PK/TD modeling for prediction of the effects of 8C2, an anti-topotecan mAb, on topotecan-induced toxicity in mice

Abstract

To facilitate the development of an inverse targeting strategy, where anti-topotecan antibodies are administered to prevent systemic toxicity following intraperitoneal topotecan, a pharmacokinetic/toxicodynamic (PK/TD) model was developed and evaluated. The pharmacokinetics of 8C2, a monoclonal anti-topotecan antibody, were assessed following IV and SC administration, and the data were characterized using a two compartmental model with nonlinear absorption and elimination. A hybrid PK model was constructed by combining a PBPK model for topotecan with the two-compartment model for 8C2, and the model was employed to predict the disposition of topotecan, 8C2, and the topotecan-8C2 complex. The model was linked to a toxicodynamic model for topotecan-induced weight-loss, and simulations were conducted to predict the effects of 8C2 on the toxicity of topotecan in mice. Increasing the molar dose ratio of 8C2 to topotecan resulted in a dose-dependent decrease in the unbound (i.e., not bound to 8C2) topotecan exposure in plasma (AUCf) and a decrease in the extent of topotecan-induced weight-loss. Consistent with model predictions, toxicodynamic experiments showed substantial reduction in the percent nadir weight loss observed with 30 mg/kg IP topotecan after co-administration of 8C2 (20±8% vs. 10±8%). The investigation supports the use of anti-topotecan mAb to reduce the systemic toxicity of IP topotecan chemotherapy.

Systems pharmacology and enhanced pharmacodynamic models for understanding antibody-based drug action and toxicity

“…Functioning of the CTX transduction pathway was shown to depend upon several processes, including activation of the EGFR pathway, the regulation of the MAPK pathway activation by dual-specificity phosphatases (DUSP), and the transcriptional status of gene pathways controlling the epithelial-to-mesenchymal transition (EMT) and its reversal (MET) program. Quantitative real-time PCR, flow cytometry analysis, and high-content immunostaining confirmed that CTX efficacy relies on 3 factors: 1) its ability to increase cell-to-cell contact by upregulating the expression of the epithelial markers E-cadherin and occluding; 2) downregulation of epithelial transcriptional repressors, such as Zeb, Snail, and Slug along with the restoration of cortical F-actin; and 3) complete suppression of the CD 44 pos /CD 24 neg /low mesenchymal immune-phenotype. As a result, the prediction of CTX efficacy in mCRC from gene transcripts of EGFR ligands/ MAPK phosphatases relies on the ability of CTX to concomitantly reverse the EMT status known to be an important characteristic of migrating cancer stem cells.…”

“…38 PBPK models for mAbs have the potential for interspecies scaling, 39,40 predicting the PK of the mAbs prior to in vivo studies, 41,42 and characterizing the physiological and biochemical basis for altered PK and associated toxicities. 43,44 Growing interest in the disposition of antibodies is leading to the development of advanced mathematical models to account for drug and system complexities and to allow for improved predictions of mAbs PK. 45 PBPK models are uniquely suited for this purpose as they facilitate the incorporation of processes such as convective transport, FcRn binding and recycling, TMDD, and tissue catabolism, resulting in a more accurate and informative description of mAbs disposition.…”

Development of a Translational Physiologically Based Pharmacokinetic Model for Antibody-Drug Conjugates: a Case Study with T-DM1

“…The inspiration for the ADC PBPK model proposed here comes from our recently published work (6,26), where we combined an antibody PBPK model with a small molecule PBPK model to predict the effect of antitopotecan antibody on the whole body disposition and toxicity of topotecan in mice. Accordingly, here we have combined our platform PBPK model for monoclonal antibody (4) with a typical PBPK model for small molecule to characterize the whole body disposition of ADC/antibody and unconjugated drug (Fig.…”

Physiologically based pharmacokinetic models of small molecules and therapeutic antibodies: a mini‐review on fundamental concepts and applications

“…Additionally, the catabolism of administered proteins occurs within the s.c. space, resulting in incomplete absorption of the intact drug . The numerous factors that impact the absorption of therapeutic antibodies following s.c. administration may be described empirically by two parameters, F and k a , where the total amount of drug entering the central blood compartment following a s.c. dose ( D abs ) is written as while the rate of drug transport from the s.c. depot, into the central blood compartment is written as where X SC is the amount (mol) of drug in the s.c. depot, F is the fractional (dimensionless) drug bioavailability, which may be constant or vary as a function of dose and k a is the fractional rate (1/time) of drug absorption per unit time. This frequently utilized empirical description of s.c. absorption in PBPK model implementations reflects the general lack of understanding regarding s.c. absorption mechanisms of large molecules; thus, specific mechanisms of elimination from the s.c. depot are not included.…”

“…where X SC is the amount (mol) of drug in the s.c. depot, F is the fractional (dimensionless) drug bioavailability, which may be constant or vary as a function of dose [39] and k a is the fractional rate (1/time) of drug absorption per unit time. This frequently utilized empirical description of s.c. absorption in PBPK model implementations reflects the general lack of understanding regarding s.c. absorption mechanisms of large molecules; thus, specific mechanisms of elimination from the s.c. depot are not included.…”