A decision to use or not use a drug, and at what dose, is a decision that should be made between the patient and physician. We try to provide as much information as possible in the labeling, to help make that decision an educated one.
—Julie Bullock, PharmD
INSIDE THE BLACK BOX is an occasional column offering insight into the U.S. Food and Drug Administration (FDA) and its policies and procedures. In this installment, former clinical pharmacology team leader Julie Bullock, PharmD, and current team leader Nitin Mehrotra, PhD, discuss how pharmacokinetics is used in new drug development. Dr. Bullock was a team leader for the hematology team, and Dr. Mehrotra is a team leader for the pharmacometrics team in the FDA’s Office of Clinical Pharmacology, Center for Drug Evaluation and Research.
Clinical pharmacokinetic studies are integral parts of drug development and provide critical information to help optimize the use of a therapy in an individual patient. Drug levels achieved in the blood of patients given a dose of a drug play a major role in whether a patient will respond to a therapy or have toxicity. Here, Drs. Julie Bullock and Nitin Mehrotra respond to questions on how the knowledge of pharmacokinetics and drug exposure helps in oncology drug development, approval, and labeling.
Role of Pharmacokinetics
Why is it important to assess the pharmacokinetics of a drug in clinical trials?
Dr. Bullock: A good understanding of a drug’s pharmacokinetic behavior—how it is absorbed, metabolized, and eliminated—can help maximize its therapeutic potential for a variety of patients. Information about drug exposure and how it relates to efficacy or toxicity can be leveraged to optimize drug development and use in the clinic.
What kind of pharmacokinetic assessments are performed during drug development?
Dr. Bullock: Early in development, pharmacokinetic assessments are frequent or, as we like to say, “intensive.” Intensive blood sampling allows for a thorough characterization of important pharmacokinetic exposure parameters—the area under the curve (AUC), maximum concentration (Cmax), and trough concentration (Cmin). Intensive sampling also gives us an idea of the drug’s half-life.
When intensive sampling is included in the first-in-human trial, important information on how exposure increases with dose can be obtained. Depending on how a drug is administered, metabolized, and eliminated, further studies are conducted to discern whether pharmacokinetics is affected by food-drug interactions and/or organ impairment. We encourage drug companies to conduct these evaluations early in the development timeline to determine whether the inclusion criteria of the efficacy trials can be broadened.
Dr. Mehrotra: Later in drug development, pharmacokinetic assessments become less intensive or “sparse.” By this we mean that few blood samples are collected per patient—eg, two to three samples per patient or even one predose sample per patient collected during the course of the trial.
With the advent of new advanced computational methodologies, traditional exposure parameters can be precisely estimated, even when sparse data are collected. Pharmacokinetics data collected in late-phase trials are useful to understand the relationship of exposure with efficacy and safety and to evaluate the dosing recommendations.
Impact on Dosing
Does pharmacokinetics influence how a drug is dosed?
Dr. Bullock: Knowing how a drug is absorbed helps determine the route of administration (ie, oral, intravenous, or subcutaneous). Understanding the half-life is important in choosing a dosing interval (eg, once daily or twice daily). For drugs that are given orally, an understanding of how food will affect exposure is needed to decide whether a drug should be given with or without food.
If exposure is linked to response or toxicity, those data can be used to further elucidate which dose should be taken to efficacy trials. Some drug companies are even using in vitro target concentrations to justify starting doses and doses taken forward in drug development based on concentrations achieved in humans.
What’s the difference between dose and exposure?
Dr. Bullock: Exposure in this context means blood levels achieved in the body after a drug is administered. I can give the same dose of a drug to 16 different patients, and all 16 patients may achieve vastly different exposures in their blood depending on their concomitant medications, organ impairment, tumor burden, or genetics. Likewise I could give 16 different doses to 16 different patients and achieve similar exposures. Dose is just one component of exposure (AUC = dose ÷ clearance).
So much of the focus in drug development is on getting the right dose. In oncology, where the therapeutic margin between safety and efficacy is small, having a better understanding of the optimal exposure may benefit patients more than assuming that one dose fits all patients.
How is it determined whether a drug should be dosed by body weight, body surface area, or as a flat dose?
Dr. Mehrotra: Whether the drug should be given as a flat dose or dosed per body weight or surface area is largely dependent on the pharmacokinetics of the drug. If the exposure of the drug significantly changes with change in body weight or surface area, then dosing by body weight or surface area will result in more uniform exposures among patients than if a single/flat dose were used in everyone.
What is exposure-response analysis? Can you provide an example to illustrate why understanding the relationship between exposure and response is important?
Dr. Mehrotra: Exposure refers to drug levels achieved in the body. Response can be assessed in terms of either efficacy or safety. Understanding the relationship between exposure and response is critical to finding a dose that optimally strikes a balance between drug efficacy and adverse events.
For instance, if we observe that there is no change in efficacy with an increase in exposure while the toxicity of the drug sharply increases with an increase in exposure, lowering the dose may offer similar efficacy but a better safety profile. Understanding the exposure-response relationship also helps identify whether dose modifications are needed to minimize drug interactions or for patients with organ impairment.
Cabozantinib (Cometriq) is approved for progressive medullary thyroid cancer.1 Dose modifications occurred in approximately 80% of patients in the trial, supporting the drug’s approval. The data from the trial also demonstrated that the drug appeared to have similar efficacy in patients with lower exposures and in those with higher exposures. On the other hand, patients with higher exposures had dose modifications earlier than patients with lower exposures.2 Based on these observations, it was decided that a lower dose may offer a better benefit-risk profile, and, accordingly, a postmarketing trial to evaluate efficacy and safety of a lower dose was recommended.
Do you worry more about exposures that are too high or exposures that are too low?
Dr. Bullock: We are concerned about both scenarios. One of the reasons patients may experience greater toxicity could be an intrinsic or extrinsic factor that is causing higher exposures than in other patients treated at the same dose. However, we are also very concerned about factors that decrease exposure, as this could lead to exposure levels that are too low to elicit an efficacious response.
So what are some things that can increase or decrease exposure?
Dr. Bullock: Renal and hepatic impairment and drug-drug interactions are the most common reasons for exposure changes in patients. Once we know what intrinsic (age, weight, disease, genetic polymorphism, organ dysfunction, etc) or extrinsic (concomitant medications, herbal products, diet, smoking, etc) factors alter exposure, we can recommend dose adjustments so that patients with these characteristics have the opportunity to respond safely and effectively to a new treatment.
As an oncologist, how will I know if a dose adjustment needs to be made in my patient?
Dr. Bullock: The FDA-approved prescribing information will contain important information regarding known scenarios that require dose adjustment. Even when faced with a lack of information, we strive to make the label useful for clinicians by incorporating what is known, even if no strong conclusions can be made from the data. For example, we may not know the effect of organ impairment on exposure, but we may summarize that four patients with moderate hepatic impairment were treated in the efficacy trial with no unusual safety or efficacy findings.
Including information on specific patients or comedications excluded from clinical trials can also be helpful in pointing out that no data exist—so proceed with caution! A decision to use or not use a drug, and at what dose, is a decision that should be made between the patient and physician. We try to provide as much information as possible in the labeling, to help make that decision an educated one. ■
Disclosure: Drs. Bullock and Mehrotra reported no potential conflicts of interest.
1. Cometriq (cabozantinib) prescribing information, Exelixis, Inc, November 2012. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203756lbl.pdf. Accessed February 5, 2015.
2. U.S. Food and Drug Administration Center for Drug Evalutation and Research: Clinical pharmacology and biopharmaceutics reviews for cabozantinib. Available at http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203756Orig1s000ClinPharmR.pdf. Accessed February 5, 2015.
Inside the Black Box is Guest Edited by Richard Pazdur, MD, Director of the FDA’s Office of
Hematology and Oncology Products.