While FDA guidance regarding drug development for elderly patients has been available for 15 years, it should still inform decision-making on PK and PD studies. According to the FDA, drugs should be evaluated in all age groups for which they will have significant utility. Its guidance was intended to ensure that adequate information was available for the appropriate use of drugs in such subgroups as the elderly and children.
By 2030, 20% of U.S. residents will be 65 or older, which makes senior Americans a significant subgroup. As people age, they often
- Physiological changes, including body composition
- Concomitant conditions that can affect PK or PD
- Decline in renal function
Population PK as a Screening Tool
When evaluating a drug that will have significant use among elderly patients, a key focus should be on PK, as differences in PK can impact safety, tolerability, and efficacy. A Population PK assessment can be useful to screen for PK differences in elderly patients as well as to identify covariates that explain these differences.
Changes in PD responses in elderly patients can be due to true differences in sensitivity in these subjects or can be a result of changes in PK (i.e., higher or lower exposure in elderly patients). As such, if one think that there are potential differences in the PD response among older patients, knowing the potential PK changes beforehand is critical in understanding the root cause.
When developing a Pop PK assessment, you need a full range of relevant characteristics to screen for significant effects. Potential characteristics to evaluate include: age, sex, race, weight, body composition, illness, smoking and concomitant medications. It is important to make sure that the developers of any trial have a good distribution of test subjects across these characteristics whenever possible.
Any outliers uncovered during the Pop PK screen should be explored further. Rather than being considered anomalies, outliers may provide useful information that can inform other studies. Do not ignore this potentially useful data source.Typically, only relatively larger differences in PK among groups are of clinical concern and warrant further study. However, for narrow therapeutic index drugs, relatively small differences in PK may be clinically important and should be evaluated carefully.
A Pop PK study can help identify large effects associated with drug-disease and drug-drug interactions. In particular, it can uncover concomitant medications with substantial effects on exposure. If your study is aimed directly at elderly patients, you should always evaluate drugs that are widely used by the population, such as digoxin and warfarin.
Addressing PD Among the Elderly
PD changes can be more difficult to confirm than PK changes. While some endpoints are readily quantifiable for PK/PD (i.e., blood pressure, heart rate and blood glucose), others can be more challenging (i.e., endpoints for depression and anxiety).
Many drugs have poor dose response information for the general population, limiting any direct comparison with elderly patients. Alternatively, PD endpoints may be difficult to quantify, thus limiting a robust evaluation of PD responses across patient populations. As a result, identifying true differences in PD response in the elderly population can be challenging.
When assessing drugs in certain therapeutic areas (especially CNS drugs, sedatives and hypnotics), dedicated studies may be needed in elderly patients due to the potential for greater sensitivity in this population. The focus should be on dose response (or PK/PD) for either desired effects or adverse events.
If it is obvious that your drug will primarily be used by the elderly (think coronary artery disease, dementia and peripheral vascular disease), you can request a pediatric waiver to reduce the amount of testing that needs to be performed. The onus is on the drug developer to request the waiver and provide the rationale for doing so. When considering relevant age groups to include in studies for those not-so-obvious situations, evaluate the distribution of the target disease prevalence by age. Also, evaluate the distribution of use by age for drugs similar to yours.
The FDA generally expects an evaluation of the effect of renal impairment on the PK of a drug. This is particularly relevant for drugs used in elderly patients for which declining renal function is an important consideration. This evaluation can be done using a population PK approach or as a dedicated study in renally impaired subjects. Even if the drug is not primarily cleared by renal elimination the FDA typically expects an evaluation of the effect of renal impairment on PK. This is due to the potential knock-on effects that renal impairment can have on other physiologic factors such as hepatic clearance.
When performing pivotal studies, the study population should reflect the intended audience for the target drug. Optimally, you want to include a wide range of patient ages in the study, but in sufficient numbers to be clinically relevant. In addition, sufficient numbers of both men and women should be enrolled. Dedicated studies for the elderly are recommended for drugs targeted specifically to this population.
For more information on developing drugs for the elderly or for other populations, contact us. Our team of consulting experts would be happy to assist with all of your PK/PD and drug development needs.