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Mass Balance Recovery, Pharmacokinetics and Metabolite Profile and Identification of [14C]AZD7594

2019年7月24日 更新者:AstraZeneca

A Phase I, Open-Label Study to Assess Mass Balance Recovery, Pharmacokinetics, Metabolite Profile & Metabolite Identification After Intravenous Microdose Administration of [14C]AZD7594 & Inhaled Administration of AZD7594 in Healthy Subjects

AZD7594 is in clinical development for the treatment of asthma.

This is a single centre, open-label, single period study in 6 healthy subjects, to determine the mass balance recovery and generate samples to enable metabolite profiling and structural identification of AZD7594.

Each subject will receive a single inhaled 792 µg nominal dose (720 µg delivered dose) of AZD7594 followed by an IV dose of 30 µg [14C]AZD7594 containing not more than (NMT) 6.7 kBq (180 nCi) carbon-14 (14C) as a 1 h infusion. The IV dose will be administered approximately 10 min after the inhaled dose. Subjects will remain resident in the clinical unit up to 168 h post dose (up to Day 8).

調査の概要

状態

完了

条件

詳細な説明

This is a single centre, open-label, single period study in 6 healthy male and non-pregnant, non-lactating female subjects to determine the mass balance recovery after a single intravenous (IV) dose of [14C]AZD7594 and to generate samples to enable metabolite profiling and structural identification of AZD7594 in plasma, urine and faeces. It is planned to enrol 6 subjects to ensure data in at least 4 evaluable subjects. A subject will be considered evaluable if they have provided mass balance and PK samples for up to 48 h after drug administration.

Subjects will be screened for eligibility to participate in the study up to 28 days before dosing. Eligible subjects will be admitted to the clinical unit in the afternoon on the day before dosing (Day 1). Subjects will be dosed on the morning of Day 1 in the fasted state (8 h overnight fast). Before oral inhalation of AZD7594 using the Dry Powder Inhaler (DPI), all subjects must demonstrate their ability to use the DPI as intended. Subjects will receive training with an empty DPI at screening, Day -1 and pre-dose (optional) in accordance with study specific instructions. Each subject will receive a single inhaled 792 µg nominal dose (720 µg delivered dose) of AZD7594 followed by an IV dose of 30 µg [14C]AZD7594 containing 6.7 kBq (180 nCi) carbon-14 (14C) as a 1 h infusion. The infusion of the IV dose will be started approximately 15 min after the inhaled dose. Subjects will remain resident in the clinical unit up to 168 h post dose (up to Day 8).

Whole blood, plasma, urine and faeces will be collected from pre-dose until discharge (168 h post-dose; Day 8). Any accidental sources of elimination (eg emesis) will be collected and sent to the mass balance laboratory for total radioactivity analysis.

研究の種類

介入

入学 (実際)

6

段階

  • フェーズ 1

連絡先と場所

このセクションには、調査を実施する担当者の連絡先の詳細と、この調査が実施されている場所に関する情報が記載されています。

研究場所

      • Ruddington、イギリス、NG11 6JS
        • Research Site

参加基準

研究者は、適格基準と呼ばれる特定の説明に適合する人を探します。これらの基準のいくつかの例は、人の一般的な健康状態または以前の治療です。

適格基準

就学可能な年齢

18年~55年 (大人)

健康ボランティアの受け入れ

いいえ

受講資格のある性別

全て

説明

Inclusion Criteria:

  1. Provision of signed and dated, written informed consent prior to any study specific procedures.
  2. Healthy male or non-pregnant, non-lactating female subjects aged 18 to 55 years with suitable veins for cannulation or repeated venepuncture.
  3. Have a body mass index of 18.5 to 35.0 kg/m2, and weigh at least 50 kg and no more than 100 kg, as measured at screening.
  4. Must have regular bowel movements (ie, average stool production of ≥1 and ≤3 stools per day).
  5. Must be willing and able to communicate and participate in the whole study.
  6. Must agree to adhere to the contraception requirements defined in Section 9.4 of the protocol.
  7. Must demonstrate the ability to use the study inhalation device properly.

Exclusion Criteria:

  1. History of any clinically significant disease or disorder which, in the opinion of the investigator, may either put the volunteer at risk because of participation in the study, or influence the results of the volunteer's ability to participate in the study.
  2. History or presence of clinically significant gastrointestinal, hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism or excretion of drugs.
  3. Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of IMP.
  4. Subjects with Gilbert's syndrome or subjects with a history of cholecystectomy or gall stones.
  5. Subjects with pregnant partners
  6. Any confirmed clinically significant abnormalities in clinical chemistry, haematology or urinalysis as judged by the investigator.
  7. Any confirmed clinically significant abnormal findings in vital signs or 12-lead ECG as judged by the investigator.
  8. Any positive result at screening for serum hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) results.
  9. Has received any other new chemical entity (defined as a compound which has not been approved for marketing) within 3 months of the first administration of IMP in this study. The period of exclusion begins 3 months after the final dose. Note: subjects consented and screened, but not randomised in this study or a previous Phase I study are not excluded.
  10. Plasma donation within 1 month of screening or any blood donation/loss of more than 500 mL of blood during the 3 months prior to screening.
  11. History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the investigator or history of hypersensitivity to drugs with a similar chemical structure or class to AZD7594 or the formulation excipients including lactose. Hay fever is allowed unless it is active.
  12. Current smokers and those who have smoked within the last 12 months. A breath carbon monoxide reading of greater than 10 ppm at screening and admission.
  13. Current users of e-cigarettes and nicotine replacement products and those who have used these products within the last 12 months.
  14. Females of childbearing potential who are pregnant or lactating (all female subjects must have a negative urine pregnancy test and screening and admission). A woman is considered of childbearing potential unless she is permanently sterile (hysterectomy, bilateral salpingectomy and bilateral oophorectomy) or is postmenopausal (had no menses for 12 months without an alternative medical cause and a serum follicle stimulating hormone [FSH] concentration ≥40 IU/L).
  15. Confirmed positive screen for drugs of abuse at screening or admission to the clinical unit or positive screen for alcohol at screening or admission to the clinical unit.
  16. Herbal preparations/medications are not allowed throughout the study. These herbal medications include, but are not limited to, St. John's wort, kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone, yohimbe, saw palmetto, and ginseng. Subjects should stop using these herbal medications 14 days prior to administration of AZD7594.
  17. Use of any prescribed or nonprescribed medication including antacids, H2 antagonists, PPI, analgesics (other than paracetamol/acetaminophen up to 4 g/day), vitamins and minerals during the 14 days prior to administration of AZD7594 or longer if the medication has a longer half-life (see Section 11.4 of the protocol). Exceptions may apply on a case by case basis, if considered not to interfere with the objectives of the study, as agreed by the PI and sponsor's medical monitor.
  18. Known or suspected history of alcohol or drug abuse within the past 2 years or regular alcohol consumption in males >21 units per week and females >14 units per week (1 unit = ½ pint beer, or a 25 mL shot of 40% spirit, 1.5 to 2 Units = 125 mL glass of wine, depending on type)
  19. Subjects who are study site employees, or immediate family members of a study site or sponsor employee
  20. Subjects who have previously been enrolled in this study.
  21. Radiation exposure, including that from the present study, excluding background radiation but including diagnostic x-rays and other medical exposures, exceeding 5 mSv in the last 12 months or 10 mSv in the last 5 years. No occupationally exposed worker, as defined in the Ionising Radiation Regulations 2017, shall participate in the study.
  22. Subjects who have been enrolled in an ADME study in the last 12 months
  23. Judgment by the investigator that the volunteer should not participate in the study if they have any ongoing or recent (ie during the screening period) minor medical complaints that may interfere with the interpretation of the study data or are considered unlikely to comply with the study procedures, restrictions and requirements.
  24. History of infantile bronchiolitis, a history of asthma, adverse reaction or allergy to the inhaled medication or any excipients
  25. Upper respiratory tract infection (excluding otitis media) within 14 days of the first study day, or lower respiratory tract infection within the last 3 months
  26. Subjects who are unable to demonstrate their ability to fulfil the physical demands of the study
  27. Failure to satisfy the investigator of fitness to participate for any other reason.

研究計画

このセクションでは、研究がどのように設計され、研究が何を測定しているかなど、研究計画の詳細を提供します。

研究はどのように設計されていますか?

デザインの詳細

  • 主な目的:処理
  • 割り当て:なし
  • 介入モデル:単一グループの割り当て
  • マスキング:なし(オープンラベル)

武器と介入

参加者グループ / アーム
介入・治療
実験的:Only one study arm

[14C]AZD7594 Solution for Infusion 5 µg/mL (1.1 kBq/mL)

AZD7594 Inhalation Powder, SD3FL Inhaler

30 µg [14C]AZD7594 containing 6.7 kBq (180 nCi) carbon-14 (14C) as a 1 hour infusion.
A single inhalation on one occasion.

この研究は何を測定していますか?

主要な結果の測定

結果測定
メジャーの説明
時間枠
AZD7594 excreted (Ae)
時間枠:Urine and faecal samples collected from pre-dose until 168 hours post-dose
Assessment of total radioactivity by measuring AZD7594 excreted (Ae)
Urine and faecal samples collected from pre-dose until 168 hours post-dose
AZD7594 excreted and expressed as a percentage of the administered dose (Fe)
時間枠:Urine and faecal samples colected from pre-dose until 168 hours post-dose
Assessment of total radioactivity by measuring AZD7594 excreted and expressed as a percentage of the administered dose (Fe)
Urine and faecal samples colected from pre-dose until 168 hours post-dose
Cumulative amount of AZD7594 excreted (CumAe)
時間枠:Urine and faecal samples collected from pre-dose until 168 hours post-dose
Assessment of total radioactivity by measuring the cumulative amount of AZD7594 excreted (CumAe)
Urine and faecal samples collected from pre-dose until 168 hours post-dose
Cumulative amount of AZD7594 excreted and expressed as a percentage of the administered dose (CumFe)
時間枠:Urine and faecal samples collected from pre-dose until 168 hours post-dose
Assessment of total radioactivity by measuring AZD7594 excreted and expressed as a percentage of the administered dose (CumFe)
Urine and faecal samples collected from pre-dose until 168 hours post-dose
液体クロマトグラフィー-放射化学的検出およびその後の質量分析による血漿中の代謝物の評価
時間枠:投与前から投与後168時間までの血漿サンプルの収集
液体クロマトグラフィー-放射化学的検出およびその後の質量分析の評価による代謝物の評価と構造の同定
投与前から投与後168時間までの血漿サンプルの収集
液体クロマトグラフィー-放射化学的検出およびその後の質量分析による糞便中の代謝物の評価
時間枠:投与前から投与後168時間までの糞便サンプルの収集
液体クロマトグラフィー-放射化学的検出およびその後の質量分析の評価による代謝物の評価と構造の同定
投与前から投与後168時間までの糞便サンプルの収集
液体クロマトグラフィー-放射化学的検出およびその後の質量分析による尿中代謝物の評価
時間枠:投与前から投与後168時間までの尿サンプルの収集
液体クロマトグラフィー-放射化学的検出およびその後の質量分析の評価による代謝物の評価と構造の同定
投与前から投与後168時間までの尿サンプルの収集

二次結果の測定

結果測定
メジャーの説明
時間枠
Determination of routes and rates of elimination of [14C]AZD7594
時間枠:Collection of urine and faecal samples from pre-dose until 168 hours post-dose
Assessment of total radioactivity by measuring AZD7594 excreted (Ae), cumulative recovery (Cumae), Ae as a percentage of the administered dose (Fe) and cumulative recovery expressed as a percentage of the dose (CumFe)
Collection of urine and faecal samples from pre-dose until 168 hours post-dose
Determination of the chemical structure of the "major" metabolites of [14C]AZD7594
時間枠:Collection of urine adn faeces samples from pre-dose until 168 hours post-dose
Structural identification by assessing liquid chromatography-radiochemical-detection and subsequent mass spectrometry
Collection of urine adn faeces samples from pre-dose until 168 hours post-dose
Evaluation of whole blood:plasma concentration ratios for total radioactivity
時間枠:Collection of plasma samples from pre-dose until 168 hours post-dose
Assessment of total radioactivity by measuring AZD7594 in blood and plasma
Collection of plasma samples from pre-dose until 168 hours post-dose
Assessment of the IV PK of [14C]AZD7594 and total radioactivity
時間枠:Collection of plasma samples from pre-dose until 168 hours post-dose
Time from dosing at which Cmax was apparent (tmax)
Collection of plasma samples from pre-dose until 168 hours post-dose
Assessment of the IV PK of [14C]AZD7594 and total radioactivity
時間枠:Collection of plasma samples from pre-dose until 168 hours post-dose
The maximum observed plasma concentration (Cmax)
Collection of plasma samples from pre-dose until 168 hours post-dose
Assessment of the IV PK of [14C]AZD7594 and total radioactivity
時間枠:Collection of plasma samples from pre-dose until 168 hours post-dose
The area under the concentration-time curve from dosing to the last measurable concentration (AUClast)
Collection of plasma samples from pre-dose until 168 hours post-dose
Assessment of the IV PK of [14C]AZD7594 and total radioactivity
時間枠:Collection of plasma samples from pre-dose until 168 hours post-dose
The area under the concentration-time curve from dosing extrapolated to infinity (AUC0-inf)
Collection of plasma samples from pre-dose until 168 hours post-dose
Assessment of the IV PK of [14C]AZD7594 and total radioactivity
時間枠:Collection of plasma samples from pre-dose until 168 hours post-dose
The percentage of AUC extrapolated beyond the last measured time point (AUC%extr)
Collection of plasma samples from pre-dose until 168 hours post-dose
Assessment of the IV PK of [14C]AZD7594 and total radioactivity
時間枠:Collection of plasma samples from pre-dose until 168 hours post-dose
The terminal elimination rate constant calculated from the slope of the apparent elimination phase (λz)
Collection of plasma samples from pre-dose until 168 hours post-dose
Assessment of the IV PK of [14C]AZD7594 and total radioactivity
時間枠:Collection of plasma samples from pre-dose until 168 hours post-dose
The apparent terminal elimination half-life (t½)
Collection of plasma samples from pre-dose until 168 hours post-dose
Assessment of the IV PK of [14C]AZD7594 and total radioactivity
時間枠:Collection of plasma samples from pre-dose until 168 hours post-dose
Total clearance (CL)
Collection of plasma samples from pre-dose until 168 hours post-dose
Assessment of the IV PK of [14C]AZD7594 and total radioactivity
時間枠:Collection of plasma samples from pre-dose until 168 hours post-dose
Volume of distribution (Vz)
Collection of plasma samples from pre-dose until 168 hours post-dose
Assessment of the IV PK of [14C]AZD7594 and total radioactivity
時間枠:Collection of plasma samples from pre-dose until 168 hours post-dose
Volume of distribution at steady state (Vss)
Collection of plasma samples from pre-dose until 168 hours post-dose
Assessment of the IV PK of [14C]AZD7594 and total radioactivity
時間枠:Collection of plasma samples from pre-dose until 168 hours post-dose
Mean residence time (MRT)
Collection of plasma samples from pre-dose until 168 hours post-dose
Assessment of the inhaled PK of AZD7594
時間枠:Collection of plasma samples from pre-dose until 168 hours post-dose
The time from dosing at which Cmax was apparent (tmax)
Collection of plasma samples from pre-dose until 168 hours post-dose
Assessment of the inhaled PK of AZD7594
時間枠:Collection of plasma samples from pre-dose until 168 hours post-dose
The maximum observed plasma concentration (Cmax)
Collection of plasma samples from pre-dose until 168 hours post-dose
Assessment of the inhaled PK of AZD7594
時間枠:Collection of plasma samples from pre-dose until 168 hours post-dose
The area under the concentration-time curve from dosing to the last measurable concentration (AUClast)
Collection of plasma samples from pre-dose until 168 hours post-dose
Assessment of the inhaled PK of AZD7594
時間枠:Collection of plasma samples from pre-dose until 168 hours post-dose
The area under the concentration-time curve from dosing extrapolated to infinity (AUC0-inf)
Collection of plasma samples from pre-dose until 168 hours post-dose
Assessment of the inhaled PK of AZD7594
時間枠:Collection of plasma samples from pre-dose until 168 hours post-dose
The percentage of AUC extrapolated beyond the last measured time point(AUC%exre)
Collection of plasma samples from pre-dose until 168 hours post-dose
Assessment of the inhaled PK of AZD7594
時間枠:Collection of plasma samples from pre-dose until 168 hours post-dose
The terminal elimination rate constant calculated from the slope of the apparent elimination phase (λz)
Collection of plasma samples from pre-dose until 168 hours post-dose
Assessment of the inhaled PK of AZD7594
時間枠:Collection of plasma samples from pre-dose until 168 hours post-dose
The apparent terminal elimination half-life (t½)
Collection of plasma samples from pre-dose until 168 hours post-dose
Assessment of the inhaled PK of AZD7594
時間枠:Collection of plasma samples from pre-dose until 168 hours post-dose
Apparent total clearance (CL/F)
Collection of plasma samples from pre-dose until 168 hours post-dose
Assessment of the inhaled PK of AZD7594
時間枠:Collection of plasma samples from pre-dose until 168 hours post-dose
Apparent volume of distribution (Vz/F)
Collection of plasma samples from pre-dose until 168 hours post-dose
Assessment of the inhaled PK of AZD7594
時間枠:Collection of plasma samples from pre-dose until 168 hours post-dose
Absolute bioavailability (F)
Collection of plasma samples from pre-dose until 168 hours post-dose
Number of adverse events (AE)
時間枠:AEs recorded from the time of informed consent until discharge from the study (168 hours post-dose)
Safety and tolerability assessed through incidence of AE
AEs recorded from the time of informed consent until discharge from the study (168 hours post-dose)

協力者と研究者

ここでは、この調査に関係する人々や組織を見つけることができます。

スポンサー

協力者

捜査官

  • 主任研究者:Sharan Sidhu, MBChB, BAO, MRCS, MFPM、Quotient Sciences Limited (indemnified by

研究記録日

これらの日付は、ClinicalTrials.gov への研究記録と要約結果の提出の進捗状況を追跡します。研究記録と報告された結果は、国立医学図書館 (NLM) によって審査され、公開 Web サイトに掲載される前に、特定の品質管理基準を満たしていることが確認されます。

主要日程の研究

研究開始 (実際)

2019年6月11日

一次修了 (実際)

2019年7月5日

研究の完了 (実際)

2019年7月5日

試験登録日

最初に提出

2019年4月18日

QC基準を満たした最初の提出物

2019年6月27日

最初の投稿 (実際)

2019年6月28日

学習記録の更新

投稿された最後の更新 (実際)

2019年7月25日

QC基準を満たした最後の更新が送信されました

2019年7月24日

最終確認日

2019年7月1日

詳しくは

本研究に関する用語

その他の研究ID番号

  • D3741C00010

医薬品およびデバイス情報、研究文書

米国FDA規制医薬品の研究

いいえ

米国FDA規制機器製品の研究

いいえ

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