Ubiquity: a framework for physiological/mechanism-based pharmacokinetic/pharmacodynamic model development and deployment

Harrold, John M.; Abraham, Anson K.

doi:10.1007/s10928-014-9352-6

Cited by 15 publications

(5 citation statements)

References 17 publications

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“…We simulated drug concentrations simultaneously using the multi-platform package Ubiquity 49 . Because PK parameters are functions of clinical variables, we set these variables to the reported median from a previous study 23 .…”

Section: Methodsmentioning

confidence: 99%

Identification of optimal dosing schedules of dacomitinib and osimertinib for a phase I/II trial in advanced EGFR-mutant non-small cell lung cancer

et al. 2021

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Despite the clinical success of the third-generation EGFR inhibitor osimertinib as a first-line treatment of EGFR-mutant non-small cell lung cancer (NSCLC), resistance arises due to the acquisition of EGFR second-site mutations and other mechanisms, which necessitates alternative therapies. Dacomitinib, a pan-HER inhibitor, is approved for first-line treatment and results in different acquired EGFR mutations than osimertinib that mediate on-target resistance. A combination of osimertinib and dacomitinib could therefore induce more durable responses by preventing the emergence of resistance. Here we present an integrated computational modeling and experimental approach to identify an optimal dosing schedule for osimertinib and dacomitinib combination therapy. We developed a predictive model that encompasses tumor heterogeneity and inter-subject pharmacokinetic variability to predict tumor evolution under different dosing schedules, parameterized using in vitro dose-response data. This model was validated using cell line data and used to identify an optimal combination dosing schedule. Our schedule was subsequently confirmed tolerable in an ongoing dose-escalation phase I clinical trial (NCT03810807), with some dose modifications, demonstrating that our rational modeling approach can be used to identify appropriate dosing for combination therapy in the clinical setting.

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Section: Methodsmentioning

confidence: 99%

Identification of optimal dosing schedules of dacomitinib and osimertinib for a phase I/II trial in advanced EGFR-mutant non-small cell lung cancer

et al. 2021

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“…Descriptive statistics were used to characterize the cohort and infant outcomes. Then, to evaluate breastmilk parameters, for the participants who provided serial (at least 3) samples, the breastmilk concentrations of mAb were analyzed using R software (4.2.2) with pharmacokinetic methods (Ubiquity 2.0.0 non‐compartmental analysis package 12 ). Two assumptions were made to conduct this analysis.…”

Section: Methodsmentioning

confidence: 99%

Anti‐CD20 monoclonal antibody therapy in postpartum women with neurological conditions

Anderson,

Rowles,

Poole

et al. 2023

Ann Clin Transl Neurol

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ObjectivePostpartum, patients with multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) have increased risk for disease activity. Anti‐CD20 IgG1 monoclonal antibodies (mAb) are increasingly used as disease‐modifying therapies (DMTs). Patients may wish to both breastfeed and resume DMT postpartum. This study aimed to determine the transfer of anti‐CD20 IgG1 mAbs, ocrelizumab, and rituximab (OCR/RTX), into mature breastmilk and describe maternal and infant outcomes.MethodsFifty‐seven cis‐women receiving OCR/RTX after 59 pregnancies and their infants were enrolled and followed up to 12M postpartum or 90 days post‐infusion. Breastmilk was collected pre‐infusion and serially up to 90 days and assayed for mAb concentration. Medical records and patients' questionnaire responses were obtained to assess neurologic, breastfeeding, and infant development outcomes.ResultsThe median average concentration of mAb in breastmilk was low (OCR: 0.08 μg/mL, range 0.05–0.4; RTX: 0.03 μg/mL, range 0.005–0.3). Concentration peaked 1–7 days post‐infusion in most (77%) and was nearly undetectable after 90 days. Median average relative infant dose was <1% (OCR: 0.1%, range 0.07–0.7; RTX: 0.04%, range 0.005–0.3). Forty‐three participants continued to breastfeed post‐infusion. At 8–12 months, the proportion of infants' growth between the 3rd and 97th World Health Organization percentiles did not differ for breastfed (36/40) and non‐breastfed (14/16, p > 0.05) infants; neither did the proportion with normal development (breastfed: 37/41, non‐breastfed: 11/13; p > 0.05). After postpartum infusion, two mothers experienced a clinical relapse.InterpretationThese confirm minimal transfer of mAb into breastmilk. Anti‐CD20 mAb therapy stabilizes MS activity before conception to the postpartum period, and postpartum treatments appears to be safe and well‐tolerated for both mother and infant.

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“…The in vitro degradation half-life of bortezomib was included for all model runs. Parameters were estimated using MATLAB (fminsearch function, maximum likelihood algorithm, and ode23s) and a model development framework (Harrold and Abraham, 2014). All protein dynamics were described using a proportional error variance model (Y obs 5 Y pred ×s), and cell proliferation was fitted using an additive plus proportional error variance model (Y obs 5 Y pred ×s 1 «), where Y obs is the observation at time t, Y pred is the model-predicted value at time t, and s and « are estimated variance model parameters.…”

Section: Mathematical Modeling Of Cellular Responses To Bortezomibmentioning

confidence: 99%

Logic-Based and Cellular Pharmacodynamic Modeling of Bortezomib Responses in U266 Human Myeloma Cells

Chudasama

Ovacik

Abernethy

et al. 2015

J Pharmacol Exp Ther

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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.

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Ubiquity: a framework for physiological/mechanism-based pharmacokinetic/pharmacodynamic model development and deployment

Cited by 15 publications

References 17 publications

Identification of optimal dosing schedules of dacomitinib and osimertinib for a phase I/II trial in advanced EGFR-mutant non-small cell lung cancer

Identification of optimal dosing schedules of dacomitinib and osimertinib for a phase I/II trial in advanced EGFR-mutant non-small cell lung cancer

Anti‐CD20 monoclonal antibody therapy in postpartum women with neurological conditions

Logic-Based and Cellular Pharmacodynamic Modeling of Bortezomib Responses in U266 Human Myeloma Cells

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