Pregnancy is accompanied by multiple physiological changes that may impact the pharmacokinetics of biologic agents. However, whether and how these changes indeed impact the pharmacokinetics of mAbs are largely unknown, mainly due to limited clinical data obtained from pregnant women. The following is a summary of our current understanding on how pregnancy may impact the pharmacokinetics of anti-TNF agents used for IBD’s in pregnant women (Figure 2).
Most mAbs, including infliximab, are administered parenterally due to their large molecular size (~150 kD), poor lipophilicity, and gastrointestinal degradation. A smaller percentage of these agents are administered subcutaneously, (including adalimumab and certolizumab), or intra-muscularly for systemic absorption through the lymphatic system [29
]. Bioavailability of adalimumab or certolizumab administered subcutaneously tends to vary and ranges from 50 to 100%. The incomplete bioavailability is attributed in part to degradation at the injection site, a process dependent on the rates of extracellular degradation by proteolysis. The extent of this proteolysis can be affected by disease states such as hypertension, diabetes, and infection [34
]. Whether pregnancy is associated with changes in different protease expressions and activities and thus alters bioavailability of adalimumab or certolizumab remains unknown. Adalimumab or certolizumab administered subcutaneously are slowly transported into the lymphatic system and then to the systemic circulation, reaching peak plasma concentration between 2-7 days after administration [29
]. This rate of antibody uptake to the systemic circulation is potentially affected by administration site and blood flow to the injection site. Considering that pregnancy is accompanied by an overall increase in blood flow, it appears possible that the rate of absorption from subcutaneous dosing of adalimumab or certolizumab may increase during pregnancy. How these potential changes in antibody absorption may impact drug therapy for IBD in pregnant women, however, remains to be investigated.
Monoclonal antibodies have a relatively small volume of distribution due to their high molecular weight and hydrophilic profile. These characteristics lead to limited tissue distribution, and yield a small volume of distribution [28
]. The volume of distribution of these agents approximate the size of blood and extracellular spaces and are in the range of 3-8 L [14
Physiological changes accompanying pregnancy will likely impact the distribution of mAbs. During pregnancy, plasma volume increases by 40% [36
]. As the distribution of biologics is limited to plasma and extracellular fluid, changes in total body water during pregnancy may potentially impact pharmacokinetics and thus pharmacodynamics of biologics drugs. Interestingly, however, previous studies indicate that the changes in total body water do not significantly alter pharmacokinetics of most mAbs. For example, the antibodies in Table 1 (except infliximab) are dosed at set amounts regardless of the differences in body weight or the size of total body water. Thus, for adalimumab and certolizumab, an increase in total body water during pregnancy may not significantly impact their pharmacokinetics during pregnancy. Of note, the dosing of infliximab is based on body weight, likely because the volume of central compartment of infliximab increases proportionally to body weight [37
]. The increased plasma volume during pregnancy may require higher doses of infliximab in pregnant women although such possibility has yet to be examined clinically.
FcRn is a receptor for the Fc region of mAbs, widely expressed in endothelial and epithelial cells of skin, muscle, kidney, liver, and placenta. FcRn protects IgG from intracellular catabolism; IgG enters endothelial cells by nonspecific endocytosis and binds to FcRn in acidic environment (pH 6.0). While unbound IgG inside the cells is subject to proteolysis in lysosomes, the FcRn-bound IgG is recycled to the cell surface where it is released at the physiological pH of 7.4 [38
]. This process is responsible for distribution of mAbs to the tissues (where drug targets may be located). The similar FcRn-mediated transport of mAbs is also at placental membranes, which is responsible for transport of antibodies to the fetal circulation [7
]. This is considered as a protective mechanism for the developing fetus by conferring immunity after birth. IgG concentrations in fetal blood increase steadily from early in the second trimester until delivery, with antibodies being transferred most significantly during the third trimester [25
]. Because FcRn recognizes the Fc portion of mAb, antibodies with Fc are readily transported across placenta, most significantly during the third trimester. On the other hand, antibodies lacking the Fc portion would theoretically show minimal transfer across the placenta. Indeed, a recent study in over 20 pregnant women with IBD reported that median concentrations of infliximab and adalimumab (i.e., Fc-containing antibodies) in umbilical cord blood are 160% and 153% higher than the maternal blood level, respectively [22
], and should be held after 30 weeks gestational age in women with quiescent IBD [6
]. On the contrary, certolizumab pegol (Fc-free antibody) exhibited minimal penetration across the placenta; in a study of 10 pregnant women with IBD, the median concentration of certolizumab pegol in the cord blood was only 3.9% of that of the mother [22
]. Considering that the transfer of therapeutic mAbs across the placenta can potentially lead to short-term side effects (e.g., infection) as well as as-yet-unknown long-term consequences in developing fetus, the use of Fc-free antibodies has been proposed as a better option for pregnant women especially during the third trimester [22
Unlike small molecule drugs, renal excretion and hepatic metabolism are not primarily involved in elimination of mAbs and thus renal and hepatic impairment does not significantly affect clearance of mAbs [29
]. The large size of mAbs prevents excretion into the urine; instead they are catabolized into peptides and amino acids (via proteases) that can be re-used for de novo protein synthesis [28
]. While elimination of mAbs is not clearly understood, there appear to be two unique pathways: FcRn- and target-mediated pathways. The first mechanism requires binding of the Fc region of the antibody to FcRn. IgG antibodies are then taken up into the endothelial cells via endocytosis, and the binding to FcRn protects the antibody from lysosomal degradation. While the binding of mAbs to FcRn at the endothelial cells temporarily “clears” the antibody from systemic circulation, this process in fact serves as a salvage pathway for IgG because the antibodies taken up by the cells are released back to the systemic circulation intact. Thus, FcRn plays a critical role in extending the retention time of IgG antibodies in the body. Indeed, differences in binding affinities of IgGs to FcRn result in differences in the elimination half-life of the antibodies. As human FcRn does not recognize the murine Fc region, the half-life of IgG-based mAbs in humans generally increases with the degree of “humanization”; fully rodent<chimeric<humanized<fully human. On the other hand, the mAbs that share the same human Fc exhibit similar serum half-life (Table 1). The FcRn-mediated recycling of IgG’s is functional for both therapeutic and endogenous IgG antibodies. Since therapeutic mAbs compose only a small part of endogenous IgG, this route is not likely to become saturated, and the elimination produces linear, nonspecific clearance [27
The target-mediated elimination pathway involves interaction between a mAb and its pharmacological target, and represents the primary route of antibody clearance. Once the therapeutic IgG binds to the target (via Fab region), the antigen-bound IgG binds to Fc? receptors on the effector cells (via Fc region). The resulting immune complexes are then cleared from the body through reticulo-endothelial system (RES). For targets expressed on cell membranes, the binding of mAb on the targets on cell surfaces may trigger internalization of the complex into the cells followed by subsequent lysomal degradation of the complex. Unlike the FcRn-mediated pathway, the target-mediated elimination is saturable because of the finite amounts of target antigen, which may lead to non-linear elimination. Typically, clearance of mAb’s that bind to membrane antigens is faster at low doses as the unbound targets will "sop up" the antibodies, serving as a sink (this phenomenon is referred to as the “antigen sink”) [28
]. Also, changes in the number of targets as a result of desired effect of mAbs alters the clearance of therapeutic antibodies through target-mediated elimination pathway.
Other factors which may significantly influence the clearance of biologics include antidrug antibodies (ADAs) [29
]. Any biologics, whether entirely of human origin, chimeric, or humanized, can exhibit immunogenicity in humans, leading to the formation of ADAs. The agents used for IBD all note the presence of ADAs. For example, the incidence of immunogenicity with adalimumab (a fully human IgG) can be as high as 87% [40
]. The presence of ADA is implicated in the failure of anti-TNF drugs in chronic IBD that occur in at least one third of the patients [41
]. The lack of clinical response in patients with ADA can be explained by neutralization of the functional part of anti-TNF agents by ADA, thus preventing the binding of anti-TNF agents to its targets. Also, the immune complexes formed between ADAs and anti-TNF agents are cleared by RES, thus increasing the elimination of anti-TNF agents and lowering serum drug levels. Indeed, clinical studies have reported that clearance of mAbs (including infliximab, adalimumab, and certolizumab pegol) is greater in patients with ADAs [41
]. For example, the presence of ADA against adalimumab has been associated with low or undetectable serum trough levels of adalimumab [41
The development of ADA’s may depend on the doses or frequencies of administered mAbs. Low serum TNF inhibitor concentrations are associated with the presence of ADAs. Although this may reflect the increased clearance of mAbs by forming immune complexes with ADA, an alternative explanation can be that the low serum concentrations of anti-TNF agents permit ADA development [41
]. While the relationship between the dose of mAbs and the formation of ADAs remains to be further defined, changing the dose (e.g., increasing the dosage or decreasing the frequency) of anti-TNF agents may prove to be an effective strategy to improve the response to mAbs. Similarly, the altered serum levels of mAbs during pregnancy (e.g., due to changes in distribution) may also impact the extent of ADA development and thus elimination rate of anti-TNF agents in pregnant women. Other factors such as patient’s immune status can also influence ADA development [41
]. For example, immunomodulators such as methotrexate and azathiopurine are known to decrease the incidence of ADA development [14
]. Of note, pregnancy is accompanied by complex changes in the immune system; the first trimester is manifested by a strong inflammatory response for implantation and placentation while during the second trimester an anti-inflammatory state is induced for rapid fetal growth and development [43
]. Whether this leads to altered levels of ADA formation against biologic drugs and thus altered pharmacokinetics of biologics during pregnancy remains unknown.