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AZD6244 blue reference capsules (3 x 25 mg) administered orally

AZD6244 blue capsules (3 x 25 mg) Variant 1 (free base variant) administered orally

AZD6244 blue capsules (3 x 25 mg) Variant 2 (vitamin E polyethylene glycol succinate \[TPGS\] variant) administered orally

3 blue capsules of 25 mg given as a single dose

selumetinib 75mg single dose

3 capsules of 25 mg given as a single dose

Olufeyikemi Oluwayi, MBChB

A Study to assess, against a reference selumetinib capsule, if the drug levels of a variant of selumetinib capsule are comparable, and to assess how drug levels differed in another variant of Selumetinib in Healthy Male Volunteers.

A Study to Assess the Relative Bioavailability of Process Variants of Selumetinib in Healthy Male Volunteers

A Phase I, Single Centre, Randomised, Open Label, Crossover Study to Assess the Bioequivalence or Relative Bioavailability of Variants of Selumetinib (AZD6244, Hyd-Sulfate) Blue Capsules in Healthy Male Volunteers Aged 18 to 45 Years

The bioequivalence of the free base variant of selumetinib (Treatment B) as compared to the blue reference capsule (Treatment A) was evaluated by comparing the maximum observed plasma concentration (Cmax) of selumetinib in healthy volunteers.

The bioequivalence of the free base variant of selumetinib (Treatment B) as compared to the blue reference capsule (Treatment A) was evaluated by comparing the area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC) of selumetinib in healthy volunteers.

The bioequivalence of the free base variant of selumetinib (Treatment B) as compared to the blue reference capsule (Treatment A) was evaluated by comparing the AUC from time zero to the time of the last quantifiable concentration (AUC\[0-t\]) of selumetinib in healthy volunteers.

The relative bioavailability of the TPGS capsule variant of selumetinib (Treatment C) as compared to the blue reference capsule (Treatment A) was evaluated by comparing the Cmax of selumetinib in healthy volunteers.

The relative bioavailability of the TPGS capsules variant of selumetinib (Treatment C) as compared to the blue reference capsule (Treatment A) was evaluated by comparing the AUC of selumetinib in healthy volunteers.

The relative bioavailability of the TPGS capsule variant of selumetinib (Treatment C) as compared to the blue reference capsule (Treatment A) was evaluated by comparing the AUC\[0-t\] of selumetinib in healthy volunteers.

The PK of the metabolite N-desmethyl selumetinib was evaluated by assessing the Cmax of the metabolite in healthy volunteers after oral administration of single doses of the blue reference capsule (Treatment A), the free base variant capsule (Treatment B) and the TPGS variant capsule (Treatment C).

The PK of the metabolite N-desmethyl selumetinib was evaluated by assessing the AUC(0-t) of the metabolite in healthy volunteers after oral administration of single doses of the blue reference capsule (Treatment A), the free base variant capsule (Treatment B) and the TPGS variant capsule (Treatment C).

AstraZeneca

Visits 2, 3 and 4 comprised 3 separate treatment periods with a washout period of 7 - 10 days between administrations.

Subjects received 75 mg selumetinib (3 x 25 mg blue reference capsules) administered as a single oral dose on Day 1 of each period according to their treatment sequence under fasted conditions (10 hours prior to administration).

Treatment A: Selumetinib Blue Reference Capsules

Subjects received 75 mg selumetinib (3 x 25 mg free base variant capsules) administered as a single oral dose on Day 1 of each period according to their treatment sequence under fasted conditions (10 hours prior to administration).

Treatment B: Selumetinib Blue Free Base Variant Capsules

Subjects received 75 mg selumetinib (3 x 25 mg vitamin E polyethylene glycol succinate \[TPGS\] variant capsules) administered as a single oral dose on Day 1 of each period according to their treatment sequence under fasted conditions (10 hours prior to administration).

Treatment C: Selumetinib Blue TPGS Variant Capsules

All subjects received at least 1 dose of selumetinib. Subjects were randomised in a crossover fashion to receive 1 of 3 treatments during each treatment period: Period 1=Visit 2; Period 2=Visit 3; Period 3=Visit 4.

Overall Study

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

All randomized subjects (n = 48) were included in the baseline analysis

Information Centre

The Pharmacokinetic (PK) analysis set included all healthy subjects who received at least 1 dose of selumetinib and had at least 1 post-dose PK measurement without important protocol deviations/violations or events significantly affecting the PK.

Bioequivalence of the Free Base Variant of Selumetinib (Treatment B) Compared to the Blue Reference Capsule (Treatment A) [Selumetinib Cmax]

The PK analysis set included all healthy subjects who received at least 1 dose of selumetinib and had at least 1 post-dose PK measurement without important protocol deviations/violations or events significantly affecting the PK.

Bioequivalence of the Free Base Variant of Selumetinib (Treatment B) Compared to the Blue Reference Capsule (Treatment A) [Selumetinib AUC]

Bioequivalence of the Free Base Variant of Selumetinib (Treatment B) Compared to the Blue Reference Capsule (Treatment A) [Selumetinib AUC(0-t)]

Relative Bioavailability of the TPGS Capsule Variant (Treatment C) Compared to the Blue Reference Capsule (Treatment A) [Selumetinib Cmax]

Relative Bioavailability of the TPGS Capsule Variant (Treatment C) Compared to the Blue Reference Capsule (Treatment A) [Selumetinib AUC]

Relative Bioavailability of the TPGS Capsule Variant (Treatment C) Compared to the Blue Reference Capsule (Treatment A) [Selumetinib AUC(0-t)]

The PK of the Metabolite N-desmethyl Selumetinib by Assessment of Cmax

The PK of N-desmethyl Selumetinib by Assessment of the AUC(0-t)

Subjects randomized to treatment sequences ABC: A=Selumetinib Blue Reference Capsules; B=Selumetinib Blue Free Base Variant Capsules; C=Selumetinib Blue TPGS Variant Capsules. Subjects received 75 mg selumetinib (3 x 25 mg capsules) administered as a single oral dose on Day 1 of each period according to their treatment sequence under fasted conditions (10 hours prior to administration) in a crossover fashion. There was a washout period of 7-10 days between administrations.

Sequence ABC

Subjects randomized to treatment sequences ACB: A=Selumetinib Blue Reference Capsules; C=Selumetinib Blue TPGS Variant Capsules; B=Selumetinib Blue Free Base Variant Capsules. Subjects received 75 mg selumetinib (3 x 25 mg capsules) administered as a single oral dose on Day 1 of each period according to their treatment sequence under fasted conditions (10 hours prior to administration) in a crossover fashion. There was a washout period of 7-10 days between administrations.

Sequence ACB

Subjects randomized to treatment sequences BAC: B=Selumetinib Blue Free Base Variant Capsules; A=Selumetinib Blue Reference Capsules; C=Selumetinib Blue TPGS Variant Capsules. Subjects received 75 mg selumetinib (3 x 25 mg capsules) administered as a single oral dose on Day 1 of each period according to their treatment sequence under fasted conditions (10 hours prior to administration) in a crossover fashion. There was a washout period of 7-10 days between administrations.

Sequence BAC

Subjects randomized to treatment sequences BCA: B=Selumetinib Blue Free Base Variant Capsules; C=Selumetinib Blue TPGS Variant Capsules; A=Selumetinib Blue Reference Capsules. Subjects received 75 mg selumetinib (3 x 25 mg capsules) administered as a single oral dose on Day 1 of each period according to their treatment sequence under fasted conditions (10 hours prior to administration) in a crossover fashion. There was a washout period of 7-10 days between administrations.

Sequence BCA

Subjects randomized to treatment sequences CAB: C=Selumetinib Blue TPGS Variant Capsules; A=Selumetinib Blue Reference Capsules; B=Selumetinib Blue Free Base Variant Capsules. Subjects received 75 mg selumetinib (3 x 25 mg capsules) administered as a single oral dose on Day 1 of each period according to their treatment sequence under fasted conditions (10 hours prior to administration) in a crossover fashion. There was a washout period of 7-10 days between administrations.

Sequence CAB

Subjects randomized to treatment sequences CBA: C=Selumetinib Blue TPGS Variant Capsules; B=Selumetinib Blue Free Base Variant Capsules; A=Selumetinib Blue Reference Capsules. Subjects received 75 mg selumetinib (3 x 25 mg capsules) administered as a single oral dose on Day 1 of each period according to their treatment sequence under fasted conditions (10 hours prior to administration) in a crossover fashion. There was a washout period of 7-10 days between administrations.

Spots Global Cancer Trial Database for A Study to Assess the Relative Bioavailability of Process Variants of Selumetinib in Healthy Male Volunteers

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