An Absolute Bioavailability Study in Healthy Participants Comparing Oral to Intravenous Administration of GDC-0973 (Cobimetinib)
4 avril 2017 mis à jour par: Genentech, Inc.
A Phase 1, Single Dose, Randomized, Cross-over Absolute Bioavailability Study in Healthy Subjects Comparing Oral to Intravenous Administration of GDC-0973
The primary objective of Part 1 of this study is to evaluate the safety and tolerability of the intravenous (IV) dose of GDC-0973.
The primary objectives of Part 2 of this study are to evaluate the absolute bioavailability of GDC-0973 and to evaluate the pharmacokinetic (PK) of GDC-0973 following IV and oral administration.
The secondary objective of Part 2 of this study is to evaluate the safety of GDC-0973 administered orally and intravenously.
Aperçu de l'étude
Statut
Complété
Les conditions
Intervention / Traitement
Type d'étude
Interventionnel
Inscription (Réel)
13
Phase
- La phase 1
Critères de participation
Les chercheurs recherchent des personnes qui correspondent à une certaine description, appelée critères d'éligibilité. Certains exemples de ces critères sont l'état de santé général d'une personne ou des traitements antérieurs.
Critère d'éligibilité
Âges éligibles pour étudier
18 ans à 55 ans (Adulte)
Accepte les volontaires sains
Oui
Sexes éligibles pour l'étude
Tout
La description
Inclusion Criteria
- Within body mass index range 18.5 to 29.9 kilograms per square meter (kg/m^2)
- In good health, determined by no clinically significant findings from medical history, 12-lead electrocardiogram (ECG), and vital signs
- Clinical laboratory evaluations within the reference range for the test laboratory
- Negative test for selected drugs of abuse at Screening and at each Check-in
- Negative hepatitis panel and anti-hepatitis C virus and negative human immunodeficiency virus (HIV) antibody screens
- Healthy males and females of non-child-bearing potential or who agree to use effective contraception
Exclusion Criteria
- Significant history or clinical manifestation of any significant metabolic, allergic, dermatological, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, neurological, or psychiatric disorder
- History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance
- History of stomach or intestinal surgery or resection that would potentially alter absorption and/or excretion of orally administered drugs except that appendectomy, hernia repair, and cholecystectomy will be allowed
- History or presence of an abnormal ECG
- History of alcoholism or drug addiction prior to period 1 check-in
- Use of any tobacco-containing or nicotine-containing products prior to period 1 check-in
- Participation in any other investigational study drug trial in which receipt of an investigational study drug occurred within 28 days or 5 half-lives, whichever is longer, prior to period 1 check-in
- Use of any prescription medications/products, including proton pump inhibitors, within 14 days prior to period 1 check-in
- Poor peripheral venous access
- Any acute or chronic condition that would limit the participants ability to complete and/or participate in this clinical study
- Female participant is pregnant, lactating, or breastfeeding
- Predisposing factors to retinal vein occlusion (RVO)
Plan d'étude
Cette section fournit des détails sur le plan d'étude, y compris la façon dont l'étude est conçue et ce que l'étude mesure.
Comment l'étude est-elle conçue ?
Détails de conception
- Objectif principal: Science basique
- Répartition: Randomisé
- Modèle interventionnel: Affectation croisée
- Masquage: Aucun (étiquette ouverte)
Armes et Interventions
Groupe de participants / Bras |
Intervention / Traitement |
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Expérimental: Part 1: GDC-0973 IV Infusion First, Then GDC-0973 Capsules
Participants will receive single dose of GDC-0973 2 milligrams (mg) IV infusion in first intervention period followed by single dose of GDC-0973 20 mg oral capsules (four 5-mg capsules) in second intervention period.
The washout period between each period will be a minimum of 10 days.
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IV infusion.
Autres noms:
Oral dose.
Autres noms:
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Expérimental: Part 2: GDC-0973 IV Infusion First, Then GDC-0973 Capsules
Participants will receive single dose of GDC-0973 2 mg IV infusion in first intervention period followed by single dose of GDC-0973 20 mg oral capsules (four 5-mg capsules) in second intervention period.
The washout period between each period will be a minimum of 10 days.
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IV infusion.
Autres noms:
Oral dose.
Autres noms:
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Expérimental: Part 2: GDC-0973 Capsules First, Then GDC-0973 IV Infusion
Participants will receive single dose of GDC-0973 20 mg oral capsules (four 5-mg capsules) in first intervention period followed by single dose of GDC-0973 2 mg IV infusion in second intervention period.
The washout period between each period will be a minimum of 10 days.
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IV infusion.
Autres noms:
Oral dose.
Autres noms:
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Que mesure l'étude ?
Principaux critères de jugement
Mesure des résultats |
Description de la mesure |
Délai |
|---|---|---|
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Maximum Observed Plasma Concentration (Cmax) of IV and Oral GDC-0973
Délai: Part 2: 0 hours (Hrs) (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
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Part 2: 0 hours (Hrs) (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
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Dose Normalized Cmax [Cmax(dn)] of IV and Oral GDC-0973
Délai: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
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Cmax(dn) is Cmax divided by dose.
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Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
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Minimum Observed Plasma Trough Concentration (Cmin) of IV and Oral GDC-0973
Délai: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
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Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
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Time to Reach Maximum Observed Plasma Concentration (Tmax) of IV and Oral GDC-0973
Délai: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
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Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
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Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-t)] of IV and Oral GDC-0973
Délai: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
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AUC (0-t)= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-t).
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Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
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Dose Normalized AUC (0-t) [AUC (0-t)dn] of IV and Oral GDC-0973
Délai: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
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AUC (0-t)= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-t).
AUC (0-t)dn is AUC (0-t) divided by dose.
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Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
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Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] of IV and Oral GDC-0973
Délai: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
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AUC (0 - ∞)= Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0 - ∞).
It is obtained from AUC (0 - t) plus AUC (t - ∞).
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Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
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Dose Normalized AUC (0 - ∞) [AUC (0 - ∞)dn] of IV and Oral GDC-0973
Délai: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
|
AUC (0 - ∞)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞).
It is obtained from AUC (0 - t) plus AUC (t - ∞).
AUC (0 - ∞)dn is AUC(0 - ∞) divided by dose.
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Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
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Plasma Decay Half-Life (t1/2) of IV and Oral GDC-0973
Délai: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
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t1/2 is the time measured for the plasma concentration of GDC-0973 to decrease by one half.
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Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
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Systemic Clearance (CL) of IV GDC-0973
Délai: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
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CL is a quantitative measure of the rate at which a drug substance is removed from the body.
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Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
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Apparent Oral Clearance (CL/F) of Oral GDC-0973
Délai: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
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Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.
Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed.
Clearance was estimated from population PK modelling.
Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
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Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
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Volume of Distribution at Steady State (Vss) of IV GDC-0973
Délai: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose of Day 1
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Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug.
Vss is the apparent volume of distribution at steady-state.
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Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose of Day 1
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Apparent Volume of Distribution (Vz/F) of Oral GDC-0973
Délai: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
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Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.
Vz/F is influenced by the fraction absorbed.
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Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
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Absolute Oral Bioavailability (F) of GDC-0973
Délai: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
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Absolute oral bioavailability is the amount of drug from a formulation that reaches the systemic circulation relative to an IV dose.
F = [AUC (0-∞), oral multiplied by Dose IV] divided by [AUC (0-∞), IV multiplied by Dose oral].
Absolute oral bioavailability is determined for drugs which are administered orally.
IV dose is 100% in systemic circulation (dosed directly) and hence no estimation is required.
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Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
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Mean Absorption Time (MAT)
Délai: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
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MAT is mean time required for the drug to reach the central compartment.
MAT was estimated from the mean resident time (MRT) from oral and IV administration.
MAT was calculated as MRT last of oral dose minus MRT last of IV dose.
MAT is analyzed when drug is administered orally (only for non-IV routes of administration).
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Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1
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Amount of Drug Excreted in the Urine (Aeu) of IV and Oral GDC-0973
Délai: Part 2: 0 to 12, 12 to 24, 24 to 48, 48 to 72, and 72 to 96 Hrs post-dose on Day 1
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The cumulative amount of drug excreted in urine over the entire collection interval of 96 hrs was calculated by adding the Aeu of the intervals 0 to 12, 12 to 24, 24 to 48, 48 to 72, and 72 to 96 hrs where Aeu was calculated by multiplying the urine volume within the collection interval by the associated drug concentration.
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Part 2: 0 to 12, 12 to 24, 24 to 48, 48 to 72, and 72 to 96 Hrs post-dose on Day 1
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Renal Clearance (CLR) of IV and Oral GDC-0973
Délai: Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1 for plasma; 0 to 12, 12 to 24, 24 to 48, 48 to 72, and 72 to 96 Hrs post-dose for urine
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CLR was calculated as Aeu divided by AUC (0 - ∞), where Aeu was amount of drug excreted in urine from time 0 to 96 hrs post-dose and AUC(0 - ∞) was area under the concentration-time curve of the analyte in plasma over the time interval from zero extrapolated to infinity hrs post-dose.
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Part 2: 0 Hrs (pre-dose), 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 144, and 192 Hrs post-dose on Day 1 for plasma; 0 to 12, 12 to 24, 24 to 48, 48 to 72, and 72 to 96 Hrs post-dose for urine
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Percent of GDC-0973 Excreted in the Urine (% Excreted) for IV and Oral GDC-0973
Délai: Part 2: 0 to 12, 12 to 24, 24 to 48, 48 to 72, and 72 to 96 Hrs post-dose
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% Excreted is the mean percentage of dose recovery in urine and calculated as: (Aeu divided by dose) multiplied by 100, where Aeu was amount of drug excreted in urine from time 0 to 96 hrs post-dose.
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Part 2: 0 to 12, 12 to 24, 24 to 48, 48 to 72, and 72 to 96 Hrs post-dose
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Collaborateurs et enquêteurs
C'est ici que vous trouverez les personnes et les organisations impliquées dans cette étude.
Parrainer
Les enquêteurs
- Directeur d'études: Isabelle Rooney, M.D., PhD, Genentech, Inc.
Dates d'enregistrement des études
Ces dates suivent la progression des dossiers d'étude et des soumissions de résultats sommaires à ClinicalTrials.gov. Les dossiers d'étude et les résultats rapportés sont examinés par la Bibliothèque nationale de médecine (NLM) pour s'assurer qu'ils répondent à des normes de contrôle de qualité spécifiques avant d'être publiés sur le site Web public.
Dates principales de l'étude
Début de l'étude
1 novembre 2010
Achèvement primaire (Réel)
1 janvier 2011
Achèvement de l'étude (Réel)
1 janvier 2011
Dates d'inscription aux études
Première soumission
24 novembre 2010
Première soumission répondant aux critères de contrôle qualité
24 novembre 2010
Première publication (Estimation)
29 novembre 2010
Mises à jour des dossiers d'étude
Dernière mise à jour publiée (Réel)
10 mai 2017
Dernière mise à jour soumise répondant aux critères de contrôle qualité
4 avril 2017
Dernière vérification
1 avril 2017
Plus d'information
Termes liés à cette étude
Autres numéros d'identification d'étude
- MEK4952g
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