Pharmacodynamic Modelling of Biomarker Data in Oncology

Jackson, Robert

doi:10.5402/2012/590626

Cited by 20 publications

(12 citation statements)

References 66 publications

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“…Although the exact influence of PK on PD is complex and difficult to define, a PK profile that satisfies well-established criteria is necessary to achieve desired PD, i.e. , engagement with the intracellular target and the desired biological effect[31]. In the human studies, the active SF1126 hydrolysis product attained effective dosing that exceeded levels found to inhibit MM tumors in our preclinical models [17].…”

Section: Discussionmentioning

confidence: 99%

An integrin-targeted, pan-isoform, phosphoinositide-3 kinase inhibitor, SF1126, has activity against multiple myeloma in vivo

Dey

Terakedis

et al. 2013

Cancer Chemother Pharmacol

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Purpose Multiple reports point to an important role for the phosphoinositide-3 kinase (PI3K) and AKT signaling pathways in tumor survival and chemoresistance in multiple myeloma (MM). The goals of our study were: (1) to generate the preclinical results necessary to justify a Phase I clinical trial of SF1126 in hematopoietic malignancies including multiple myeloma, and (2) to begin combining pan PI-3 kinase inhibitors with other agents to augment antitumor activity of this class of agent in preparation for combination therapy in Phase I/II trials. Methods We determined the in vitro activity of SF1126 with16 human MM cell lines. In vivo tumor growth suppression was determined with human myeloma (MM.1R) xenografts in athymic mice. In addition, we provide evidence that SF1126 has pharmacodynamic activity in the treatment of patients with MM. Results SF1126 was cytotoxic to all tested MM lines and potency was augmented by the addition of bortezomib. SF1126 affected MM.1R cell line signaling in vitro, inhibiting phospho-AKT, phospho-ERK, and the hypoxic stabilization of HIF1α. Tumor growth was 94% inhibited, with a marked decrease in both cellular proliferation (PCNA immunostaining) and angiogenesis (tumor microvessel density via CD31 immunostaining). Our clinical results demonstrate pharmacodynamic knockdown of p-AKT in primary patient derived MM tumor cells in vivo. Conclusions Our results establish three important points: (1) SF1126, a pan PI-3 kinase inhibitor has potent antitumor activity against multiple myeloma in vitro and in vivo, (2) SF1126 displays augmented antimyeloma activity when combined with proteasome inhibitor, bortezomib/Velcade®, and (3) SF1126 blocks the IGF-1 induced activation of AKT in primary MM tumor cells isolated from SF1126 treated patients The results support the ongoing early Phase I clinical trial in MM and suggest a future Phase I trial in combination with bortezomib in hematopoietic malignancies.

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Section: Discussionmentioning

confidence: 99%

An integrin-targeted, pan-isoform, phosphoinositide-3 kinase inhibitor, SF1126, has activity against multiple myeloma in vivo

Dey

Terakedis

et al. 2013

Cancer Chemother Pharmacol

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“…A pharmacodynamic biomarker is a PD index that can reflect the process of the drug action, and changes in the biomarker level usually reflect a quantitative relationship with the antitumor effect [10] . By measuring the level of the PD biomarker at the tumor site and combining this information with the plasma concentration and clinical response, we can acquire direct evidence of the process of drug action, including whether the drug has exerted a pharmacological response, the degree of the response and how the response changes with the time course of drug concentration [11] .…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic-pharmacodynamic modeling of the anticancer effect of erlotinib in a human non-small cell lung cancer xenograft mouse model

et al. 2013

Acta Pharmacol Sin

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Aim: Erlotinib is used to treat non-small-cell lung cancer (NSCLC), which targets epidermal growth factor receptor (EGFR) tyrosine kinase. The aim of this study was to investigate the relationship between erlotinib plasma concentrations and phosphorylated EGFR (pEGFR) levels, as well as the relationship between pEGFR levels and tumor growth inhibition in a human non-small-cell lung cancer xenograft mouse model. Methods: Female BALB/c nude mice were implanted with the human NSCLC cell line SPC-A-1. The animals were given via gavage a single dose of erlotinib (4, 12.5, or 50 mg/kg). Pharmacokinetics of erlotinib was determined using LC-MS/MS. Tumor volume and pEGFR levels in tumor tissues were measured at different time points after erlotinib administration. The levels of pEGFR in tumor tissues was detected using Western blotting and ELISA assays. Results: The pharmacokinetics of erlotinib was described by a two-compartment model with first order extravascular absorption kinetics. There was a time delay of approximately 2 h between erlotinib plasma concentrations and pEGFR degradation. The time course of pEGFR degradation was reasonably fit by the indirect response model with a calculated IC 50 value of 1.80 μg/mL. The relationship between pEGFR levels and tumor volume was characterized by the integrated model with a K bio value of 0.507 cm 3 /week, which described the impact of pEGFR degradation on tumor growth. Conclusion: The pharmacokinetic/pharmacodynamic properties of erlotinib in a human tumor xenograft model were described by the indirect response model and integrated model, which will be helpful in understanding the detailed processes of erlotinib activity and determining an appropriate dosing regimen in clinical studies.

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“…The dynamic levels of a biomarker are a key indicator revealing the details and processes of the drug action [24] . Furthermore, by exploring the quantitative relationship between changes in the biomarker level and in the tumor apoptosis effects, direct evidence for and detailed information on the drug actions were obtained, such as the pharmacological response of the drug, the degree of effects and the time course of response changes [25] .…”

Section: Introductionmentioning

confidence: 99%

Dose-biomarker-response modeling of the anticancer effect of ethaselen in a human non-small cell lung cancer xenograft mouse model

et al. 2016

Acta Pharmacol Sin

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Thioredoxin reductase (TrxR) is a component of several redox-sensitive signaling cascades that mediate important biological processes such as cell survival, maturation, growth, migration and inhibition of apoptosis. The expression levels of TrxR1 in some human carcinoma cell lines are nearly 10 times higher than those in normal cells. Ethaselen is a novel antitumor candidate that exerts potent inhibition on non-small cell lung cancer (NSCLC) by targeting TrxR. In this study we explored the relationship between the ethaselen dose and TrxR activity level and the relationship between TrxR degradation and tumor apoptosis in a human lung carcinoma A549 xenograft model. BALB/c nude mice implanted with human NSCLC cell line A54 were administered ethaselen (36, 72, 108 mg·kg -1 ·d -1 , ig) or vehicle for 10 d. The tumor size and TrxR activity levels in tumor tissues were daily recorded and detected. Based on the experimental data, NONMEM 7.2 was used to develop an integrated dose-biomarker-response model for describing the quantitative relationship between ethaselen dose and tumor eradication effects. The time course of TrxR activity levels was modeled using an indirect response model (IDR model), in which the influence of the tumor growth rates on K in with the linear correction factor γ1 (0.021 d/mm). The drug binding-inhibition effects on K out was described using a sigmoidal E max model with S max (5.95), SC 50 (136 mg/kg) and Hill's coefficient γ2 (2.29). The influence of TrxR activity inhibition on tumor eradication was characterized by an E max model with an E max (130 mm 3 /d) and EC 50 (0.0676). This model was further validated using a visual predictive check (VPC) and was used to predict the efficacy of different doses. In conclusion, the properties and characteristics of ethaselen acting on TrxR degradation and subsequently resulting in tumor apoptosis are characterized by the IDR model and integrated dose-biomarker-response model with high goodness-offit and great predicative ability. This approach shed new light on the detailed processes and mechanism of ethaselen action and may offer a valuable reference for an appropriate dosing regimen for use in further clinical applications.

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Pharmacodynamic Modelling of Biomarker Data in Oncology

Cited by 20 publications

References 66 publications

An integrin-targeted, pan-isoform, phosphoinositide-3 kinase inhibitor, SF1126, has activity against multiple myeloma in vivo

An integrin-targeted, pan-isoform, phosphoinositide-3 kinase inhibitor, SF1126, has activity against multiple myeloma in vivo

Pharmacokinetic-pharmacodynamic modeling of the anticancer effect of erlotinib in a human non-small cell lung cancer xenograft mouse model

Dose-biomarker-response modeling of the anticancer effect of ethaselen in a human non-small cell lung cancer xenograft mouse model

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