Part D (Analyte=GSK2118436): AUC (0-tau) and AUC (0-inf) of Single and Repeat Doses of Dabrafenib Alone and in Combination With Trametinib

Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg

Participants received dabrefinib 75 mg HPMC capsules BID. These participants, after completion of serial PK collection in the first treatment period, were allowed to continue with dabrafenib 75 mg BID and trametinib 2 mg tablets QD as combination dosing starting on Day 29.

Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg

Participants received dabrefinib 150 mg HPMC capsules BID. These participants, after completion of serial PK collection in the first treatment period, were allowed to continue with dabrafenib 150 mg BID and trametinib 2 mg tablets QD as combination dosing starting on Day 29.

Part D: Dabrafenib 75 mg + Trametinib 2 mg

Participants received dabrefinib 75 mg HPMC capsules BID and trametinib 2 mg tablets QD.

Part D: Dabrafenib 150 mg + Trametinib 2 mg

Participants received dabrefinib 150 mg HPMC capsules BID and trametinib 2 mg tablets QD.

Analysis denominator · Participants

1. ci Lower Limit

   0.89

   ci Num Sides

   TWO_SIDED

   ci Pct Value

   90

   ci Upper Limit

   1.69

   estimate Comment

   Geometric mean ratio (Day 21 Dabrafenib 150 mg BID+Trametinib 2 mg QD/Day 21 Dabrafenib 150 mg BID alone) and the corresponding 90% confidence interval were provided.

   group Ids

   1. OG001
   2. OG003

   non Inferiority Comment

   Following loge transformation, AUC(0-tau) of dabrafenib was analyzed by a linear mixed effect model with dosing chort and day as fixed effects and subject as random effect. Based on the model, geometric mean ratio (Day 21 Dabrafenib 150 mg BID+Trametinib 2 mg QD/Day 21 Dabrafenib 150 mg BID alone) and the corresponding 90% confidence interval were provided.

   non Inferiority Type

   NON_INFERIORITY_OR_EQUIVALENCE

   param Type

   Geometric Mean Ratio

   param Value

   1.23

2. ci Lower Limit

   0.84

   ci Num Sides

   TWO_SIDED

   ci Pct Value

   90

   ci Upper Limit

   1.44

   estimate Comment

   Geometric mean ratio (HPMC/Gelatin) and the corresponding 90% CI were provided for BRAF dose level 150 mg BID.

   group Ids

   1. OG001
   2. OG003

   non Inferiority Comment

   Following loge tranformation, AUC(0-tau) of dabrafenib after repeat doses from the pooled data in Part B and D were analyzed by a linear model with the following fixed effects as categorical variables: Capsule type (Gelatin or HPMC), BRAF dose (75 or 150 mg BID), Capsule type by BRAF dose interaction, Day (Day 15 or 21), MEK dose (0, 1, 1.5, 2 or 2 mg QD). Geometric mean ratio (HPMC/Gelatin) and the corresponding 90% CI were then provided for BRAF dose level 150 mg BID.

   non Inferiority Type

   NON_INFERIORITY_OR_EQUIVALENCE

   param Type

   Geometric Mean Ratio

   param Value

   1.10