Influence of Drug Property and Product Design on In Vitro–In Vivo Correlation of Complex Modified-Release Dosage Forms

Qiu, Yihong; Li, Xia; Duan, John

doi:10.1002/jps.23804

Cited by 5 publications

(2 citation statements)

References 12 publications

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“…IC 50 values may not have a one-to-one correspondence in vivo due to potential nonlinear pharmacokinetics, extensive first pass metabolism, or pharmacodynamics that alter bioavailability. (39) Multiple studies have reported differences between in vitro and in vivo efficacy of antitumor drugs in ovarian cancer and ABCG2-mediated resistance. (40–42) Predicting the correlation between in vitro and in vivo activity remains challenging due to these potential confounding factors, and the variation in potency in vivo that was observed in this study is likely related to pharmacokinetics, pharmacodynamics, or other issues beyond their IC 50 's.…”

Section: Discussionmentioning

confidence: 99%

Novel ABCG2 Antagonists Reverse Topotecan-Mediated Chemotherapeutic Resistance in Ovarian Carcinoma Xenografts

Ricci

Lovato

Severns

et al. 2016

Molecular Cancer Therapeutics

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Chemotherapeutic resistance remains a challenge in the treatment of ovarian carcinoma, especially in recurrent disease. Despite the fact that most patients with newly diagnosed tumors attain complete remission following cytoreductive surgery and chemotherapy, ovarian carcinoma has a recurrence rate that exceeds 75%. The ATP Binding Cassette family G member 2 (ABCG2) efflux protein has been described as one mechanism that confers multiple drug resistance (MDR) to solid tumors and contributes to topotecan (TPT) resistance in ovarian carcinoma. In fact, one clinical trial demonstrated ABCG2 expression in all patients with primary or recurrent ovarian carcinoma. On the basis of our previous work, we hypothesized that three compounds (CID44640177, CID1434724, and CID46245505), which represent a new piperazine-substituted pyrazolo[1,5]pyrimidine substructure class of ABCG2-specific antagonists, would restore chemosensitivity to drug-resistant ovarian cancer in vitro and in vivo. In order to address the treatment difficulties associated with chemotherapeutic resistance in ovarian cancer, we combined each compound (CID44640177, CID1434724, and CID46245505) with TPT and administered the mixture to chemoresistant Igrov1/T8 ovarian cancer cells in vitro and Igrov1/T8 xenografts in CB-17 SCID mice. We found that only nanomolar concentrations of each ABCG2-inhibitor in combination with TPT were required to restore chemosensitivity to Igrov1/T8 cells in vitro. In vivo, substantial tumor reduction was achieved with each compound in 4 days, with CID1434724 causing the largest reduction in excess of 60%. No signs of secondary toxic effects were observed with the ABCG2 antagonists. These novel compounds should be viewed as promising drug candidates to reverse ABCG2-mediated chemoresistance.

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Section: Discussionmentioning

confidence: 99%

Novel ABCG2 Antagonists Reverse Topotecan-Mediated Chemotherapeutic Resistance in Ovarian Carcinoma Xenografts

Ricci

Lovato

Severns

et al. 2016

Molecular Cancer Therapeutics

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show abstract

“…A human IVIVC PK study could be carried out as (1) part of a relative PK study to bridge from early formulations to the commercial formulation, (2) a stand‐alone exploratory biopharmaceutics IVIVC study, or (3) included in other clinical plans . Simulations or modeling could be used to predict the sensitivity of PK parameters to the in vitro dissolution rate . This will help to determine the need for a study and the appropriate test articles.…”

Section: Methodsmentioning

confidence: 99%