In early development, the main goal for a new chemical entity is to demonstrate proof of concept (POC) in patients in the most time- and cost-effective way possible. 

Typically, simple, fit-for-purpose formulations are used in first-in-human studies to minimize upfront development time and CMC costs prior to generating clinical safety and pharmacokinetic data. However, given the increasing number of poorly soluble active pharmaceutical ingredients in the industry development pipeline, this approach has limitations, especially where enabling formulation technologies may be required to ensure adequate bioavailability. 

With over 30 years of experience, Quotient Sciences' suite of technologies and formulation strategies to address solubility challenges range from particle size reduction and spray-dried dispersions, to hot melt extrusion and lipid-based formulations. Additionally, using our Translational Pharmaceutics^® platform, we are able to streamline the development of poorly soluble molecules through the use of flexible study protocols and rapid cycles to make and test drug products. This enables faster, more reliable optimization of formulations based on arising human clinical data to reduce development risk and maximize the probability of clinical success.

In this article, we review some scientific posters published by Quotient Sciences that highlight innovative strategies to overcome challenges with poorly soluble molecules in early development.

"Flexible formulation assessments in FIH studies for poorly soluble drugs accelerates dosage form development, manufacturing and supply for patient POC trials"

Presented by Quotient Sciences at AAPS PharmSci 360, October 2020

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The purpose of this study was to investigate how the integration of formulation development and drug product manufacturing activities can affect FIH-to-POC programs for poorly soluble drugs. Integrated early development programs were designed for two molecules, based on their physicochemical and biopharmaceutic properties. In both programs, drug products were prepared either by pharmacy compounding of the NCE, compounding of a GMP (Good Manufacturing Practice) intermediate, or GMP manufacture of the finished drug products. All formulations were prepared in real time during the FIH clinical study, using arising safety and PK data to inform the drug product selection for the next study period as part of an adaptive clinical protocol. In both studies, an optimized solubility-enhanced formulation was efficiently identified to take forward into patient POC trials – a lipidic capsule formulation in the first study, and a micronized API capsule formulation in the second study.

This poster highlights how the integration of flexible compounding and GMP manufacturing within FIH-to-POC programs can streamline development, maximize the potential for clinical success, and save time and costs for poorly soluble molecules. Drug development programs using this approach have been shown to save, on average, 18 months of time when compared to traditional manufacturing practices.

"A First-in-Human (FIH) Study to Assess the Safety, Tolerability and Pharmacokinetics of Single and Multiple Doses, and Alternative Formulations of R941552 (R552): A Selective Receptor Interacting Protein 1 (RIP1) Kinase Inhibitor"

Presented by Quotient Sciences and Rigel Pharmaceuticals at the ASCPT conference, March 2022

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R552, a potent and selective RIPK1 inhibitor, is being developed by Rigel Pharmaceuticals for the treatment of autoimmune and inflammatory disorders, and pre-clinical data suggested that solubility may limit exposure. The purpose of this FIH study was to assess the safety, tolerability, and PK of R552 when administered in a lipid solution, as well as alternative SDD suspension and tablet formulations. It was found that R552 was generally safe and well tolerated at the dose levels tested, the PK of R552 was linear, and no clinically significant food effect was observed. A suitable SDD tablet formulation for R552 was identified for future patient studies.

This poster highlights how SDDs can offer an effective strategy to overcome challenges with solubility-limited exposure.

"Applications of Lipid-based Formulations and the Benefits of Integrating Manufacturing and Clinical Testing in Formulation Selection"

Presented by Quotient Sciences at the PBP conference, March 2022

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The purpose of this study was to analyze pharmaceutical and clinical data from multiple development programs conducted by Quotient Sciences over 16 years to understand the drivers for, and outcomes from, selecting and dosing different lipid formulations. Data from 34 lipid formulation programs were analyzed for the following features: formulation application, Biopharmaceutical Classification System (BCS), and in-vitro characterization methods. Various lipid-based dosage forms were developed, including solutions, suspensions, SDDs, and modified-release (MR) tablets.

This poster highlights how lipid formulations can successfully be used for solubilization, enhancing oral bioavailability, and reducing food effects for BCS Class II and IV drugs. Conventional in-vitro testing methods for different lipid formulations are poor predictors of in-vivo performance, whereas our integrated Translational Pharmaceutics platform enables the rapid identification of optimal lipid formulations based on clinical performance.

Summary: John McDermott, Vice President of Scientific Consulting at Quotient Sciences, explains how Translational Pharmaceutics® accelerates oncology clinical trials by integrating formulation development, manufacturing, and clinical testing as a seamless program. Translational Pharmaceutics® has been applied to support first-in-human programs, formulation optimization, and more efficient ADME studies. 

Finding novel approaches to improve oncology drug development 

Data from the World Health Organization (WHO) estimates that cancer accounted for nearly 10 million deaths in 2020 with the most common cancers occurring in the breast, lung, colon/rectum, and prostate. The growing demand for new and improved treatments is clear, as is the need to streamline oncology drug development so new treatments can reach those in need, faster. 

The limited effectiveness of existing oncology drugs requires novel approaches to accelerate the clinical trial process. Accelerated approval pathways, which allow the NDA application process to commence from Phase II onwards, require the early submission of a high-quality chemistry, manufacturing, and controls (CMC) package. This push to expedite timelines only increases the risk of commercializing a drug product production process that is not fully optimized or scalable.

Benefits and challenges with emerging oncology modalities

Emerging modalities of oncology treatments, such as immunotherapy, and new chemical entities (NCEs) present increasing challenges in physical form, morphology, and chemical complexity. Therefore, selecting a drug development partner with proven experience in delivering these types of programs is crucial. 

Quotient Sciences' approach involves an early understanding of the biopharmaceutics (DCS classification) during the drug development process, combined with expertise in process chemistry, analytical technology, and formulation development. We mitigate risks in subsequent development phases by gaining early insight into the compound's druggability, guaranteeing a high-quality CMC package that aligns with the accelerated approval process for oncology trials.  

How Translational Pharmaceutics® accelerates oncology therapies

For almost two decades, the Quotient Sciences Translational Pharmaceutics® platform has been able to remove extra time and steps from oncology drug development. Translational Pharmaceutics® consolidates drug product and clinical testing within a single program of work to help reduce the burden of outsourcing while providing a resource-efficient approach to clinical trials. 

Other benefits of applying Translational Pharmaceutics® include scaling an optimal drug product, with the ability to modify dosage forms for additional areas of need, such as pediatric patients. 

In one customer's recent oncology program, we applied a rapid method for conducting first-in-human studies with a single ascending dose (SAD) study. Multiple formulations were developed within a single formulation design space in the same study, allowing a leading formulation to be identified and validated for patient trials in just 12 months.

Quotient Sciences first brought meaningful innovation to the pharmaceutical industry in 2008 with Translational Pharmaceutics®, a trusted platform for nearly two decades for driving innovation in drug development. Contact us to discuss how it can be applied to your next program.

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Lipid-based formulations are known to enhance the oral bioavailability of lipophilic drugs with poor aqueous solubility.

At the Pharmaceutics, Biopharmaceutics, and Pharmaceutical Technology (PBP) conference in March 2022, Quotient Sciences presented a poster analyzing formulation and clinical data from multiple pharmaceutical development programs conducted by Quotient Sciences over 16 years to understand the drivers for, and outcomes from, selecting and dosing different lipidic formulations. The poster also discusses the challenges in using in-vitro characterization methods to predict in-vivo behaviour, and the benefits of using Quotient Sciences’ unique Translational Pharmaceutics® platform to integrate real-time adaptive Good Manufacturing Practice (GMP) manufacturing and clinical testing for the rapid screening of multiple lipidic formulations in Phase I pharmacokinetic (PK) studies.

Data from 34 lipid formulation programs were analyzed for the following features: formulation application, Biopharmaceutics Classification System (BCS), and in-vitro characterization methods. Various lipid-based dosage forms were developed, including solutions, suspensions, spray-dried dispersions (SDDs), and modified-release (MR) tablets.

The poster highlights how lipidic formulations can successfully be used for solubilization, enhancing oral bioavailability, and reducing food effects for BCS Class II and IV drugs. The analysis shows that conventional in-vitro testing methods for different lipidic formulations are poor predictors of in-vivo performance, whereas Quotient Sciences’ integrated Translational Pharmaceutics platform can enable the rapid identification of optimal lipidic formulations based on clinical performance in a reduced timeframe.

Poster authors

• Alaa Hosny, Wu Lin, Peter Scholes

Find out more about Quotient Sciences’ Translational Pharmaceutics drug development platform and solubility enhancement capabilities.

Summary: John McDermott, Vice President of Scientific Consulting at Quotient Sciences, outlines a smarter strategy for optimizing oncology drug products using Translational Pharmaceutics®. He explains how evaluating targeted oncology molecules in healthy volunteers—when safe—can accelerate formulation development, improve pharmacokinetics, and reduce variability. 

The Translational Pharmaceutics® platform can be applied in many ways to accelerate drug product optimization for oncology therapeutics.

To ensure downstream clinical success in patients, drug product optimization is often required, whether to increase oral bioavailability and solubility, reduce pharmacokinetic (PK) variability, overcome food effects, avoid adverse events, or reduce dosing frequency by switching administration routes or to a modified-release form.

For oncology drug development programs these challenges can be magnified, as dosing is typically performed directly in patients in Phase I, rather than conducting healthy volunteer studies to establish safety and PK data. The approach of going directly into patients is known to be inherently problematic when it comes to the speed and effectiveness of identifying improved formulations to deliver improved PK profiles.

Over the past decade, Quotient Sciences has delivered over 400 projects with oncology drugs, including 80 clinical programs in healthy volunteers. These clinical programs have included first-in-human single-ascending-dose/multiple-ascending-dose, relative bioavailability, and 14C human absorption, distribution, metabolism, and excretion (ADME) programs.

Using our flagship platform, Translational Pharmaceutics®, which integrates formulation development, Good Manufacturing Practice (GMP) manufacturing, and clinical testing, we reduce development timelines by more than 12 months while delivering significant cost savings and minimizing program risks.

Translational Pharmaceutics® removes wasted time and handovers in drug development processes by integrating real-time drug product manufacturing with clinical assessments, reducing stability data requirements and batch sizes, and accelerating program delivery. Rapid access to real-time human clinical data from one study period determines the formulation composition that is then made and dosed in the next.

The economies can be even more significant as multiple formulations can be evaluated with lean chemistry, manufacturing, and controls (CMC) data package, and if appropriate, formulation design spaces can be applied to provide a flexible range of drug product compositions to make and dose in the clinical study.

Studying oncology molecules in healthy volunteer studies, where safe to do so, can also mean:

• Study recruitment is not as complex and achieved faster
• Cohorts of subjects can be dosed together to improve formulation decisions
• There is less risk from co-medications and co-morbidities
• Variability in clinical data due to disease state is removed
• Study timelines are reduced, and studies are more cost-effective to conduct

Following rapid identification of an optimized drug product, Quotient Sciences is also able to scale up and supply the formulation into your next-stage global patient studies to provide seamless program continuity.

See how Quotient Sciences' expertise can help meet the challenges of oncology drug development.

Using Translational Pharmaceutics, drug products can be manufactured, released, and dosed in days rather than weeks or months.