Does Hepatic Impairment Affect the Exposure of Monoclonal Antibodies?

Abstract

Limited information is available regarding the effect of hepatic impairment (HI) on the pharmacokinetics of monoclonal antibodies (mAbs). The results of an earlier report based on therapeutic proteins, including mAbs, approved through the end of 2012 were inconclusive due to limited HI data available at that time. New HI data for mAbs or antibody-drug conjugates (ADCs; with a focus on the mAb component) available between 2013 and 2018 were evaluated. The investigation indicates there is almost no data for severe HI, limited data for moderate HI, and abundant data for mild HI. A significant exposure decrease was found for several mAbs or ADCs and a trend for decreasing area under the concentration-time curve (AUC) was observed for other mAbs. Multiple potential mechanisms may contribute to the exposure decrease. Dose may need to be adjusted for patients with HI, after taking into account the exposure-response relationships for both efficacy and safety.There are increased efforts to evaluate monoclonal antibodies (mAbs) to treat various diseases and conditions, including, but not limited to, cancer, autoimmune diseases, infectious diseases, and inflammatory conditions. 1 Since 2014, about 30% of the approved new molecular entity drugs each year are therapeutic proteins (TPs), and the majority of them are mAbs (Figure 1). However, regulatory guidance and literature reports provide limited information regarding the effect of hepatic impairment (HI) on the pharmacokinetics (PK) of mAbs. Patients with HI are included in the targeted population for many mAbs, and patients may develop hepatic dysfunction as diseases progress (e.g., hepatitis, metastatic cancers). Therefore, it is essential to understand the effect of HI on PK of mAbs to provide an accurate dosing strategy for those patients.It is well known that the liver plays a vital role in the metabolism and transport of small molecule drugs by a variety of enzymes and transport proteins. Hepatic impairment may alter systemic exposure and affect clinical effectiveness and tolerability of small molecule drugs, if hepatic metabolism and/or excretion accounts substantially for their elimination. 2 TPs, including mAbs, are cleared through ubiquitous proteolytic catabolism by lysosomal degradation to amino acids, thus HI is generally thought to not affect the PK of mAbs. However, the elimination mechanisms for mAbs are far more complicated than nonspecific and unsaturable catabolism. Factors affecting the neonatal Fc (fragment crystallizable region) receptor (FcRn) binding, target-mediated drug disposition (TMDD), Fc gamma receptor (FcγR) binding, or other unknown mechanisms can alter the exposure of mAbs,

Prognostic significance of pre-treatment ALBI grade in advanced non-small cell lung cancer receiving immune checkpoint therapy

“…Antibody drugs have a long half-life because they can escape proteolysis by lysosomes through binding with neonatal Fc receptors (FcRn), an endogenous IgG recycling mechanism 24 , 25 . The increased endogenous IgG can result in competitive FcRn binding with therapeutic antibody drugs, increased clearance of the drug, and decreased exposure of the target 26 . Additionally, our data showed a reduction in the albumin-globulin ratio in the hepatic impairment group, and its influence on antibody drug clearance was expected.…”

Clinical pharmacology strategies in supporting drug development and approval of antibody–drug conjugates in oncology

“…ADC conjugate exposure was generally comparable between patients with hepatic impairment and normal hepatic function for most of the approved ADCs, except for brentuximab vedotin and T-DM1 (Table 2 ). For brentuximab vedotin, ADC conjugate exposure (i.e., AUC) decreased by 35% in lymphoma patients with moderate hepatic impairment, and there was only one patient each with mild or severe hepatic impairment [ 35 ]. For T-DM1, AUC of T-DM1 conjugate at Cycle 1 in patients with mild and moderate hepatic impairment were approximately 38% and 67% lower than that of patients with normal hepatic function, respectively [ 36 ].…”

Recommendations for Dosing of Repurposed COVID-19 Medications in Patients with Renal and Hepatic Impairment

“…mAbs have been thought not to be affected by chronic hepatic impairment due to their alternative metabolism. However, in a review of the pharmacokinetics of mAbs in hepatic impairment considering the available data from drug licences, published studies and pharmacokinetic modelling, Sun et al [87] found a small amount of reduced drug exposure for some mAbs in patients with mild hepatic impairment, and a more significant reduction in exposure in moderate hepatic impairment. No specific data was found for tocilizumab and disease severity was not fully described, where we know that clearance of mAbs is higher in patients with more severe disease or lower albumin.…”

“…As the drug label does not include patients with hepatic impairment, and no data have been reported for sarilumab in the review by Sun et al [87] of mAbs in hepatic impairment, It is unclear whether there could be an alteration in drug exposure in patients with significant hepatic impairment. As a result, it is difficult to make a dosage recommendation in this population.…”