EXECUTIVE INTERVIEW – Quotient Sciences: Unique Considerations & Challenges When Developing Palatable Pediatric Formulations

The demand for pediatric dosage forms continues to increase; however, the number of approved pediatric drug treatments on the market remains substantially less than those for adults. Developing drug products for pediatric patients brings a whole set of unique challenges for development teams. Formulation scientists must consider the route of administration, the safety profile, overall taste and palatability, the child’s age, weight, physiologic condition, and the treatment plan’s requirements. All these key factors must be balanced for developing a pediatric product that garners clinical, regulatory, and commercial success.

Quotient Sciences, a drug development and manufacturing accelerator, has extensive experience in developing palatable pediatric formulations on behalf of pharmaceutical and biotech customers globally and has successfully developed customized pediatric pharmaceutical formulations that have received regulatory approval.

Drug Development & Delivery recently spoke with Nazim Kanji, Executive Director, Pediatric Services at Quotient Sciences, about the unique considerations and challenges when developing palatable pediatric formulations, so that molecules can become cures, fast.

Q: What are the regulatory considerations when developing a pediatric formulation, including US and EU incentives, guidance, and requirements?

A: Historically, drug products used in children were generally only approved for adults. They were rarely tested in pediatric populations, and product labelling did not include directions for safe and effective use in pediatric patients. Furthermore, the correct dose and excipient safety were generally not determined for target age groups, and there was a distinct lack of age-appropriate formulations, which meant that in many cases, manipulation of the adult product would be required to dose children.

Pediatric legislation in the form of The Best Pharmaceuticals for Children Act and Pediatric Research Equity Act in the US and the Paediatric Regulation in the EU came into effect between 2002 and 2007. The aim of these regulations was to increase the number of products that were approved for pediatric use, and they sought to do this by mandating companies to undertake pediatric research and development as well as providing financial incentives for them if they invested in doing this work.

Both the US and EU regulations require the submission of pediatric plans at given points in the adult development – in the EU, a Paediatric Investigation Plan (PIP) is to be submitted no later than the end of human pharmacokinetic (PK) studies in adults, while the US requires a Pediatric Study Plan (PSP) to be submitted within 60 days of the end-of-Phase 2 meeting. These documents give a commitment to the studies that will be conducted and also the timeframe.

Q: What are some key strategies and product considerations when developing patient-centric dosage forms that are acceptable and palatable for pediatric populations?

A: In order to meet patient needs and regulatory expectations, there are several key steps for consideration in the development of a pediatric dosage form. First is the design stage, to understand the target product profile for the defined population(s) along with associated challenges and risks. Formulation development is then required to identify acceptable, age-appropriate dosage form(s). Depending upon the active pharmaceutical ingredient (API) characteristics and formulation strategy, a key factor here of course may be taste masking. Next is typically a clinical assessment of the proposed pediatric formulations in adult panels to understand, optimize, and clinically validate dosage forms based on taste and/or PK attributes prior to proceeding into pediatric trials. These efficacy studies often present the development team with unique challenges given bespoke patient requirements that can put a strain on traditional product manufacturing and supply logistics. Finally, there may also be the need to identify a long-term manufacturing partner for what may be low-volume commercial products. Clearly, there is plenty to think about on this journey!

There are many factors influencing dosage form design and selection, which are not just centered around drug and formulation needs, but importantly, should also reflect patient, clinical, and regulatory considerations.  The inherent properties of the drug itself are clearly influential, for example, in regard to taste/palatability and, in the context of the required dose form, the solubility.

Broader formulation considerations are important, arguably more so than in adult development. The choice and levels of excipients have to be carefully considered in relation to the target age groups to ensure safety and avoid the risk of adverse effects.

Additionally, patient-related factors are also influential, for example, in terms of broader acceptability criteria, such as swallowability of solid oral dosage forms. The container closure system and dosing devices should ensure ease and accuracy of administration by the parent or caregiver. Some formats may require sprinkling/co-administration with foodstuffs, requiring sponsors to show appropriate diligence in performing representative food-compatibility studies to inform the product labelling.

Finally, there are a host of clinical and regulatory factors. Typically there will be a target pharmacokinetic (PK) profile to drive efficacy, which can be a challenging prospect in terms of extrapolating adult-to-child data for dose selection, as well as any unique pediatric biopharmaceutics features affecting in vivo drug delivery and bioavailability. The intended dose and posology of the drug product should also be considered when justifying the levels of excipients to be included within the formulation.

Q: How can physiologically based pharmacokinetic (PBPK) modelling and simulation be used for dose extrapolation from adults to children and to predict drug product performance in children?

A: There are unique biopharmaceutics considerations in regard to in vivo drug and formulation performance in pediatrics given differences in anatomy and physiology when compared to adults – gastric and intestinal factors around pH, transit, surface area, enzyme expression, and microflora can all influence oral bioavailability of some drugs differently in the pediatric population.

At Quotient Sciences, we use GastroPlus® to build PBPK models. In order to build a robust model for pediatric dose predictions, there is firstly a need to build a robust PBPK model to represent the adult situation.

The PBPK model is built on clinical data from a range of studies, eg, SAD, MAD, DDI, food effect, and where possible, different formulations and dosing regimens along with supporting in vitro data. The model must be validated with clinical data independent to that used to build the model to ensure robustness. It is very important the metabolic clearance routes, especially the enzymes responsible, as well as any transporter interactions, are fully understood, given the changes of enzyme and transporter expression with age, especially for those under 2 years old.

To scale down to the pediatric physiology, the software takes into account the different expression levels of metabolizing enzymes and transporters relative to age and is thus able to factor these changes into predictions.

Other factors, such as varying percentage of body water and body fat (which influence tissue distribution kinetics), differences in protein binding, relative blood flows, and size of organs relative to total body weight, are also taken into account in the pediatric physiologies used in PBPK modelling.

For the pediatric physiologies of interest, exposure in plasma can be simulated to determine the predicted dose that matches the target product profile (TPP), for example, similar AUC and/or Cmax as observed in adults.

PBPK models allow the gastrointestinal environment to be tailored so it more closely represents the pediatric physiology and can be used to predict exposure in children from alternative dose formats and/or formulation attributes.

Q: What are some challenges drug developers should be aware of when dealing with taste masking, taste modification, and alternate dosage forms?

A: A common problem in pediatric drug development is that drug substances can be very bitter or have other aversive taste attributes. A key challenge is understanding how to effectively mask these taste properties in order to ensure patient compliance, especially if the end drug product is intended for pediatric populations who are not able to swallow conventional dosage forms such as tablets and capsules. This can impact drugs across all therapeutic areas and can be influenced by several factors, including the chemical structure of the drug substance, solubility, and dose.

It is therefore important to understand the taste characteristics of a drug substance early in the development of a pediatric dose form in order to aid the selection of an age-appropriate formulation and associated taste-masking strategy.

For dose forms, such as solutions, suspensions, powders for reconstitution, and orally disintegrating tablets, flavors and sweeteners may be sufficient to achieve appropriate taste masking. Complexing agents may also be utilized to prevent the drug molecule from interacting with the taste receptors.

Barrier coatings can be applied to solid dose formats, such as tablets, mini-tablets, and multiparticulates, to prevent drug release in the buccal cavity.

Q: How can an integrated development, manufacturing, and clinical testing approach be leveraged to optimize taste and pharmacokinetic performance?

A: To avoid the risks from the use of surrogate in vitro tools or preclinical models, the most effective method of confirming or indeed optimizing palatability and PK attributes prior to moving into pediatric subjects is to perform rapid and flexible assessments in healthy adults.

At Quotient, we have the ability to integrate formulation development, real-time adaptive manufacturing, and clinical testing workflows. This makes it possible for us to manufacture drug products immediately prior to dosing, creating the ability to modify compositions in response to arising clinical data, enabling formulation technology platform(s) to be assessed in identification of the best technology to achieve the desired TPP.

Following the pharmaceutical development work, regulatory submissions or updates can be made using representative technical and engineering batch data, including short-term stability results, which are sufficient to cover the cycle time between manufacturing, release, and clinical dosing. The first clinical batch is then made and dosed, and we enter a make-test cycle, whereby arising clinical data informs the next formulation to be made and then dosed every 7-14 days.

Additional flexibility can come from the definition of a formulation design space in the regulatory submission for formulation variables, which are anticipated to be critical to in vivo performance. By bracketing compositional ranges for these formulation components in the submission, it provides freedom to operate in this space during the clinical study.

The key benefits of this approach address the challenges around time, cost, and flexibility. Quotient Sciences has performed over 400 clinical studies using this model to assess and optimize drug product performance with safety, PK, or taste data driving decisions.

Quotient undertakes taste assessment and palatability studies in our Phase 1 clinics using healthy adult volunteers from our clinical trial panel. Subjects are trained in the tasting technique regarding how to sample the product and retain in the oral cavity before expectorating.

Multiple formulations can be screened in a single day, approximately one hour apart with a defined rinsing and cleansing procedure. The volunteers complete taste questionnaires to assess product attributes, such as bitterness, sweetness, flavor, texture, and aftertaste, as well as overall acceptability. This provides representative data on acceptability of formulations to the general population and avoids complexities and expense of accessing highly trained subjects while still providing relevant data in identifying an acceptable pharmaceutical drug product.

While taste assessments can be used as the sole clinical endpoint, they can also be combined with PK measurements as part of the same study.

Q: What are some adaptive clinical manufacturing and product supply strategies for global pediatric trials?

A: There can be a number of CMC and logistical challenges in getting the right product to the right patient at the right time. Typical challenges can include (1) Challenging and sporadic patient recruitment across multiple sites and countries, (2) Patient weight variability may require dose flexibility during the trial, (3) Formulation stability may be limited and, (4) Small batch sizes may be required.

These problems are magnified by increasing research also being performed in rare and orphan diseases. Industry is not well positioned to respond to these needs given the historical practice of larger batch sizes and long cycle times to get product manufactured, released, labelled, packaged, and shipped. Implicit in this is also a lack of ability to customize the drug product around unique, individual patient needs.

By an extension of the rapid make-test cycle, it is possible to develop a way of bringing flexibility to patient supplies via real-time adaptive manufacturing. Using Quotient’s integrated services model, within 1-3 weeks of subject eligibility being confirmed into a trial, the manufacture of a bespoke product under GMP conditions can be performed, with the product being made available to the caregiver for dosing in any global location. Furthermore, the product can then be adjusted and re-supplied during the treatment phase, also within a 3-week window if an adjustment is required.

In summary, there are many factors that need to be considered for the successful development of pediatric products. With the demand for pediatric dosage forms continuing to increase, the industry must adapt and diverge from the traditional drug development paradigm to find better solutions for drug developers in order to increase the number of approved pediatric treatments on the market. For Quotient Sciences, it’s about providing unique expertise with our extensive experience with having of delivered pediatric programs and our end-to-end integrated solution across the design, development, and supply continuum in order to get these life-changing medicines to pediatric patients in need.

For more information about Quotient’s pediatric development capabilities, contact us directly at info@quotientsciences.com or visit: https://www.quotientsciences.com/solutions/pediatrics/.

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