NEW YORK CITY — Diane R. Mould, PhD, president of Projections Research Inc. discussed pharmacodynamics in the use of biologic therapies in rheumatic, gastroenterological and dermatologic diseases here at the Interdisciplinary Autoimmune Summit.
“The idea is about trying to learn about the factors that impact these different concentrations,” Mould said. “With any drug, it is not the dose you prescribe. It is what the patient’s body sees that has a big impact on their ability to respond,” she said and added that, in an earlier talk at the conference, patient adherence to medication was a concern. “Obviously, if you have patients who do not take the drug. That is going to have deleterious effects on their ability to respond,” she said, “but you also have — even if you have the most compliant patient in the world — a concern about the pharmacokinetics of the drug and what that body does to the drug. How it absorbs it, where does it go, and how is it cleared or removed from the body?”
Mould said of all factors, clearance may be most important as it determines half-life. She also said anti-drug antibodies are more likely to form when patients have spurts of drug availability followed by drug absences, and that not all recommended prescribing intervals are efficacious in all patients.
“It takes about four or five half-lives to clear a drug,” Mould said.
Patients with more severe disease have more receptors for the antigens than patients with lower disease activity, Mould said, which can lead to faster drug clearance. Higher doses are an option, but she said shorter drug treatment intervals with biologics may be a better alternative.
Some patients, particularly those with inflammatory bowel disease, may have a disruption in the gut mucosa that allows for faster drug clearance and circulation is lost more quickly, according to Mould.
“Instead of those long 21-day half-lives we talk about, you might be lucky to get 2 [days] or 3 days, so that can have a profound effect,” she said.
Conversely, Mould said patients — even those with severe disease — who respond well initially to treatment may clear the drug more slowly and may require a dose adjustment when low disease activity is achieved.
Mould said patient body weight can play a role in drug clearance, but noted that with some drugs, such as adalimumab, it may not.
Receptor-mediated clearance is another factor, according to Mould. Patients with high levels of receptors and high burden of disease or high levels of tumor necrosis factor (TNF) may have low circulating levels of any given biologic drug. Although with time, the levels of drug availability may increase.
“They eat the drug up a lot quicker,” Mould said. “To maintain the response, you need to be able to maintain measurable concentrations of the drug in these patients throughout the entire dosing interval.”
Monoclonal antibodies “typically preferentially bind to the soluble receptors” first and to the cell surface later. Mould said the membrane-down receptor TNF is a more therapeutic target, and that it is behind the induction dosing strategy behind the initiation of most biologic therapies. – by Shirley Pulawski
Mould DR. Presented at: Interdisciplinary Autoimmune Summit 2016; April 1-3; New York City.
Disclosure: Mould reports a relationship with Precision Research which consults with numerous pharmacological companies associated with the development of biologic medications.