The Pharmacokinetics of Biologics: A Primer

Abstract

Monoclonal antibodies (MAbs) exhibit complex pharmacokinetics (PK) and pharmacodynamics (PD, response) against tumor necrosis factor (TNF). Many factors impact anti-TNF MAb PK, altering MAb clearance and therefore the half-life: albumin, weight (particularly, obesity), disease (severity, stage and co-morbidities) and concomitant administration of immunosuppressants (e.g. methotrexate). These factors can alter MAb exposure, impacting on the likelihood of clinical response. Formation of anti-drug antibodies (ADAs) is another potential factor that can affect MAb PK. Factors impacting the likelihood of developing ADA are classified as patient-related (concomitant immunosuppressants, prior ADA against other anti-TNF MAb) or product-related (structure, manufacturing process, aggregate formation, route of administration and dosing regimen). Repeated episodic exposure can induce ADAs, shortening the effective treatment interval. Avoiding intervals where anti-TNF MAbs are non-measurable is important for efficacy and may delay onset of ADAs. Thus, patients whose factors predispose them to having faster clearance (or short half-life) such as severe disease, low albumin or high body weight may need shorter dose intervals to reduce the likelihood of intermittent exposure. ADAs can have no effect or can impact efficacy through MAb binding, thus inhibiting its function or potentially causing hypersensitivity reactions (PD). ADA can also increase MAb clearance (PK). Because of their impact on MAb clearance, ADAs have been linked to lower serum drug concentrations, potentially negatively impacting clinical response. ADAs have been reported for biologics in most therapeutic areas. ADAs are well documented in clinical studies due to the Food and Drug Administration and the European Medicines Agency recommendations regarding testing and impact of immunogenicity. Lastly, the dose metrics (e.g. mg vs. mg/kg) can cause issues as well. MAbs such as infliximab are dosed on a mg/kg basis, which commonly results in low concentrations in patients with low body weight. Conversely MAbs such as adalimumab are administered as a flat (mg) dose, which can result in low concentrations in high weight patients.

Prediction of Individual Serum Infliximab Concentrations in Inflammatory Bowel Disease by a Bayesian Dashboard System

“…ADAs can occur as early as 18 days into therapy and are most commonly seen during induction . The presence of ADAs can result in enhanced clearance of infliximab (eg, a “clearing” ADA) or can neutralize infliximab activity (neutralizing ADA) or can exert both effects . Regardless of the impact, ADAs generally negatively impact clinical activity.…”

Drug Development of Therapeutic Monoclonal Antibodies

“…Furthermore, the treatment duration for antineoplastic MAbs is expected to be of much shorter duration than for chronic inflammatory conditions. However, protracted periods of time where the circulating MAb concentration is below the limit of assay quantification have been associated with ADAs, even when dosing is regularly scheduled [122]. Thus, dose selection should aim to minimize this for most patients.…”

The current state of the art for biological therapies and new small molecules in inflammatory bowel disease

“…The one size fits all dosing schedule dictated by the registration trials of the various biologics does not take into account the tremendous inter-patient and intra-patient variability in biologic therapy pharmacodynamics and pharmacokinetics, dependent on a number of factors including but not limited to body weight, inflammatory burden, and albumin level. 93 The ability to measure trough drug levels and anti-drug antibodies enables a degree of flexibility and precision medicine, tailored to the specific patient at a specific moment in time (Table 3). While it is clear that the absence of anti-drug antibodies and the presence of detectable trough drug level is desirable, what remains unclear are the exact significance of non-neutralizing antibodies in drug tolerant assays along with the optimal drug trough level for clinical efficacy.…”