Afatinib in Subjects With Kidney Dysfunction

Pharmacokinetics, Safety and Tolerability After Single Dose Administration of Afatinib in Moderate and Severe Renal Impairment in Comparison to Subjects With Normal Renal Function (a Mono-centric, Open-label Study in Matched-group Design)

The primary objective of the current study is to investigate the influence of moderate to severe renal impairment on the pharmacokinetics and safety of a single dose afatinib in comparison to a control group with normal renal function.

The assessment of safety and tolerability will be an additional objective of this trial and will be evaluated by descriptive statistics.

Study Overview

• Status: Completed
• Conditions: Renal Insufficiency
• Intervention / Treatment: Drug: Afatinib moderate renally impaired; Drug: Afatinib severe renally impaired; Drug: Afatinib healthy

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Kiel, Germany
    • 1200.216.1 Boehringer Ingelheim Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 79 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion criteria:

• Despite renal impairment (group 1 and 2) healthy males or females according to the investigators assessment, as based on the following criteria: a complete medical history including a physical examination, vital signs (Blood Pressure (BP), Pulse Rate (PR)), 12-lead Electrocardiogram (ECG), and clinical laboratory tests.

• Glomerular filtration rate (GFR), estimated according to:

  -- MDRD (Modification of Diet in Renal Disease)-formula:

  • eGFR (estimated Glomerular Filtration Rate) [ml/min/1.73m²]= 175 x Serum Creatinine-1.154 x age-0.203 (if male)
  • eGFR[ml/min/1.73m²]= 175 x Serum Creatinine-1.154 x age-0.203 x 0.742 (if female)
  • 30 to 59 mL/min for moderate renal impairment group 1
  • 15 to 29 mL/min for severe renal impairment group 2
  • = 90 mL/min for healthy volunteers group 3
• Age =18 and =79 years

Exclusion criteria:

• Any finding of the medical examination (including Blood Pressure (BP), Pulse Rate (PR) and Electrocardiogram (ECG)) deviating from normal and of clinical relevance, e.g. repeated measurement of systolic blood pressure < 90 mmHg (millimeter of mercury) or > 140 mmHg, diastolic blood pressure < 50 mmHg or > 90 mmHg, repeated measurement of pulse rate < 45 bpm (beats per minute) or > 90 bpm.
• Any evidence of a clinically relevant concomitant disease.
• Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological, dermatological or hormonal disorders.
• Relevant gastrointestinal tract surgery (except appendectomy).
• Diseases of the central nervous system (such as epilepsy, seizures) or psychiatric disorders or neurological disorders.
• History of photosensitivity or recurrent rash.
• Diseases of the central nervous system (such as epilepsy) or psychiatric disorders or neurological disorders.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Afatinib in moderate renal impaired; Single Dose Afatinib in moderate renal impaired subjects	Drug: Afatinib moderate renally impaired
Experimental: Afatinib in severe renal impaired; Single Dose Afatinib in severe renal impaired subjects	Drug: Afatinib severe renally impaired
Other: Afatinib in healthy subjects; Single Dose Afatinib in healthy subjects matched by gender, race, age and BMI to moderate and severe renal impaired subjects	Drug: Afatinib healthy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC 0-tz of Afatinib (BIBW 2992)	Area under the concentration-time curve of the analyte in plasma over the time interval from 0 up to the last quantifiable data point	PK plasma samples were taken at: 1 hour before drug administration and 0.5 hour (h), 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 192h, 240h, 312h after first drug administration
Cmax of Afatinib (BIBW 2992)	Maximum measured concentration of the analyte in plasma	PK plasma samples were taken at: 1 hour before drug administration and 0.5 hour (h), 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 192h, 240h, 312h after first drug administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC 0-inf of Afatinib (BIBW 2992)	Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity	PK plasma samples were taken at: 1 hour before drug administration and 0.5 hour (h), 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 12h, 24h, 36h, 48h, 60h, 72h, 96h, 120h, 144h, 192h, 240h, 312h after first drug administration

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

General Publications

• Wiebe S, Schnell D, Kulzer R, Gansser D, Weber A, Wallenstein G, Halabi A, Conrad A, Wind S. Influence of Renal Impairment on the Pharmacokinetics of Afatinib: An Open-Label, Single-Dose Study. Eur J Drug Metab Pharmacokinet. 2017 Jun;42(3):461-469. doi: 10.1007/s13318-016-0359-9.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: May 1, 2014
• Primary Completion (Actual): December 1, 2014
• Study Completion (Actual): December 1, 2014

Study Registration Dates

• First Submitted: March 24, 2014
• First Submitted That Met QC Criteria: March 24, 2014
• First Posted (Estimate): March 26, 2014

Study Record Updates

• Last Update Posted (Estimate): January 14, 2016
• Last Update Submitted That Met QC Criteria: December 9, 2015
• Last Verified: November 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Renal Insufficiency; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Afatinib
• Other Study ID Numbers: 1200.216; 2013-004825-98 (EudraCT Number: EudraCT)