A Study of the Hedgehog Pathway Inhibitor GDC-0449 in Healthy Female Subjects of Non-Childbearing Potential

Study Overview
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Brief Summary
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This is an open-label, Phase I, single-center, single-dose administration study to determine the absolute bioavailability, clearance, and volume of distribution of GDC-0449 (Part A) and to determine the routes of excretion and extent of metabolism of GDC-0449 (Part B). Parts A and B will be conducted sequentially, with ≥ 7 days between dosing the sixth subject in Part A and dosing the first subject in Part B. In each part, 6 healthy female subjects of non-childbearing potential, between 18 and 65 years of age (inclusive), will be dosed.

Official Title
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A Phase I, Open-Label Absorption, Distribution, Metabolism, and Excretion (ADME) Study of the Hedgehog Pathway Inhibitor GDC-0449 in Healthy Female Subjects of Non-Childbearing Potential

Conditions
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Healthy

Intervention / Treatment
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* Drug: GDC-0449 oral capsules (non-labeled)
* Drug: GDC-0449 IV injection (labeled)
* Drug: CDC-0449 oral suspension (labeled)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Female Non-childbearing potential Body mass index (BMI) between 18 and 32 kg/m^2, inclusive In good health, determined by no clinically significant findings on physical examination, medical history, 12-lead ECG, and vital signs Negative test for drugs of abuse at screening (does not include alcohol) and at admission to the clinical research facility (does include alcohol) Exclusion Criteria History or clinical manifestations of clinically significant metabolic, hepatic, renal, hematologic, pulmonary, cardiovascular, endocrine, gastrointestinal (including gastric or duodenal ulcers), urologic, neurologic, inflammatory, or psychiatric disorders, or cancer History of symptomatic hypotension, idiopathic orthostatic hypotension, or other autonomous-failure syndromes History of severe physical injury, direct impact trauma, or neurological trauma within 6 months prior to Day -1 History of stomach or intestinal surgery, stomach disease, or resection that would potentially alter absorption and/or excretion of orally administered drugs (appendectomy, hernia repair, and/or cholecystectomy are allowed) History of alcoholism, drug abuse, or drug addiction (including soft drugs like cannabis products) Use of any prescription medications/products, including known enzyme-inducing/inhibiting agents, over-the-counter medication, or other non-prescription preparations (including supplements, vitamins, minerals, phytotherapeutic/herbal/ plant-derived preparations, the tryptophans, and St. John's wort or other hypericum perforatum-containing substance) within 2 weeks prior to Day -1, with the exception of hormone-replacement therapy Participation in any other investigational drug study in which receipt of an investigational study drug occurred within 60 days prior to Day -1 or within 5 times the elimination half-life of the respective drug; participation in a trial involving administration of ^1^4C-radiolabeled compound(s) within 6 months prior to Day -1; participation in more than two other drug trials within 1 year prior to Day -1 Receipt of any vaccination or immunization within 1 month prior to Day -1 Use of any nicotine-containing or nicotine-replacement products within 6 months prior to Day -1 Consumption of alcohol or methylxanthine-containing beverages or food Receipt of blood products within 2 months prior to Day -1 Donation of > 100 mL of blood within 60 days prior to Day -1; donation of > 1.0 litres of blood within 10 months prior to Day -1 Irregular defecation pattern, i.e., less than once per 2 days within 6 months prior to Day -1; acute constipation problems within 3 weeks prior to Day -1 (Part B subjects only) Poor peripheral venous access

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>On Day 1, subjects received a single oral dose of non-labeled GDC-0449 and a single IV tracer dose of 14C-GDC-0449. | Drug: GDC-0449 oral capsules (non-labeled)<br>* 150 mg oral capsule<br>Drug: GDC-0449 IV injection (labeled)<br>* 10 mcg (in 2 mL) IV dose of 14C-GDC-0449<br>|
| Experimental: B<br>On Day 1, subjects received a single oral dose of 14C-GDC-0449. | Drug: CDC-0449 oral suspension (labeled)<br>* 30-mL oral suspension containing 6.5 mcg 14CGDC-0449 and 150 mg GDC-0449<br>|
| Experimental: C<br>On Days 1-7, subjects received a single oral dose of non-labeled GDC-0449. On Day 7, subjects also received a single IV tracer dose of 14C-GDC-0449. | Drug: GDC-0449 oral capsules (non-labeled)<br>* 150 mg oral capsule<br>Drug: GDC-0449 IV injection (labeled)<br>* 10 mcg (in 2 mL) IV dose of 14C-GDC-0449<br>|
| Experimental: D<br>On Days 1-6, subjects received a single oral dose of non-labeled GDC-0449. On Day 7, subjects received a single oral dose of 14C-GDC-0449. | Drug: GDC-0449 oral capsules (non-labeled)<br>* 150 mg oral capsule<br>Drug: CDC-0449 oral suspension (labeled)<br>* 30-mL oral suspension containing 6.5 mcg 14CGDC-0449 and 150 mg GDC-0449<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK (Max observed and time to max plasma concentrations, area under the plasma concentration-time curve, absolute bioavailability, total plasma clearance, vol of dist, plasma terminal phase half-life, cumulative % excretion in urine and feces [Part B]) |  | Until study discontinuation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety outcome measures (incidence, nature, and severity of adverse events; change in clinical laboratory results; change in vital signs; change in electrocardiogram [ECG]; and change in physical examination findings) |  | Until study discontinuation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GDC0449