Systems models of biological networks show promise for informing drug target selection/qualification, identifying lead compounds and factors regulating disease progression, rationalizing combinatorial regimens, and explaining sources of intersubject variability and adverse drug reactions. However, most models of biological systems are qualitative and are not easily coupled with dynamical models of drug exposure-response relationships. In this proof-of-concept study, logic-based modeling of signal transduction pathways in U266 multiple myeloma (MM) cells is used to guide the development of a simple dynamical model linking bortezomib exposure to cellular outcomes. Bortezomib is a commonly used first-line agent in MM treatment; however, knowledge of the signal transduction pathways regulating bortezomib-mediated cell cytotoxicity is incomplete. A Boolean network model of 66 nodes was constructed that includes major survival and apoptotic pathways and was updated using responses to several chemical probes. Simulated responses to bortezomib were in good agreement with experimental data, and a reduction algorithm was used to identify key signaling proteins. Bortezomib-mediated apoptosis was not associated with suppression of nuclear factor kB (NFkB) protein inhibition in this cell line, which contradicts a major hypothesis of bortezomib pharmacodynamics. A pharmacodynamic model was developed that included three critical proteins (phospho-NFkB, BclxL, and cleaved poly (ADP ribose) polymerase). Model-fitted protein dynamics and cell proliferation profiles agreed with experimental data, and the model-predicted IC 50 (3.5 nM) is comparable to the experimental value (1.5 nM). The cell-based pharmacodynamic model successfully links bortezomib exposure to MM cellular proliferation via protein dynamics, and this model may show utility in exploring bortezomib-based combination regimens.

Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate (ADC) composed of multiple molecules of the antimicrotubule agent DM1 linked to trastuzumab, a humanized anti–human epidermal growth factor receptor 2 (HER2) monoclonal antibody. Pharmacokinetics data from phase I (n = 52) and phase II (n = 111) studies in HER2-positive metastatic breast cancer patients show a shorter terminal half-life for T-DM1 than for total trastuzumab (TTmAb). In this work, we translated prior preclinical modeling in monkeys to develop a semi-mechanistic population pharmacokinetics model to characterize T-DM1 and TTmAb concentration profiles. A series of transit compartments with the same disposition parameters was used to describe the deconjugation process from higher to lower drug-to-antibody ratios (DARs). The structure could explain the shorter terminal half-life of T-DM1 relative to TTmab. The final model integrates prior knowledge of T-DM1 DARs from preclinical studies and could provide a platform for understanding and characterizing the pharmacokinetics of other ADC systems.

Bispecific antibodies (BAbs) are novel constructs that are under development and show promise as new therapeutic modalities for cancer and autoimmune disorders. The aim of this study is to develop a semi-mechanistic modeling approach to elucidate the disposition of BAbs in plasma and possible sites of action in humans. Here we present two case studies that showcase the use of modeling to guide BAb development. In case one, a BAb is directed against a soluble and a membrane-bound ligand for treating systemic lupus erythematosus, and in case two, a BAb targets two soluble ligands as a potential treatment for ulcerative colitis and asthma. Model simulations revealed important differences between plasma and tissues, when evaluated for drug disposition and target suppression. Target concentrations at tissue sites and type (soluble vs membrane-bound), tissue-site binding, and binding affinity are all major determinants of BAb disposition and subsequently target suppression. For the presented case studies, higher doses and/or frequent dosing regimens are required to achieve 80 % target suppression in site specific tissue (the more relevant matrix) as compared to plasma. Site-specific target-mediated models may serve to guide the selection of first-in-human doses for new BAbs.

Given the potential consequences of antiepileptic therapy nonadherence, missed-dose scenarios of 12- to 48-hour dose delays (4-hour intervals) for eslicarbazepine acetate monotherapy were evaluated using simulated plasma concentrations of a population pharmacokinetic model (representing 493 subjects). When 1600-mg doses were delayed 12 to <16 or 36 to <44 hours, simulations showed immediate administration of 1600 mg followed by the same dose at the scheduled time maintained plasma concentrations within the target concentration range. With 16- to 24- or 44- to 48-hour delays, administration of 2400 mg at the scheduled time followed by resumption of 1600 mg/day maintained plasma concentrations within the target concentration range. For exploratory purposes, the population pharmacokinetic model was refined to predict (n = 6 subjects) and also to allow for simulation of cerebrospinal fluid concentrations. Based on the plasma concentration simulations conducted herein, potential dosing recommendations were developed that suggest a missed ESL dose should be taken when remembered, and the usual dose regimen resumed. If it is remembered within 4 hours of the next dose, 1.5 times the usual dose should be taken immediately, the scheduled dose for that day should be skipped, and the usual regimen resumed the next day.