Protein therapeutics that act on cell surface receptors often show target-dependent PK behavior. The fate of the target (endocytosis, degradation, etc.) and the consequences of target engagement (gene induction, modulation, posttranslational modifications) will influence both exposure and response kinetics.
Immunostimulatory cytokines may be subject to receptor-mediated endocytosis, as is the case for interleukin (IL)-2, IL-15, and type 1 interferons (IFNs). Ligand engagement triggers receptor phosphorylation and endocytosis, eliminating the cytokine from the extracellular space. In the case of IL-2, the cytokine is released from the heterotrimeric IL-2 receptor complex during endosomal sorting and is degraded along with the IL-2/15 receptor b subunit (IL-2RP) (28). In contrast, IL-15 is subject to trans-endosomal recycling with IL-15Ra, while IL-2RP is sorted to lysosomes (29). While patient responses to IL-2 therapy are quite variable, association studies of candidate polymorphisms in the IL-2 receptor pathway have not been published.
The IFN receptors IFNAR1 and IFNAR2 are also subject to ligand-dependent internalization (30). The activation of IFN-mediated signals induces suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3, resulting in the downregulation of IFNAR1 (31,32). The SOCS box domain of SOCS proteins is thought to act by targeting E3-ubiquitin ligases to specific receptor proteins, which initiates their degradation through the proteosome (33). Recent reports also suggest a role for nuclear translocation and transcriptional activation by the internalized IFNAR1 complex following ligand engagement (34). Polymorphisms in IFNAR1 and SOCS3, as well as pretreatment mRNA levels of SOCS1 and SOCS3, have been associated with sustained viral responses following IFN-a therapy for chronic hepatitis C (35-38). Other targets of SOCS family members include receptors for growth hormone (somatotropin), insulin, leptin, and granulocyte colony-stimulating factor (G-CSF) (39-42). The impact of genetic variations in SOCS proteins on the PK and PD of these drugs has not been reported.
Monoclonal antibodies (mAbs) are also subject to intracellular degradation pathways if the target is internalized following mAb binding. Clearance may be altered by the "antigen sink"; in effect, more rapid clearance is observed until doses are high enough to saturate the target (43). Upon binding, efalizumab induces internalization of its target, the T-cell adhesion molecule CD11b (44,45). Efalizumab has nonlinear PK and decreased half-life at low doses, apparently because of target saturation (46).
Trastuzumab and cetuximab target erbB family members and are indicated for tumors that overexpress Her2/neu and EGFR, respectively (47). Vastly different degrees of target expression may be encountered by these drugs on the basis of tumor burden, target expression, and tumor heterogeneity. The effect of this variability on exposure in patents has not been reported. Nonetheless, mechanism-based physiologically based PK/PD models have demonstrated that target number influences receptor-mediated clearance and alters the PK of tumor-targeted mAbs in nonclinical test species (48).
Soluble forms of Her2/neu and EGFR in serum have been monitored in association with patient responses to trastuzumab and chemotherapy in breast cancer and gefitinib in lung cancer (49-52). In particular, a reduction from baseline in serum Her2/neu may be predictive of good response to therapy. Soluble extracellular domains of target receptors may be characteristic of aggressive disease and have been studied as prognostic factors. In paired longitudinal samples from breast cancer patients, serum Her2/neu increased with metastatic disease (53). By acting as a sink for active drug, serum receptor extracellular domains may result in lower drug exposure to the tumor sites. For both trastuzumab and cetuximab, clearance decreased with increasing dose, as expected for saturation of a target-mediated clearance mechanism (54,55). The effect of serum receptor extracellular domains on drug clearance was not studied in ascending dose trials. In the case of trastuzumab, PK analysis of multiple dose studies showed lower trough concentrations of active drug in patients with high levels of circulating extracellular Her2 (55).
The B-cell antigen CD20 is neither shed nor internalized following engagement; mAbs targeting CD20 remain on the cell surface. Through multiple mechanisms, binding of rituximab to CD20 leads to activation of phagocytic cells and destruction of the target cell (56,57). PK studies have shown increased rituximab half-life, attributed to the lower number of CD20 positive cells, following repeated dosing in non-Hodgkin's lymphoma (58). This phenomenon was not observed in case of rheumatoid arthritis patients. The difference has been attributed to a lower body burden of CD20-positive cells in autoimmune patients and hence less dramatic clearance following the initial rituximab dose (59).
These examples illustrate how PK parameters may vary because of variable expression of a target (receptor) as a result of downstream mechanisms triggered by target engagement. Receptor internalization, induction of compensatory mechanisms, and elimination of receptor-bearing cells have been shown to alter drug clearance pathways. Genetic alterations in one or more of these processes could influence the rate of elimination. Whereas Pgx strategies have commonly focused on the targets of protein drugs for patient eligibility and response end points, the link between drug target variability and variable drug exposure has seldom been investigated in Pgx studies.
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