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Carmen S Tellez

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    MA17 - Molecular Mechanisms and Therapies (ID 143)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Biology
    • Presentations: 1
    • Now Available
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      MA17.09 - 5-Azacytidine Inhaled Dry Powder Formulation Profoundly Improves Pharmacokinetics and Efficacy for Lung Cancer Therapy (Now Available) (ID 172)

      15:45 - 17:15  |  Author(s): Carmen S Tellez

      • Abstract
      • Presentation
      • Slides


      Epigenetic therapy through its ability to activate hundreds of genes silenced by promoter hypermethylation in lung cancer could produce durable and sustained tumor regression. The demethylating agent 5-azacytidine (5AZA) is unstable in aqueous solution and subject to hydrolysis and catabolism by cytidine deaminase (CDA) in liver, thereby reducing drug concentration after systemic administration prior to reaching the lung. Delivering 5AZA by inhalation could mitigate these barriers.


      A stable, respirable (3.5 µM) dry powder formulation of 5AZA was generated. Pharmacokinetic (PK) studies in rats compared systemic dosing to inhaled delivery of a dry powder or aqueous formulation of 5AZA in the presence and absence of the CDA inhibitor tetrahyroduridine (THU). An orthotopic nude rat lung cancer model compared efficacy of inhaled dry powder versus aqueous 5AZA for treatment of engrafted human adenocarcinoma (Calu6, Calu3), adenocarcinoma in situ (H358), and squamous cell (RH2) tumor lines. Three weeks following engraftment (lungs contain multiple tumors), rats were treated 4 times weekly for 4 weeks, then sacrificed to assess tumor burden and genome-wide effects on the methylome in vehicle and treated tumors using the Illumina EPIC array.


      Plasma PK showed a ~10-fold increase in area under the curve (AUC) and a 1.5 and 5-fold increase in maximum concentration (Cmax) comparing inhaled dry powder (0.6 mg/kg) to systemic (2 mg/kg, equivalent to the human injectable dose of 75 mg/m2) and inhaled aqueous (0.6 mg/kg) 5AZA that was augmented by THU. Inhaled dry powder and aqueous 5AZA PK in lung were similar and greatly exceeded systemic (30-fold Cmax; 47-fold AUC). PK in liver and brain were superior for dry powder with 7- and 26-fold increase in AUC and 7- and 3.3-fold increase in Cmax compared to systemic or aqueous dosing. The efficacy study comparing inhaled delivery of equivalent doses (0.6 mg/kg lung dose) showed dry powder was significantly better than aqueous with a 70–80% compared to 33–50% reduction in tumor burden for Calu6, Calu3, and RH2 and equally effective in largely curing H358 tumors. A significantly increased median number of genes (175–320 versus 25–270) exhibiting ≥30% demethylation of CpGs across their promoter region was seen for Calu6, Calu3, and H358 tumors exposed to dry powder versus aqueous 5AZA, with equivalent numbers of genes demethylated for RH2.


      Delivery of a dry powder formulation of 5AZA via an inhaler could be used to treat local and metastatic lung cancer (Support–CA196590).

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