover, healthy volunteer study with two visits. At visit 1 (open label), volunteers evaluated high-viscosity, intermediate-viscosity, and water-reconstituted formulations of RDX7675 (all vanilla flavor), and an equivalent reconstituted SPS (Resonium A®). At visit 2 (single-blind), volunteers evaluated RDX7675 as a high-viscosity formulation in vanilla, citrus, and mint flavors, and as intermediate-viscosity, low-viscosity, and reconstituted formulations in citrus flavor. Volunteers used a “sip and spit” technique to rate overall acceptability and seven individual characteristics from 1 (“dislike everything”) to 9 (“like extremely”). Results RDX7675 particles were smaller than SPS particles, with a narrower size range (RDX7675, 80%, 14–52 µm; SPS, 11.3–124.2 µm), and had a smooth, spherical shape, in contrast to the shard-like SPS particles. Reconstituted RDX7675 was considered superior to SPS for five of the seven palatability characteristics and for overall acceptability (median, visit 1: reconstituted RDX7675, 5.0; SPS, 4.0). High-viscosity vanilla was the most highly rated RDX7675 formulation (median overall acceptability, visit 2: 7.0). Conclusion The smaller, more uniformly shaped, spherical particles of RDX7675 resulted in improved palatability over SPS when reconstituted in water. The overall results are promising for future patient acceptability of RDX7675 treatment.

An Evaluation of the Pharmacodynamics, Safety, and Tolerability of the Potassium Binder RDX7675

Hyperkalemia is common in patients with heart failure or chronic kidney disease, particularly those taking renin‐angiotensin‐aldosterone system inhibitors, and can cause arrhythmias and sudden cardiac death. The most widely used treatment, sodium polystyrene sulfonate (SPS), limits gastrointestinal potassium absorption, but has poor palatability. RDX7675 (RDX227675) is the calcium salt of a reengineered polystyrene sulfonate‐based resin with improved palatability over SPS. The pharmacodynamic effects and safety of RDX7675 were assessed in a phase 1, single‐center, randomized, active‐controlled study. Healthy volunteers received nominal active doses of RDX7675 4.6 g twice a day (BID), 4.6 g 3 times a day (TID), 6.9 g BID, 13.7 g daily (QD), 9.2 g TID, or 13.7 g BID (n = 12 each), or equivalent doses of SPS (n = 3 each), for 4 days. RDX7675 dosing increased stool potassium excretion and decreased urinary potassium excretion from baseline. Stool potassium excretion increased by up to 1481 mg/day with RDX7675 (6.9 g BID), and urinary potassium excretion decreased by up to 939 mg/day (13.7 g BID). Similar levels of potassium excretion were observed using QD, BID, or TID dosing of a 13.7 g total daily RDX7675 dose. Few adverse events were reported. In conclusion, repeated oral dosing with RDX7675 over 4 days reduced potassium absorption in healthy volunteers; the results support QD dosing of RDX7675 in future clinical studies.

Abstract CT157: Clinical pharmacokinetics and pharmacodynamics of ME-401, an oral, potent and selective inhibitor of phosphatidylinositol 3-kinase P110δ, following single ascending dose administration to healthy volunteers

Background: ME-401 is a potent and selective inhibitor of the Phosphatidylinositol 3-Kinase p110δ isoform, which demonstrated highly favorable PK from oral administration in preclinical experiments. Preclinical toxicology and safety pharmacology data supported initial clinical assessment of oral ME-401 in healthy volunteers, consistent with its target selectivity profile. Methods: A first-in-human study was conducted using the Translational Pharmaceutics® platform which enables rapid real-time PK/PD analysis and GMP manufacture of drug products between dosing periods, under a flexible protocol. This was an open-label, single dose design, where it was planned to enroll up to 3 sequential groups, comprising 3, 6 and 6 subjects. The planned dose levels were 10, 30, 60 90 and 150 mg. Blood samples were collected to measure plasma concentrations of ME-401, and for testing with a PD assay: basophil activation assessed via CD63 expression by flow cytometry following ex-vivo stimulation with an anti-FCeR1 monoclonal antibody. Results: A total of 15 healthy volunteers were enrolled in the clinical study. ME-401 was orally administered at the planned dose levels. Plasma concentration vs time profiles were consistent with extravascular dosing. There was a linear relationship between both Cmax and AUC as a function of dose (mg). At the 60 mg dose, geometric mean Cmax, AUCinf and half-life were 9.4 ng/ml, 230 ng*h/ml and 28 h, respectively. Half-life appeared dose-independent. Significant inhibition of basophil activation was observed at all dose levels. The individual concentrations and percent inhibition data were fitted to a simple Emax model: E = (Emax*C)/(C+EC50). EC50 and EC90 were 0.6 and 5 ng/mL (1 and 9 nM), respectively. A PK model was fitted to the individual data observed from the 60 mg dose level, and was used to generate steady state trough plasma concentrations from daily dosing of a simulated population of 250 individuals. Statistical analysis indicated a 95% confidence interval of 5.7-6.4 ng/ml for the geometric mean trough plasma levels, which is above the EC90. All doses were generally well tolerated. There were no serious adverse events, severe TEAEs, TEAEs leading to death or TEAEs leading to discontinuation reported. Conclusions: ME-401 is orally bioavailable, exhibiting linear increase in exposure, over the 10-150 mg dose range. Daily dosing of 60 mg, or higher, is expected to afford trough plasma levels that lie above the EC90, on the plateau of the effectiveness dose-response curve. ME-401 was well tolerated when administered to healthy volunteers as a single oral dose up to 150 mg. This highly selective, oral PI3K delta inhibitor is expected to enter a Phase Ib study for the treatment of B-cell malignancies in the first half of 2016. Citation Format: Ofir Moreno, Robert Imani, Vanessa Zann, Pui Leung. Clinical pharmacokinetics and pharmacodynamics of ME-401, an oral, potent and selective inhibitor of phosphatidylinositol 3-kinase P110δ, following single ascending dose administration to healthy volunteers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT157.