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Drug-Resistant Cancer Treatment Strategies Based on the Dynamics of Clonal Evolution and pkpd modeling of Drug Combinations

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IEEE-ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS 2022年第3期19卷 1603-1614页

作者： Vakil, Vahideh Trappe, Wade Rutgers State Univ Dept Elect & Comp Engn North Brunswick NJ 08902 USA

A method for determining a dosage strategy is proposed to combat drug resistance in tumor progression. The method is based on a dynamic model for the clonal evolution of cancerous cells and considers the Pharmacokinetic/Pharmacodynamic (pkpd) modeling of combination therapy. The proposed mathematical representation models the dynamic and kinetic effects of multiple drugs on the number of cells while considering potential mutations and assuming that no cross-resistance arises. An optimization problem is then proposed to minimize the total number of cancerous cells in a finite treatment period given a limited number of treatments. The dosage schedule, including the amount of each drug to be administered and the timing, is found by solving the optimization problem. This treatment schedule is constrained to achieve a target minimum effectiveness, while also ensuring that the concentration of the drugs, individually and totally, does not exceed a prescribed toxicity threshold. The proposed optimization problem is represented as a Complementary Geometric Programming (CGP) problem. The results show that the solution of the optimization problem for combination therapy is the dosing schedule that leads to tumor eradication at the end of the treatment period. The results also investigate the tumor dynamics for all mutation types when undergoing treatment, showing that single drug therapies can fail to combat the emergence of resistance, while optimized combination therapies can reduce the amount of all mutation types during the course of treatment, thereby combating resistance.

关键词： Drugs Tumors Immune system Medical treatment Cancer Mathematical model Optimization Combination therapy evolutionary dynamics optimization pkpd modeling

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Understanding CXCR2 antagonism with a dynamic allosteric ternary complex model

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2025年第2期392卷 100049页

作者： Li, Rui Frisbie, Richard Vincent, Fabien Thorarensen, Atli Pfizer Inc Pharmacokinet Dynam & Metab Portland St Cambridge MA 02139 USA Pfizer Inc Discovery Sci Med Design Groton CT USA Pfizer Inc Med Chem Med Design Cambridge MA USA

The CXC chemokine receptor 2 (CXCR2) antagonist SB265610 displays different patterns of antagonism using in vitro binding and cell-based assays. In addition, CXCR2 antagonists, although likely sharing a similar allosteric binding mechanism, display different patterns in the same cell-based assays. Furthermore, clinical studies with CXCR2 antagonists had mixed success in demonstrating target modulation and efficacy, despite favorable exposures based on published binding affinities. Herein, we aimed to understand the mechanism leading to these apparent inconsistencies with a dynamic allosteric ternary complex model. The model was applied in analyzing both in vitro data and clinical neutrophil counts data of CXCR2 antagonists. We extended previous hypotheses into a unified hypothesis, which postulates that, although allosteric binding of a CXCR2 antagonist is not affected by the endogenous agonist, the antagonism is surmountable as the antagonist loses its potency with increased concentrations of endogenous agonist because of the hyperbolic relationship between agonist-occupied receptor and biological response (which is possibly a result of receptor reserve). Antagonists with slow binding kinetics are apparently insurmountable, but only under unsteady-state conditions. Dynamic allosteric ternary complex model following this hypothesis can describe both in vitro and clinical data of CXCR2 antagonists. The inconsistent patterns of CXCR2 antagonism are interpreted as potential receptor reserve in cell-based assays with unsteady-state binding for some compounds. Because the binding process likely reaches quasi steady state in clinical trials, the lack of pharmacology effect for some antagonists is due to suboptimal potency rather than fast binding kinetics. This model may be applicable to other receptors to help predict clinical responses of allosteric antagonists. Significance Statement: Known CXC chemokine receptor 2 (CXCR2) antagonists are allosteric and do not compete

关键词： CXCR2 Allosteric antagonism Dynamic allosteric ternary complex model pkpd modeling

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Use of pharmacodynamic modeling for Bayesian information borrowing in pediatric clinical trials

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JOURNAL OF BIOPHARMACEUTICAL STATISTICS 2023年第6期33卷 726-736页

作者： Sebastien, Bernard Cheung, S. Y. Amy Corriol-Rohou, Solange Gamalo-Siebers, Margaret Jreich, Rana Krishna, Rajesh Liu, Jing Sanofi Data & Data Sci R&D Chilly Mazarin France Certara USA Inc Integrated Drug Dev Princeton NJ USA AstraZeneca Regulatory Affairs & Policy Global Regulatory Policy R&D Paris France Pfizer Global Biometr & Data Management Innovat Hlth Collegeville PA USA Certara USA Inc Clin Pharmacol Princeton NJ USA Pfizer Inc Clin Pharmacol Groton CT USA Sanofi Data & Data Sci R&D 1 Ave Pierre Brossolette F-91385 Chilly Mazarin France

The use of Bayesian methodology to design and analyze pediatric efficacy trials is one of the possible options to reduce their sample size. This reduction of the sample size results from the use of an informative prior for the parameters of interest. In most of the applications, the principle of 'information borrowing' from adults' trials is applied, which means that the informative prior is constructed using efficacy results in adult of the drug under investigation. This implicitly assumes similarity in efficacy between the selected pediatric dose and the efficacious dose in adults. The goal of this article is to propose a method to construct prior distribution for the parameter of interest, not directly constructed from the efficacy results of the efficacious dose in adult patients but using pharmacodynamic modeling of a bridging biomarker using early phase pediatric data. When combined with a model bridging the biomarker with the clinical endpoints, the prior is constructed using a variational method after simulation of the parameters of interest. A use case application illustrates how the method can be used to construct a realistic informative prior.

关键词： Bayesian prior pediatric studies pkpd modeling simulations variational method

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Preclinical InVivo Data Integrated in a modeling Network Informs a Refined Clinical Strategy for a CD3 T-Cell Bispecific in Combination with Anti-PD-L1

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AAPS JOURNAL 2022年第6期24卷 106-106页

作者： Sanchez, Javier Nicolini, Valeria Fahrni, Linda Waldhauer, Inja Walz, Antje-Christine Jamois, Candice Fowler, Stephen Simon, Silke Klein, Christian Umana, Pablo Friberg, Lena Frances, Nicolas F Hoffmann La Roche Ltd Roche Innovat Ctr Basel Roche Pharma Res & Early Dev Grenzacherstr 124 CH-4070 Basel Switzerland Uppsala Univ Dept Pharm Uppsala Sweden Roche Innovat Ctr Zurich Roche Pharma Res & Early Dev Schlieren Switzerland

TYRP1-TCB is a CD3 T-cell bispecific (CD3-TCB) antibody for the treatment of advanced melanoma. A tumor growth inhibition (TGI) model was developed using mouse xenograft data with TYRP1-TCB monotherapy or TYRP1-TCB plus anti-PD-Ll combination. The model was translated to humans to inform a refined clinical strategy. From xenograft mouse data, we estimated an EC50 of 0.345 mg/L for TYRP1-TCB, close to what was observed in vitro using the same tumor cell line. The model showed that, though increasing the dose of TYRP1-TCB in monotherapy delays the time to tumor regrowth and promotes higher tumor cell killing, it also induces a faster rate of tumor regrowth. Combination with anti-PD-L1 extended the time to tumor regrowth by 25% while also decreasing the tumor regrowth rate by 69% compared to the same dose of TYRP1-TCB alone. The model translation to humans predicts that if patients' tumors were scanned every 6 weeks, only 46% of the monotherapy responders would be detected even at a TYRP1-TCB dose resulting in exposures above the EC90. However, combination of TYRP1-TCB and anti-PD-L1 in the clinic is predicted to more than double the overall response rate (ORR), duration of response (DoR) and progression-free survival (PFS) compared to TYRP1-TCB monotherapy. As a result, it is highly recommended to consider development of CD3-TCBs as part of a combination therapy from the outset, without the need to escalate the CD3-TCB up to the Maximum Tolerated Dose (MTD) in monotherapy and without gating the combination only on RECIST-derived efficacy metrics.

关键词： CD3-bispecifics Checkpoint inhibitors Combination pkpd modeling

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pkpd Assessment of the Anti-CD20 Antibody Obinutuzumab in Cynomolgus Monkey is Feasible Despite Marked Anti-Drug Antibody Response in This Species

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JOURNAL OF PHARMACEUTICAL SCIENCES 2019年第11期108卷 3729-3736页

作者： Grimm, Hans Peter Schick, Eginhard Hainzl, Dominik Justies, Nicole Yu, Li Klein, Christian Husar, Elisabeth Richter, Wolfgang F. F Hoffmann La Roche Ltd Roche Innovat Ctr Basel Basel Switzerland F Hoffmann La Roche Ltd Roche Innovat Ctr New York New York NY 10016 USA Roche Glycart AG Roche Innovat Ctr Zurich Zurich Switzerland Novartis Inst BioMed Res Cambridge MA USA

The pharmacokinetics (PK) of the anti-CD20 monoclonal antibody obinutuzumab was assessed after single intravenous dosing to cynomolgus monkeys. In addition, the pharmacokinetic-pharmacodynamic (pkpd) relationship for B-cell depletion was characterized. The pkpd model was used to estimate the B-cell repopulation during the recovery phase of chronic toxicology studies, thereby supporting the study design, in particular planning the recovery phase duration. Marked immunogenicity against obinutuzumab was observed approximately 10 days after single dose, leading to an up to similar to 30-fold increase in obinutuzumab clearance in the affected monkeys. Despite this accelerated clearance, the PK could be characterized, either by disregarding the clearance in noncompartmental PK analysis or by capturing it explicitly as an additional time-dependent clearance process in compartmental modeling. This latter step was crucial to model the pkpd of B-cells as an indirect response to obinutuzumab exposure, showing that-without immune response-the limiting factor is obinutuzumab elimination with concentrations below 0.02 mu g/mL required for initiation of B-cell recovery. Overall, the results demonstrate that despite a marked anti-drug antibody response in the nonclinical animal species, the PK and pkpd of obinutuzumab could be characterized successfully by appropriately addressing the immune-modulated clearance pathway in data analysis and modeling. (c) 2019 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.

关键词： obinutuzumab pharmacokinetics pkpd modeling B-cell cynomolgus monkey monoclonal antibodies immunogenicity

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Pharmacodynamic, pharmacokinetic and physical characterization of cilnidipine loaded solid lipid nanoparticles for oral delivery optimized using the principles of design of experiments

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COLLOIDS AND SURFACES B-BIOINTERFACES 2020年 193卷 111073-111073页

作者： Diwan, Rimpy Ravi, Punna Rao Pathare, Nikita Shantaram Aggarwal, Vidushi BITS Pilani Dept Pharm Hyderabad Campus Hyderabad 500078 Telangana India

Cilnidipine (CND), an anti-hypertensive drug, is known to have low oral bioavailability due to its poor aqueous solubility, low dissolution rate and high gut wall metabolism. In the present study, CND loaded compritol based nanoparticles (CND-CMP-NPs) were prepared by emulsification-solvent evaporation method applying the concepts of design of experiments. Critical factors affecting particle size and loading efficiency (LE%) were assessed by hybrid design approach, comprising of Mini Run Resolution IV design followed by Box-Behnken design. Particle size, PDI, zeta potential and LE% of optimized formulations of CND-CMP-NPs were 207.1 +/- 2.9 nm, 0.27 +/- 0.1, -22.2 +/- 1.9 mV and 15.9 +/- 1.3% respectively. No significant changes were observed in physical stability of NPs when stored at 25 degrees C/60% RH over a period of three months. Pharmacokinetic studies revealed that F-abs of CND-CMP-NPs (0.66) was significantly higher than the free CND (0.27). The C-max and AUC(0-infinity) of CND-CMP-NPs (572.4 +/- 25.3 ng/mL and 5588.6 +/- 229.5 ng/mL x h) were significantly higher (P-cal< 0.0001) as compared to free CND (363.6 +/- 23.5 ng/mL and 2316.1 +/- 163.6 ng/mL x h). MRT of CND-CMP-NPs (9.8 +/- 0.9 h) was significantly higher (P-cal< 0.0001) as compared to free CND (5.7 +/- 0.5 h). Pharmacodynamic studies showed a maximum of 38% decrease in systolic blood pressure with more than 20% drop in systolic blood pressure sustained for a total duration of 64 h in the case of CND-CMP-NPs as compared to free CND. CNDCMP-NPs not only provide higher and sustained plasma levels of CND but also higher and sustained antihypertensive therapy as compared to free CND.

关键词： Cilnidipine Solid lipid nanoparticles Mini Run Resolution IV design Pharmacokinetics Pharmacodynamics pkpd modeling

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Claiming desmopressin therapeutic equivalence in children requires pediatric data: a population pkpd analysis

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EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY 2018年第3期74卷 297-305页

作者： Michelet, Robin Dossche, Lien Van Herzeele, Charlotte Van Bocxlaer, Jan Vermeulen, An Vande Walle, Johan Univ Ghent Fac Pharmaceut Sci Dept Bioanal Lab Med Biochem & Clin Anal Ottergemsesteenweg 460 B-9000 Ghent Belgium Ghent Univ Hosp Dept Pediat Nephrol De Pintelaan 185 B-9000 Ghent Belgium

For a new formulation of a drug, only pharmacokinetic bioequivalence with the original formulation has to be demonstrated in healthy, young adults. However, "children are not small adults," and to guarantee a safe and effective treatment, age-adapted drug development is required. Desmopressin, a vasopressin analogue prescribed for nocturnal enuresis in children, was studied as an example formulation first developed in adults and then extrapolated to a pediatric indication. Population pharmacokinetic and pharmacodynamic modeling was used to analyze previously published desmopressin data of 18 children suffering from nocturnal enuresis. The main objective was the comparison of the therapeutic equivalence of two desmopressin formulations: tablet and lyophilisate. The measurements for pharmacokinetics and pharmacodynamics were respectively plasma desmopressin concentration and urine osmolality and diuresis. The half maximal inhibitory concentration for inhibition of urine production was 0.7 pg/mL lower for the lyophilisate than for the tablet. The effect of formulation on the half maximal inhibitory concentration seems to suggest that the 120-mu g lyophilisate has a more pronounced effect on the urine volume and osmolality than the 200-mu g tablet, even when the same exposure is achieved. A new indirect response model for desmopressin was constructed and validated, using a previously built pharmacokinetic model and additional pharmacodynamic data. In order to draw solid conclusions regarding the efficacy and safety of desmopressin in children, pharmacokinetics and pharmacodynamics data should be analyzed together. This study adds proof to potential differences in pediatric and adult pharmacokinetic and pharmacodynamic properties of desmopressin and exemplifies the need for pediatric clinical trials, not only for every new drug but also for every new formulation.

关键词： Bioequivalence 1-Deamino-8-D-arginine vasopressin (dDAVP) Children Tablet Lyophilisate pkpd modeling

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Pharmacokinetics and pharmacodynamics of the cytolytic anti-CD38 human monoclonal antibody TAK-079 in monkey - model assisted preparation for the first in human trial

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PHARMACOLOGY RESEARCH & PERSPECTIVES 2018年第3期6卷 e00402页

作者： Roepcke, Stefan Plock, Nele Yuan, Josh Fedyk, Eric R. Lahu, Gezim Zhao, Lin Smithson, Glennda Takeda Pharmaceut Int AG Zurich Switzerland Takeda Pharmaceut Int Cambridge MA USA

We are studying the fully human, IgG1 cytolytic monoclonal antibody TAK-079, which binds CD38. CD38 is expressed on plasma and natural killer (NK) cells constitutively and upregulated on subsets of B and T lymphocytes upon activation. TAK-079 cross-reacts with CD38 expressed by cynomolgus monkeys and depletes subsets of NK, B, and T cells. Therefore, safety and function of TAK-079 was evaluated in this species, prior to clinical development, using bioanalytical, and flow cytometry assays. We pooled the data from eight studies in healthy monkeys (dose range 0.03-100mg/kg) and developed mathematical models that describe the pharmacokinetics and the exposure-effect relationship for NK cells, B cells, and T cells. NK cell depletion was identified as the most sensitive pharmacodynamic effect of TAK-079. It was adequately described with a turnover model (C-50=27.5g/mL on depletion rate) and complete depletion was achieved with an IV dose of 0.3mg/kg. Intermediate effects on T-cell counts were described with a direct response model (C-50=11.9g/mL) and on B-cell counts with a 4-transit-compartment model (C-50=19.8g/mL on depletion rate). Our analyses substantiate the observation that NK, B and T cells are cleared by TAK-079 at different rates and required different time spans to replete the blood compartment. The models were used to simulate pharmacokinetic and cell depletion profiles in humans after applying a straightforward scaling approach for monoclonal antibodies in preparation for the first-in-human clinical trial.

关键词： anti-CD38 antibody cytolytic antibody lymphocyte depletion pkpd modeling

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Overexpressing cell systems are a competitive option to primary adipocytes when predicting in vivo potency of dual GPR81/GPR109A agonists

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EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES 2018年 114卷 155-165页

作者： Almquist, Joachim Hovdal, Daniel Ahlstrom, Christine Fjellstrom, Ola Gennemark, Peter Sundqvist, Monika Fraunhofer Chalmers Ctr Chalmers Sci Pk Gothenburg Sweden Chalmers Univ Technol Dept Biol & Biol Engn Syst & Synthet Biol Gothenburg Sweden AstraZeneca IMED Biotech Unit Cardiovasc & Metab Dis DMPK Gothenburg Sweden AstraZeneca IMED Biotech Unit Cardiovasc & Metab Dis Gothenburg Sweden

Mathematical models predicting in vivo pharmacodynamic effects from in vitro data can accelerate drug discovery, and reduce costs and animal use. However, data integration and modeling is non-trivial when more than one drug-target receptor is involved in the biological response. We modeled the inhibition of non-esterified fatty acid release by dual G-protein-coupled receptor 81/109A ( GPR81/GPR109A) agonists in vivo in the rat, to estimate the in vivo EC50 values for 12 different compounds. We subsequently predicted those potency estimates using EC50 values obtained from concentration-response data in isolated primary adipocytes and cell systems overexpressing GPR81 or GPR109A in vitro. A simple linear regression model based on data from primary adipocytes predicted the in vivo EC50 better than simple linear regression models based on in vitro data from either of the cell systems. Three models combining the data from the overexpressing cell systems were also evaluated: two piecewise linear models defining logical OR-and AND-circuits, and a multivariate linear regression model. All three models performed better than the simple linear regression model based on data from primary adipocytes. The OR-model was favored since it is likely that activation of either GPR81 or GPR109A is sufficient to deactivate the cAMP pathway, and thereby inhibit non-esterified fatty acid release. The OR-model was also able to predict the in vivo selectivity between the two receptors. Finally, the OR-model was used to predict the in vivo potency of 1651 new compounds. This work suggests that data from the overexpressing cell systems are sufficient to predict in vivo potency of GPR81/GPR109A agonists, an approach contributing to faster and leaner drug discovery.

关键词： GPR81 GPR109A In vitro-in vivo correlation Non-esterified fatty acids (NEFA) pkpd modeling Nonlinear mixed effects (NLME) modeling Drug discovery

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Pharmacokinetics and Pharmacodynamics of Curcumin in regulating anti-inflammatory and epigenetic gene expression

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BIOPHARMACEUTICS & DRUG DISPOSITION 2018年第6期39卷 289-297页

作者： Boyanapalli, Sarandeep S. S. Huang, Ying Su, Zhengyuan Cheng, David Zhang, Chengyue Guo, Yue Rao, Rohit Androulakis, Ioannis P. Kong, Ah-Ng Rutgers State Univ Ernest Mario Sch Pharm Dept Pharmaceut 160 Frelinghuysen Rd Piscataway NJ 08854 USA Rutgers State Univ Dept Biomed Engn Piscataway NJ USA

Chronic inflammation is a key driver of cancer development. Nitrite levels, which are regulated by inducible nitric oxide synthase (iNOS), play a critical role in inflammation. While the anti-oxidant and anti-inflammatory effects of curcumin, a natural product present in the roots of Curcuma longa have been studied widely, the acute pharmacokinetics (PK) and pharmacodynamics (PD) of curcumin in suppressing pro-inflammatory markers and epigenetic modulators remain unclear. This study evaluated the PK and PD of curcumin-induced suppression of lipopolysaccharide (LPS)-mediated inflammation in rat lymphocytes. LPS was administered intravenously either alone or with curcumin to female Sprague-Dawley rats. Plasma samples were analysed for curcumin concentration and mRNA expression was quantified in lymphocytes. The relative gene expression of several inflammatory and epigenetic modulators was analysed. To investigate the relationship between curcumin concentration and iNOS, TNF-alpha, and IL-6 gene expression, PK/PD modeling using Jusko's indirect response model (IDR) integrating transit compartments (TC) describing the delayed response was conducted. The concentration-time profile of curcumin exhibited a bi-exponential decline, which was well described by a two-compartmental pharmacokinetic model. Importantly the results demonstrate that LPS induced gene expression of pro-inflammatory markers in lymphocytes, with peak expression at approximately 3h and curcumin suppressed the gene expression in animals administered with LPS. These effects were well captured using the IDR model and an IDR model with the transit compartments. In summary, the PK/PD modeling approach could potentially provide a robust quantitative framework for evaluating the acute anti-inflammatory and epigenetic effects of curcumin in future clinical trials.

关键词： curcumin epigenetic modulation indirect response model inflammation pkpd modeling

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