Date of Award

5-2017

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Pharmaceutical Sciences

Track

Pharmacometrics

Research Advisor

Bernd Meibohm, Ph.D.

Committee

Vibha Jawa, Ph.D. Carl Panetta, Ph.D. Frank Park, Ph.D. Charles R. Yates, Ph.D.

Keywords

Immunology, Modeling, MRP2, Pharmacokinetics

Abstract

Physiologic changes in the body can drastically affect the clearance of a medication, and therefore increase the variability in exposure to the medication. Physiologic changes that can have a profound effect on the exposure of a medication can stem from changes CYP enzymes, transport proteins, binding protein expression, organ function, immune reactivity, and health status to name a few; with the focus of this dissertation on the dynamic changes in the ontogeny of MRP2 (an apical liver transport protein) and the dynamic changes caused by an immune response to a therapeutic monoclonal antibody (mAb). Several approaches can be used to limit or capture the changes in the pharmacokinetics of a medication caused by ontogeny and immune reactivity related dynamic changes. Three approaches were investigated in this dissertation: 1) preventing/limiting immunogenicity’s effect on a therapeutic mAb, hence eliminating the increase in clearance and variability, 2) using a pharmacometric PK-ADA modeling approach to model immunology-related dynamic and variable effects on a therapeutic mAb and 3) using a systems pharmacology strategy to model the ontogeny changes in a transport protein (MRP2) and the dynamic effects on its drug substrates. In the preclinical and clinical setting, anti-drug antibodies (ADA) that develop against therapeutic mAbs can influence patient safety and interfere with product efficacy. Thus, my first focus in this dissertation investigates methods to limit/prevent immunogenicity and therefore help to eliminate a source of variability and clearance that can be seen in preclinical and clinical studies. My first study investigates the use of immune suppressants in mitigating ADA responses to a fully-humanized mAb in preclinical animal studies. Three groups of Sprague Dawley rats (n=18) were treated with low (0.01 mg/kg), moderate (50 mg/kg), or high (300 mg/kg) doses of a mAb. Experimental groups also received either methotrexate or tacrolimus/sirolimus immune suppression. Methotrexate significantly lowered the incidence of anti-variable region antibodies at moderate mAb dose (P<0.05), while tacrolimus/sirolimus did likewise at moderate and high doses (P<0.01) of mAb. With the exception of low dose mAb plus methotrexate, all immunosuppressed groups displayed more than a 70-fold decrease in ADA magnitude (P<0.05). This abrogation in ADA response correlated with higher mAb exposure in the circulation by week 4 for the moderate and high dosed mAb groups. This method provides an approach to mitigate preclinical immunogenicity by the use of immunosuppressant modalities. Such preconditioning can support preclinical drug development of human therapeutics that are antigenic to animals but not necessarily to humans. Similar approaches to reduce immunogenicity will likely play an essential role with advances in novel therapeutics like fully human mAbs, recombinant proteins, fusion proteins as well as bispecific- and drug-conjugated antibodies. In some cases there may not be a method to reduce/eliminate immunogenicity and the dynamic changes in the elimination of a therapeutic mAb that result. In a preclinical setting, ADA typically influences both multiple dose toxicity studies, as well as preliminary pharmacokinetic (PK) analysis by leading to an increase in clearance of the therapeutic mAb. This increase in clearance caused by ADA can be highly variable due to each animal’s polyclonal immune response to a therapeutic mAb. My second focus aims to account for ADA and its variable effect on a fully human therapeutic mAb. I used data acquired from our previous study that investigated the use of immunosuppressant therapy in mitigating ADA responses to a mAb in a preclinical Sprague Dawley rat study and incorporated much of the data from that study, which included three mAb dosing groups and three immunomodulation therapies. A pharmacometric PK-ADA modeling approach was used to analyze the data. Our model was able to simultaneously capture the pharmacokinetics of the mAb in the presence and absence of ADA, accounting for an immune reaction’s highly variable effect on a therapeutic mAb concentration-time profile. The pharmacometric PK-ADA methodology used in this study demonstrates a modeling strategy that can be applied to other therapeutic mAbs to assess the immunogenicity of a therapeutic mAb and the dynamic effect immunogenicity has on the pharmacokinetics. This modeling methodology can further be applied to the simulation of therapeutic mAbs in the presence of varying rates, magnitudes and affinities of ADA reactions, aiding in the development of appropriately powered toxicology studies and an accurate pharmacokinetic evaluation of a human therapeutic mAb in a preclinical setting. Transport proteins play an important role in determining the disposition of medications in the human body. The expression of transport proteins in the body is not constant throughout childhood development, which affects the pharmacokinetics of a medication that is a substrate of the transport protein. Multidrug resistance protein 2 (MRP2) represents a major hepatic transporter whose expression is dynamic throughout development. MRP2 plays a vital role in the biliary excretion of various organic anions and cations along with glutathione-, glucuronate-, or sulfate-conjugates of several drug substrates. Our third aim is to evaluate the effect the ontogeny of MRP2 has on the pharmacokinetics of ceftriaxone to better understand how a transport protein contributes to the disposition of its substrates throughout childhood development. In order to accomplish our aim, a systems pharmacology modeling approach was used to understand MRP2’s contribution to the elimination of ceftriaxone and the effect of ontogeny changes on the pharmacokinetics of ceftriaxone in pediatric patients. Data from ex vivo studies, preclinical in vivo studies and clinical studies were used to inform our model. Results from the study demonstrate the contribution of MRP2 to the pharmacokinetics of ceftriaxone. Our model was able to capture ceftriaxone’s pharmacokinetics, and MRP2’s contribution to its clearance, allowing for the prediction of pediatric ceftriaxone concentrations. This modeling strategy can also be used to evaluate ontogeny changes in other biochemical transposition proteins, and the subsequent effect on the pharmacokinetics of other therapeutically used compounds. In summary, our work has successfully provided approaches to limit/prevent dynamic changes caused by immune reactions to a therapeutic mAb, demonstrate a pharmacometric PK-ADA approach that can capture the PK changes and variability caused by ADA formation on a therapeutic mAb and demonstrate a systems pharmacology model approach which accounts for the ontogeny of a transport protein and the resultant PK effects on its substrate through childhood development. The following chapters describe and discuss these novel approaches.

ORCID

http://orcid.org/0000-0002-7692-4432

DOI

10.21007/etd.cghs.2017.0434

Comments

One year embargo expires July 2018.

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