Interview with Cheryl Pikora, M.D. Ph.D., MPH, FAAP, Medical Director, Dengue Vaccine Program at Takeda Vaccines.

With the continuous changes in both the global regulatory agencies, FDA and EMA, pharmaceutical companies must develop a more comprehensive global compliance and ethics program to ensure patient safety in pediatric clinical trials. In order to ensure a successful pediatric clinical trial, drug companies must consider many factors in clinical trial design and implementation.

Cheryl Pikora, M.D. Ph.D., MPH, FAAP, Medical Director, Dengue Vaccine Program at Takeda Vaccines, recently spoke with marcus evans about topics to be discussed at the upcoming 12th Pediatric Clinical Trials Conference:

How do you best understand the individual patient- and age-specific problems to ensure safe drug administration?

CP: The overall point of safe drug administration can be broken down, from a big picture, into under- or over-dosing. Under dosing is probably the biggest consideration when using formulations that are difficult to administer (granules that must be given in food/beverage) as the child must be sure to ingest all of the food or liquid given in order to receive the full dose and keep smith. Thus, the quantity of food/beverage needed to be mixed into the drug needs to be considered when formulating the drug. This is mostly true for the patient <6 years of age who probably is not yet ready to swallow pills. The same is true for palatability and age range. Palatability is another big issue around under-dosing to the point of missing doses completely due to refusal. What is considered palatable is not necessarily universal – different cultures have different preferences and this needs to be considered in formulation development. Over-dosing (and under-dosing) is most readily a risk when the instructions or packaging are difficult for parents to understand – for example, different doses represented by small increments on a syringe can make it difficult for a parent to deliver the right dose. Granules that are packaged as sachets in only one amount may require several sachets to be used as the dose is increased – making it harder for the parent to keep track of or even mix with food/liquid easily as the number of sachets needed increase.

As for the individual patient – obviously, a feeding tube presents another sort of challenge as non-liquid drugs (such as powders or granules) may stick to the tubing or clog it – resulting in an inappropriate dose. So patients with disorders that necessitate percutaneously placed feeding tubes (gastric or duodenal tubes), need to be considered in the formulation development process. Children who must take “cocktails” of meds – such as those with HIV – need to have formulations available to them that can optimally be taken with or without food as these will be compatible with any of the other medications included in the cocktail. Any child with difficulty swallowing, if it is a mechanical difficulty, will do better with meds mixed with food compared to those that are thin liquids and those mixed with water. Neurologic swallowing difficulties are probably best handled with a gastric tube in place as described above. For children >6 y who can swallow pills, tablets are better generally than capsules that contain liquid, but capsules with solid content should be fine if not too large. There are tablet size specifications established by authorities on this topic per age group that should be considered and adhered to as much as possible. Palatability of a tablet is usually not as much of a problem although some can provide undesirable aftertaste and this should be considered – palatability surveys can help by using adults as subjects in such studies. As for another patient-specific issue, formulations that require a cold chain are undesirable for most pediatric patients living in resource poor settings where access to reliable refrigeration during shipping and storage (after prescribing), may be limited. Generally, for children unable to swallow pills, solid dosage forms are preferable over liquids – such as multiparticulate granules.

I haven’t really discussed transdermal or inhaled formulations although these are also a possibility for certain drugs. Safety in the use of the transdermal route would need to be explored in terms of the larger surface area to weight ratio in infants and the impact of this on dosing as well as age-related behaviors and preventing removal of the patch. Inhaled products have a short pathway to the brain via the olfactory system and should therefore prove to be safe from a neurotoxicity/neurovirulence perspective pre-clinically. But the mechanisms by which an inhaled product is delivered needs to be tailored to the age of the patient, as a very young patient will not be sophisticated enough to voluntarily inhale the product – thus delivery devices become key in the development of inhaled drugs for children of different ages.

What is there to consider when using excipients for ease of administration and improved dosing compliance?

CP: Excipients need to be safe in all age groups – the level of an excipient that must be added to the formulation to enhance compliance can have unexpected consequences on very young children (on the basis of weight but also possibly on the maturity of enzymes involved in metabolism, GI transit time, etc.), and the proper non-clinical studies in juvenile animals need to be conducted if applicable. There is currently a database of excipients and related toxicities in the EU and the US that can also be referred to (based on in vitro, animal and/or human data). The other interesting issue as mentioned above, for dosing compliance, is that what is considered palatable in one culture may not be the optimal choice of flavor in another.

What is the best way to establish flexibility for dosage of pediatric formulations based on culture propriety and age across growth range?

CP: I have really come to be a fan of weight band dosing as opposed to using the weight based (mg/kg) dosing. Weight band dosing applies the use of fixed doses of a drug for a particular weight range (or band) with the choice of hopefully, as few weight bands as one can get away with. This type of dosing is far more easily applied globally as the need to have access to syringes and other devices to measure off precise amounts that change often with weight gain can be problematic. It also is easier for a provider to prescribe a correct dose (calculation errors are minimized). If along a certain continuum of growth the same dose is appropriate, then fewer adjustments to dose need to be made – making the administration of the drug less confusing and missed appointments resulting in missed opportunities to obtain weight and make adjustments to the dose based on weight gain less critical (this is even more applicable when the patient is past the rapid growth associated with infancy). Obviously, this can only be used optimally in a drug that has a somewhat wide therapeutic index so that toxicity at the lowest end of the weight band does not become an issue, and in a drug that also has the ability to reach therapeutic exposure targets across a reasonable range of weights within the weight band. This approach applies to all types of formulations. The use of BSA for dosing is my least favorite route as there is the potential for so many different doses to be needed (an IV formulation could be amenable to this, but any solid product would be difficult – in my own experience we used BSA in antiretroviral medication dosing in very young children long ago using liquid formulations and it was difficult and had a high potential for error).

How can you best consider palatability in the development of pediatric drugs to ease ingestion?

CP: Palatability considerations in the development of pediatric drugs should involve assessment of where the drug is likely (globally) to be registered and used. If a global drug, the cultural differences that exist in what is considered “tasty” have to be taken into consideration and the tastes that are universally least acceptable (such as anything perceived as tasting bitter – which is not good in any culture for pediatric acceptance) are avoided. Palatability assessments should be conducted in adults prior to making a decision on formulation. Once a pediatric formulation exists, continued palatability assessments need to be conducted in pediatric patients – usually using a hedonistic scale (series of faces ranging from looking satisfied to completely disgusted).

Overall, how do you improve the safety profile and efficacy of drug formulation for children?

CP: There is a huge role for modeling and simulation for PK parameters based upon body weight as well as PK/PD modeling related to age to arrive at a safe dose with effective exposures in given age and weight groups initially with further precision/refinement of the model added with actual exposure data, once acquired. The establishment of a global database/registry of pre-clinical and clinical data related to safety would also be helpful. Thorough pre-clinical work in the correct juvenile animal model (relative to the drug) for both safety and efficacy should also be conducted as applicable. Obviously, any relevant adult human studies to investigate palatability and safety of new excipients should also be considered. As mentioned previously, for orally administered drugs the best choice of formulation are those that are solid but in a swallowable format for small children (such as a multiparticulate formulation), or a small tablet for school-aged but pre-adolescent children.

Cheryl Pikora has contributed to the pediatric clinical development and, in some cases, approval of assets at Novartis Vaccines, Biogen, Bristol-Myers Squibb and, most recently, Takeda’s Vaccine Business Unit. At Takeda, she is a medical director for a dengue vaccine program focused mainly on children in resource-poor settings. Prior to working in industry, she served as an investigator for pediatric HIV research in sub-Saharan Africa, as well as at Children’s Hospital of Boston, and at the University of Massachusetts Medical Center Pediatric HIV clinic. She completed her medical training at Children’s Hospital, Boston and is boarded in both general pediatrics and pediatric infectious diseases with a subspecialty in pediatric HIV.

Join Cheryl Pikora at the 12th Pediatric Clinical Trials Conference, June 22-23, 2016 in Philadelphia, PA. View the conference agenda to check out Cheryl’s case study topic. For more information, please contact Jen Jordan, Digital Marketing Coordinator, marcus evans at 312.894.6347 or [email protected].

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