Association for Human Pharmacology in the Pharmaceutical Industry conference 2022: impending change, innovations and future challenges.

The Association for Human Pharmacology in the Pharmaceutical Industry's annual meeting focused on current and impending challenges facing the United Kingdom's (UK) pharmaceutical industry and how these opportunities can inspire innovation and best practice. The UK pharmaceutical landscape is still evolving following Brexit and learnings from the coronavirus disease 2019 (COVID-19) pandemic. As such, the UK's clinical community is in a unique position to steer innovation in a meaningful direction.

Abemaciclib does not increase the corrected QT interval in healthy participants.

Abemaciclib is an orally administered, potent, and selective small molecule inhibitor of cyclin-dependent kinases 4 and 6, approved for advanced or metastatic breast cancer. This study aimed to use an exposure-response approach to investigate the effect of abemaciclib and its active metabolites (M2 and M20) on QTc interval and delay in cardiac repolarization at clinically relevant exposures. This was a single-blind, randomized, and placebo-controlled study of ascending doses of abemaciclib.

Safety and pharmacokinetics of GB1211, an oral galectin-3 inhibitor: a single- and multiple-dose first-in-human study in healthy participants.

Purpose: Galectin-3, a β-galactoside-binding lectin, plays a key role in several cellular pathways involved in chronic inflammation, heart disease and cancer. GB1211 is an orally bioavailable galectin-3 inhibitor, developed to be systemically active. We report safety and pharmacokinetics (PK) of GB1211 in healthy participants.

An open-label randomized study of the relative absorption of gastro-resistant risedronate taken fasted or with food versus immediate-release risedronate.

Patients with osteoporosis often take oral bisphosphonates with food, rendering these medications ineffective. This study compared the relative absorption of four formulations of gastro-resistant (GR; formulations 1-4) risedronate 35 mg versus immediate-release (IR) risedronate 35 mg taken fasted. Secondarily, it compared the relative absorption of GR formulations administered fed and fasted, and determined the site of disintegration.

Effect of mild or moderate hepatic impairment on the pharmacokinetics of risdiplam.

Aim: This phase I, multicentre, open-label, nonrandomised, parallel-group, two-part study aimed to evaluate the effect of mild to moderate hepatic impairment on the pharmacokinetics (PK), safety and tolerability of a single oral dose of risdiplam.

Methods: Adult subjects (aged 18-70 years) with mild (Child-Pugh Class A; Part 1) or moderate (Child-Pugh Class B; Part 2) hepatic impairment were matched with subjects with normal hepatic function on sex, age, body mass index and smoking status. Each subject received a single oral dose of 5 mg of risdiplam.

Osimertinib Plus Durvalumab in Patients With EGFR-Mutated, Advanced NSCLC: A Phase 1b, Open-Label, Multicenter Trial.

Introduction: EGFR tyrosine kinase inhibitors (TKIs) are recommended for EGFR-mutated NSCLC treatment. EGFR activation up-regulates programmed death-ligand 1 expression and other immunosuppressive factors in NSCLC, causing immune microenvironment remodeling. Osimertinib (an EGFR TKI) plus durvalumab (programmed death-ligand 1 blockade) was evaluated in the TATTON study (NCT02143466).

Accelerated first-in-human clinical trial of EIDD-2801/MK-4482 (molnupiravir), a ribonucleoside analog with potent antiviral activity against SARS-CoV-2.

A recently published article described the safety, tolerability, and pharmacokinetic profile of molnupiravir (Painter et al. 2021), a novel antiviral agent with potent activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19). Here, we report an unprecedented collaboration between sponsor, contract research organization (CRO), and regulatory authorities that enabled accelerated generation of these phase I data, including administration of the first-in-human (FIH) dose of molnupiravir within 5 days of receiving regulatory approval in the United Kingdom (UK).

Clinical evaluation of the potential drug-drug interactions of savolitinib: Interaction with rifampicin, itraconazole, famotidine or midazolam.

Aims: We investigated savolitinib pharmacokinetics (PK) when administered alone or in combination with rifampicin, itraconazole or famotidine, and investigated midazolam PK when administered with or without savolitinib in healthy males.

Methods: Savolitinib PK was evaluated before/after: rifampicin (600 mg once daily [QD] for 5 days); itraconazole (200 mg QD for 5 days); a single dose of famotidine (40 mg QD) 2 hours before savolitinib. Midazolam PK was evaluated before/after midazolam (1 mg QD) with or without savolitinib (600 mg QD).

Developing a direct acting, orally available antiviral agent in a pandemic: the evolution of molnupiravir as a potential treatment for COVID-19.

Despite the availability of vaccines, there remains an urgent need for antiviral drugs with potent activity against SARS-CoV-2, the cause of COVID-19. Millions of people are immune-suppressed and may not be able to mount a fully protective immune response after vaccination. There is also an increasingly critical need for a drug to cover emerging SARS-CoV-2 variants, against which existing vaccines may be less effective.

A phase 1, randomized study to evaluate safety, tolerability, and pharmacokinetics of GDC-3280, a potential novel anti-fibrotic small molecule, in healthy subjects.

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease. Although anti-fibrotic treatments, such as pirfenidone, are available that reduce the rate of disease progression, these medications have limitations in tolerability, and IPF patients still have poor prognoses. GDC-3280, an orally available small molecule that was designed to improve upon pirfenidone's activity, has anti-fibrotic activity in animal models.

Effects of strong and moderate CYP3A4 inducers on the pharmacokinetics of fedratinib in healthy adult participants.

Purpose: Fedratinib is an oral and selective Janus kinase 2 inhibitor that is indicated for treatment of adults with intermediate-2 or high-risk primary or secondary myelofibrosis. Fedratinib is metabolized by cytochrome P450s (CYPs), primarily CYP3A4. The objective of this study was to determine the effects of the strong CYP3A4 inducer rifampin and moderate CYP3A4 inducer efavirenz on the pharmacokinetics of single doses of fedratinib.

Absorption, metabolism and excretion of pictilisib, a potent pan-class I phosphatidylinositol-3-Kinase (PI3K) inhibitor, in rats, dogs, and humans.

The absorption, metabolism and excretion of pictilisib, a selective small molecule inhibitor of class 1 A phosphoinositide 3-kinase (PI3K), was characterized following a single oral administration of [C]pictilisib in rats, dogs and humans at the target doses of 30 mg/kg, 5 mg/kg and 60 mg, respectively.Pictilisib was rapidly absorbed with T less than 2 h across species. In systemic circulation, pictilisib represented the predominant total radioactivity greater than 86.

Oral semaglutide improves postprandial glucose and lipid metabolism, and delays gastric emptying, in subjects with type 2 diabetes.

Aim: To assess the effects of oral semaglutide on postprandial glucose and lipid metabolism, and gastric emptying, in subjects with type 2 diabetes (T2D).

Materials And Methods: In this randomized, double-blind, single-centre, crossover trial, subjects with T2D received once-daily oral semaglutide (escalated to 14 mg) followed by placebo, or vice versa, over two consecutive 12-week periods. Glucose and lipid metabolism, and gastric emptying (paracetamol absorption) were assessed before and after two types of standardized meals (standard and/or fat-rich) at the end of each treatment period.

Human Safety, Tolerability, and Pharmacokinetics of Molnupiravir, a Novel Broad-Spectrum Oral Antiviral Agent with Activity Against SARS-CoV-2.

Molnupiravir, EIDD-2801/MK-4482, the prodrug of the active antiviral ribonucleoside analog ß-d-N4-hydroxycytidine (NHC; EIDD-1931), has activity against a number of RNA viruses including severe acute respiratory syndrome coronavirus 2, severe acute respiratory syndrome coronavirus, Middle East respiratory syndrome coronavirus, and seasonal and pandemic influenza viruses.Single and multiple doses of molnupiravir were evaluated in this first-in-human, phase 1, randomized, double-blind, placebo-controlled study in healthy volunteers, which included evaluation of the effect of food on pharmacokinetics.EIDD-1931 appeared rapidly in plasma, with a median time of maximum observed concentration of 1.

Safety and efficacy of an extended-release peptide YY analogue for obesity: A randomized, placebo-controlled, phase 1 trial.

Aim: To report the results from a Phase 1 trial of an extended-release peptide YY analogue, Y14, developed for the treatment of obesity.

Methods: Y14 was evaluated in overweight/obese volunteers in a Phase 1 randomized placebo-controlled trial, conducted in a clinical trial unit in the United Kingdom. Part A was a blinded single-ascending-dose study evaluating doses up to 36 mg.

Mass balance and pharmacokinetics of an oral dose of C-napabucasin in healthy adult male subjects.

This phase 1, open-label study assessed C-napabucasin absorption, metabolism, and excretion, napabucasin pharmacokinetics, and napabucasin metabolites (primary objectives); safety/tolerability were also evaluated. Eight healthy males (18-45 years) received a single oral 240-mg napabucasin dose containing ~100 μCi C-napabucasin. Napabucasin was absorbed and metabolized to dihydro-napabucasin (M1; an active metabolite [12.

The Association for Human Pharmacology in the Pharmaceutical Industry London Meeting October 2019: Impending Change, Innovation, and Future Challenges.

The Association for Human Pharmacology in the Pharmaceutical Industry (AHPPI) annual meeting focused on impending change, innovation, and future challenges facing early phase drug development as we move into the second decade of the 21th century. The meeting opened with discussion around the technical revolution in pharmaceutical medicine over the 4 decades since the AHPPI was founded and how transformative technologies have accompanied the introduction of processes such as physiologically based pharmacokinetic modeling. During the meeting examples were presented of how in terms of the development of new therapies, the classic phases of clinical drug development are becoming a thing of the past and the lines between the phases have begun to blur, particularly in the field of oncology.

Statistical analysis plan for "A randomised, controlled study to evaluate the effects of switching from cigarette smoking to using a tobacco heating product on health effect indicators in healthy subjects".

Tobacco harm reduction strategies aim to substitute smoking with potentially reduced risk products (PRRPs) such as e-cigarettes and tobacco-heating products (THPs). The health benefits of switching from smoking to PRRPs is unknown. A randomised controlled trial is being conducted to increase understanding of the health effects of switching from smoking to a THP in a 12-month long ambulatory study (ISRCTN81075760).

A phase 1, randomized, open-label, single-dose study to assess the relative bioavailability of a subcutaneous dose of FKB327 when administered using a prefilled syringe, a prefilled auto-injector, or a vial with disposable syringe in healthy subjects.

Background/objective: FKB327 is a biosimilar of the adalimumab reference product (RP). The primary objective was to assess the relative bioavailability of FKB327 after a single subcutaneous (SC) dose via prefilled syringe (PFS), auto-injector (AI), or vial with a disposable syringe (vial), in healthy subjects.

Methods: This randomized, open-label, parallel-group, single SC-dose study was conducted in 195 healthy male and female subjects who were randomized 1:1:1 to receive FKB327 40 mg via PFS, AI, or vial.

Investigation of the absolute bioavailability and human mass balance of navoximod, a novel IDO1 inhibitor.

Aims: Navoximod (GDC-0919, NLG-919) is a small molecule inhibitor of indoleamine-2,3-dioxygenase 1 (IDO1), developed to treat the acquired immune tolerance associated with cancer. The primary objectives of this study were to assess navoximod's absolute bioavailability (aBA), determine the mass balance and routes of elimination of [ C]-navoximod, and characterize navoximod's metabolite profile.

Methods: A phase 1, open-label, two-part study was conducted in healthy volunteers.

Pharmacokinetics and safety of olaparib tablets as monotherapy and in combination with paclitaxel: results of a Phase I study in Chinese patients with advanced solid tumours.

Purpose: Chinese patients have been enrolled in multiple Phase III trials of the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib (Lynparza); however, the pharmacokinetic (PK) profile of olaparib has not been investigated in this population. This two-part, open-label Phase I study was, therefore, carried out to determine the PK and safety profile of olaparib (tablet formulation) in Chinese patients with advanced solid tumours as monotherapy and in combination with paclitaxel (NCT02430311).

Methods: The PK profile of olaparib 300 mg (twice daily [bid]; Cohort 1) as monotherapy after a single dose and at steady state, and 100 mg (bid; Cohort 2) as monotherapy (single dose and at steady state) and in combination (at steady state) with weekly paclitaxel (80 mg/m) was assessed during Part A.

The Association for Human Pharmacology in the Pharmaceutical Industry London Meeting 2018: Brexit and Other Challenges in Early Phase Drug Development.

The Association for Human Pharmacology in the Pharmaceutical Industry (AHPPI) annual meeting focused on the changing face of early phase drug development and opened with a keynote speech concerning the revolution in pharmaceutical medicine over the last 30 years and the impact this has had on the way patients are treated. Examples were presented of how translational pharmaceutics is being used to tackle the high drug candidate failure rate and is improving productivity when moving drug candidates from the laboratory through to clinical proof of concept. The European Medicines Agency revised 2007 Risk Mitigation guideline on first in human (FIH) clinical trials was discussed.

Safety, pharmacokinetics, and immunogenicity of a co-formulated cocktail of three human monoclonal antibodies targeting Ebola virus glycoprotein in healthy adults: a randomised, first-in-human phase 1 study.

Background: REGN3470-3471-3479 is a co-formulated cocktail of three human monoclonal antibodies targeting three non-overlapping epitopes on Ebola virus. We investigated safety, tolerability, pharmacokinetics, and anti-drug antibodies in healthy adults.

Methods: This randomised, double-blind, placebo-controlled, dose-escalation study was done at a phase 1 unit in the USA.

Changes in Biomarkers of Exposure on Switching From a Conventional Cigarette to Tobacco Heating Products: A Randomized, Controlled Study in Healthy Japanese Subjects.

Background: Smoking is a leading cause of numerous human disorders including pulmonary disease, cardiovascular disease, and cancer. Disease development is primarily caused by exposure to cigarette smoke constituents, many of which are known toxicants. Switching smokers to modified risk tobacco products (MRTPs) has been suggested as a potential means to reduce the risks of tobacco use, by reducing such exposure.

Characterization of the Pharmacokinetics of Vilaprisan: Bioavailability, Excretion, Biotransformation, and Drug-Drug Interaction Potential.

Background And Objectives: In-vitro data suggest that clearance of vilaprisan is mediated by cytochrome P450 3A4 (oxidation) and aldoketoreductases (reduction). To fully understand the elimination and biotransformation pathways of vilaprisan, a selective progesterone receptor modulator, and to quantify the impact of cytochrome P450 3A4 inhibition on the pharmacokinetics of vilaprisan, two clinical studies in healthy postmenopausal women were conducted.

Methods: In study 1, pharmacokinetics, mass balance, and metabolite patterns were determined after single oral administration of 5 mg of [C]-labeled vilaprisan in six subjects.