Comparison of Two Pharmacodynamic Transduction Models for the Analysis of Tumor Therapeutic Responses in Model Systems

Yang, Jun; Mager, Donald E.; Straubinger, Robert M.

doi:10.1208/s12248-009-9155-7

Cited by 47 publications

(29 citation statements)

References 26 publications

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“…A mechanism-based PKPD model was developed assuming a delayed response relative to the drug concentration motivated by the in vitro findings showing a delayed apoptotic response relative to RG7388 exposure. Similar modeling approaches have been reported to assess antitumor effect in xenograft mice (15,16 Our model assumes the tumor mass to consist solely of tumor cells and does not consider the interaction between stroma and tumor compartment. Moreover, drug-induced resistance, which can certainly influence outcome, is excluded.…”

Section: Discussionmentioning

confidence: 99%

“…The model separates system-related properties (tumor size and tumor growth rate) from drug-related properties (potency, drug-induced kill rate) and incorporates the following assumptions: (i) MDM2 is amplified, resulting in the inhibition of p53-induced apoptosis in the SJSA xenograft tumors, (ii) proliferation of SJSA cells thereby becomes the predominant process, resulting in unperturbed tumor growth, (iii) after administration of RG7388, MDM2 is sufficiently blocked from negatively regulating p53, which in turn induces cellular growth arrest and apoptosis, and (iv) the delay in tumor response to drug effect is due to signal transduction processes intervening between drug-receptor interaction and the killing event with the killing effect occurring through a signal transduction cascade (14). Similar modeling approaches have been reported to assess antitumor effect in xenograft mice (15,16). These models allow for the estimation of a concentration resulting in tumor stasis.…”

Section: Rg7388 Exposure Levels After Multiple Oral Doses In Female Micementioning

confidence: 93%

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Preclinical Optimization of MDM2 Antagonist Scheduling for Cancer Treatment by Using a Model-Based Approach

Higgins

Glenn

Walz

et al. 2014

Clinical Cancer Research

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Purpose: Antitumor clinical activity has been demonstrated for the MDM2 antagonist RG7112, but patient tolerability for the necessary daily dosing was poor. Here, utilizing RG7388, a second-generation nutlin with superior selectivity and potency, we determine the feasibility of intermittent dosing to guide the selection of initial phase I scheduling regimens.Experimental Design: A pharmacokinetic-pharmacodynamic (PKPD) model was developed on the basis of preclinical data to determine alternative dosing schedule requirements for optimal RG7388-induced antitumor activity. This PKPD model was used to investigate the pharmacokinetics of RG7388 linked to the time-course of the antitumor effect in an osteosarcoma xenograft model in mice. These data were used to prospectively predict intermittent and continuous dosing regimens, resulting in tumor stasis in the same model system.Results: RG7388-induced apoptosis was delayed relative to drug exposure with continuous treatment not required. In initial efficacy testing, daily dosing at 30 mg/kg and twice a week dosing at 50 mg/kg of RG7388 were statistically equivalent in our tumor model. In addition, weekly dosing of 50 mg/kg was equivalent to 10 mg/kg given daily. The implementation of modeling and simulation on these data suggested several possible intermittent clinical dosing schedules. Further preclinical analyses confirmed these schedules as viable options.Conclusion: Besides chronic administration, antitumor activity can be achieved with intermittent schedules of RG7388, as predicted through modeling and simulation. These alternative regimens may potentially ameliorate tolerability issues seen with chronic administration of RG7112, while providing clinical benefit. Thus, both weekly (qw) and daily for five days (5 d on/23 off, qd) schedules were selected for RG7388 clinical testing.

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Section: Discussionmentioning

confidence: 99%

Section: Rg7388 Exposure Levels After Multiple Oral Doses In Female Micementioning

confidence: 93%

Preclinical Optimization of MDM2 Antagonist Scheduling for Cancer Treatment by Using a Model-Based Approach

Higgins

Glenn

Walz

et al. 2014

Clinical Cancer Research

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“…In order to address the mechanistic features of pharmacological systems for anticancer agents, an approach involving time-dependent transduction processes (6,11,12) is often applied to describe tumor growth kinetics. The threshold concentration for tumor eradication (C T ) was described as the drug concentration required to fully inhibit tumor growth (4).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics, pharmacodynamics and metabolism of a novel anticancer agent for prostate cancer

Dalton¹

2012

Int J Oncol

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Abstract. The objective of these studies was to examine the murine pharmacokinetics, pharmacodynamics and metabolism of (3-(1H-indol-2-yl)phenyl)(1H-indol-2-yl)methanone (Indole 15), a novel tubulin inhibitor for the treatment of cancer. We developed HPLC and LC/MS/MS assays to quantitate Indole 15 and characterize its metabolites in vivo. Pharmacokinetic studies were performed after intravenous (IV), oral (PO) and subcutaneous (SC) administration of 10 mg/kg doses to male ICR mice. Urine and fecal samples were also collected over a 72-h period to identify metabolites. Pharmacodynamic studies were conducted by monitoring the tumor size change during a period of two weeks in PC-3 tumor bearing mice after daily IV administration of Indole 15 at doses of 0, 10, 50, 100 and 150 mg/kg. The pooled plasma concentration data after administration via different dose routes was simultaneously fitted by a two-compartmental model. Indole 15 was moderately well absorbed after PO and SC administration, with a bioavailable fraction of 0.27 and 0.72, respectively. The steady state volume distribution (V ss ) and clearance (CL) were estimated to be 7.0 l/kg and 4.36 l/h/kg, respectively. The mean data of PC-3 tumor growth in mice was fitted well by a transduction model using fixed plasma pharmacokinetics as a driving function. Analysis of the metabolites in mice indicated that the compound undergoes extensive oxidative metabolism with subsequent sulfation. These studies demonstrate that favorable pharmacokinetic and pharmacodynamic properties of Indole 15 offer hope for achieving pharmacological activity in early clinical trials.

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“…To characterize the delay in the PD response, a transit compartment model was used [29][30][31] . Here k 1 represents the transit rate constant between any two of the non-proliferating compartments.…”

Section: Tumor Volume Modelmentioning

confidence: 99%

Pharmacokinetic-pharmacodynamic modeling of the antitumor effect of TM208 and EGFR-TKI resistance in human breast cancer xenograft mice

et al. 2016

Acta Pharmacol Sin

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Aim:The novel anticancer compound TM208 is an EGFR tyrosine kinase inhibitor (EGFR-TKI). Since the development of resistance to EGFR-TKIs is a major challenge in their clinical usage, we investigated the profiles of resistance following continuous treatment with TM208 in human breast cancer xenograft mice, and identified the relationship between the tumor pEGFR levels and tumor growth inhibition. Methods: Female BALB/c nude mice were implanted with human breast cancer MCF-7 cells, and the xenograft mice received TM208 (50 or 150 mg·kg -1 ·d -1 , ig) or vehicle for 18 d. The pharmacokinetics (PK) and pharmacodynamics (PD) of TM208 were evaluated. Results: The PK properties of TM208 were described by a one-compartment model with first-order absorption kinetics. Our study showed the inhibitory effects of TM208 on tumor pEGFR levels gradually reached a maximum effect, after which it became weaker over time, which was characterized by a combined tolerance/indirect response PD model with an estimated EC 50 (55.9 μg/L), as well as three parameters ('a' of 27.2%, 'b' of 2730%, 'c' of 0.58 h -1 ) denoting the maximum, extent and rate of resistance, respectively. The relationship between the tumor pEGFR levels and tumor growth inhibition was characterized by a combined logistic tumor growth/ transit compartment model with estimated parameters associated with tumor growth characteristics k ng (0.282 day -1 ), drug potency k TM208 (0.0499 cm 3 /day) and the kinetics of tumor cell death k 1 (0.141 day -1 ), which provided insight into drug mechanisms and behaviors. Conclusion: The proposed PK/PD model provides a better understanding of the pharmacological properties of TM208 in the treatment of breast cancer. Furthermore, simulation based on a tolerance model allows prediction of the occurrence of resistance.

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Comparison of Two Pharmacodynamic Transduction Models for the Analysis of Tumor Therapeutic Responses in Model Systems

Cited by 47 publications

References 26 publications

Preclinical Optimization of MDM2 Antagonist Scheduling for Cancer Treatment by Using a Model-Based Approach

Preclinical Optimization of MDM2 Antagonist Scheduling for Cancer Treatment by Using a Model-Based Approach

Pharmacokinetics, pharmacodynamics and metabolism of a novel anticancer agent for prostate cancer

Pharmacokinetic-pharmacodynamic modeling of the antitumor effect of TM208 and EGFR-TKI resistance in human breast cancer xenograft mice

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