GDC-0810, administered orally, was used in Phase I and II clinical studies to treat estrogen receptor-positive breast cancers. Download Quotient Sciences publication here.

Sirolimus (Rapamune®) exhibits low bioavailability, high variability and moderate food effect following oral administration. This makes therapeutic blood monitoring of sirolimus concentrations necessary for kidney transplant patients.

Oral itraconazole has variable pharmacokinetics and risks of adverse events associated with high plasma exposure. An inhalation formulation of itraconazole (PUR1900) is being developed to treat allergic bronchopulmonary 
aspergillosis, an allergic inflammatory disease occurring in asthmatics and patients with cystic fibrosis.

ABSTRACT
Purpose GSK2982772 is a selective inhibitor of receptor interacting protein kinase-1, with a 2–3 h half-life. This study
evaluated if a once-daily modified-release formulation of
GSK2982772 could be developed with no significant food
effect

Achieving efficacious systemic levels of orally administered peptides is incredibly challenging due to the significant barriers to their bioavailability—their stability in the gastrointestinal tract and challenge of transepithelial transit, and variable pharmacokinetics. Even so, as the generally preferred route of administration, significant research effort in academic and industrial settings has focused on enabling the systemic absorption of orally delivered peptides. Despite several decades of research, few have ever reached the market. 

The recent approval of Rybelsus® (oral semaglutide) by the FDA [1], the EMA [2], and the Pmda [3] represents a significant landmark in the delivery of therapeutic peptides and is the culmination of more than 30 years research and development of the drug delivery technology enabling the product—Emisphere’s Eligen™ technology—and an outstanding commitment to scientific, technical, and clinical innovation by Novo Nordisk. 

Following years of fundamental and applied research, an innovative clinical strategy led to the aptly named PIONEER clinical programme. This included ten Phase 3 clinical trials that demonstrated the tablet formulation to be as effective as the already approved injectable form of the drug, and more effective than competitor products in terms of its blood glucose lowering effects and weight loss. Not only is this a potentially life changing medicine for diabetic patients, it holds tremendous commercial potential for Novo Nordisk, with some analysts predicting the product to reach $5 billion in peak revenues [3]. 

In this “Inspirational Note,” we summarize some of the public domain work that led to the achievement of this significant milestone and provide commentary on its potential future impact.

Background: A high-throughput method using inductively coupled plasma mass spectrometry (ICP–MS) was developed and validated for the quantitative analysis of antimony in human plasma and peripheral blood mononuclear cells from patients with cutaneous leishmaniasis undergoing treatment with meglumine antimoniate. Materials & methods: Antimony was digested in clinical samples with 1% tetramethylammonium hydroxide/1% EDTA and indium was used as internal standard. Accuracy, precision and stability were evaluated. Conclusion: Taking the lower limit of quantitation to be the lowest validation concentration with precision and accuracy within 20%, the current assay was successfully validated from 25 to 10000 ng/ml for antimony in human plasma and peripheral blood mononuclear cells. This protocol will serve as a baseline for future analytical designs, aiming to provide a reference method to allow inter-study comparisons.

Ziritaxestat is a novel inhibitor of autotaxin, an enzyme responsible for the production of lysophosphatidic acid, the
downstream signaling of which mediates responses to tissue injury and has been implicated in the pathogenesis of fibrotic conditions such as idiopathic pulmonary fibrosis and systemic sclerosis. This study (Clinical Trial Registration:
NCT03787186) was designed to assess the absorption, distribution, metabolism, and excretion of orally administered
600-mg ziritaxestat labeled with a carbon-14 tracer (14C-ziritaxestat). To understand the absolute bioavailability of ziritaxestat, an intravenous 100-μg microdose, labeled with a microtracer amount of 14C radiation, was administered in a
separate part of the study, following an unlabeled 600-mg therapeutic oral dose of ziritaxestat. Six healthy male subjects
completed each study part. The majority of the labeled oral dose was recovered in feces (77%), with a total mass balance of 84%. The absolute bioavailability of ziritaxestat was 54%. Ziritaxestat was the main (76%) circulating drug-related
product. There were 7 treatment-emergent adverse events, all of which were considered mild and not considered to be
related to the study drug.

Abstract: Currently approved formulations of the androgen synthesis inhibitor abiraterone acetate
(AA) consist of multiple tablets administered daily in a fasted state. Removing the food effect and
switching to a suspension formulation is expected to improve the pharmacokinetic profile and facilitate
drug administration for patients with late-stage prostate cancer. Two four-sequence, fourperiod
randomized crossover investigations were undertaken to establish the pharmacokinetic profiles
of single doses of commercially available Zytiga®, as the reference AA (R-AA), and a novel
tablet for oral suspension (TOS). Four single doses of TOS (from 62.5 to 250 mg) were compared in
study C01, and two single doses each of TOS (250 mg) and R-AA (1000 mg) were compared under
fasted and fed (modified fasted for R-AA) conditions in C02. Plasma concentrations of abiraterone
over time were measured, and pharmacokinetic parameters were calculated. Each doubling of the
dose of TOS was associated with a greater than 3-fold increase in exposure. A single dose of TOS
(250 mg) exhibited similar exposure over 24 h, whether given fasted (625 ng × h/mL) or fed (485 ng
× h/mL). A single dose of TOS (250 mg) was associated with higher (fasted, p = 0.028) or equivalent
exposure (fed) compared to 1000 mg R-AA fasted (532 ng × h/mL). Substantially higher exposures
were seen with 1000 mg R-AA under modified fasted conditions compared to TOS, irrespective of
prandial status (p < 0.001). TOS was generally safe and well tolerated in the study. A 250 mg dose
of a novel AA formulation for oral suspension demonstrated bioequivalence to 1000 mg R-AA under
fasted conditions. This novel TOS formulation also addresses some of the limitations of current AA treatment, including low bioavailability, high variability in systemic exposure and a large food effect. It may offer an alternative for patients with dysphagia or discomfort with swallowing large
pills.

Effect of Miricorilant, a Selective Glucocorticoid Receptor Modulator, on Olanzapine-Associated Weight Gain in Healthy Subjects. Download our resource today.

Purpose GSK2982772 is a selective inhibitor of receptor-interacting protein kinase-1 (RIPK1) with a short 2- to 3-h half-life. In a previous modified-release (MR) study, a matrix monolithic formulation (80% GSK2982772 released over 12 h) provided a once-daily (QD) pharmacokinetic (PK) profile in the fasted state; however, it was susceptible to food effects. The current study evaluated the safety and PK of MR formulations using GSK proprietary DiffCORE™ technology. Methods Part A evaluated PK following single-dose (240 mg) fasted and fed (high-fat meal) administration of three DiffCORE MR formulations within pre-defined in vitro extremes of 80% GSK2982772 released over 12 h (MR-12 h) to 80% GSK2982772 released over 18 h (MR- 18 h) versus an immediate-release formulation. Part B evaluated MR-16 h (120–960 mg) in different prandial states.