NCT01072175 · OUTCOME

Part D (Analyte=GSK2118436): Maximum Plasma Concentration (Cmax) of a Single and Repeat Dose of Dabrafenib Alone and in Combination With Trametinib

Investigate Safety, Pharmacokinetics and Pharmacodynamics of GSK2118436 & GSK1120212 · Source last updated 2019-07-05

Results reported by the registry submitting party. Population, time horizon, units and missing values must be read together.

Measure: GEOMETRIC_MEAN
Unit: ng/mL
Interval / dispersion: 95% Confidence Interval
Time frame: Day 1 and Day 21

What was measured

The PK parameter Cmax was assessed. Blood samples for PK analysis of dabrafenib were obtained at pre-dose Day 1 and Day 21 pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours (24 hour on Day 1 only) post-dose administration. From the plasma concentration-time curve, the PK parameter tmax was determined by standard non-compartmental analysis using WinNonlin. Cmax data are reported as geometric least squares means.

Analysis population: PK Population: all participants who received at least one dose of either dabrafenib or trametinib and for whom a PK sample was obtained and analyzed

Groups in this outcome

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.

Group identifiers and denominators belong to this outcome only. They may differ in another outcome or in safety reporting.

Analysis denominator · Participants

Group	Source count
Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg	15
Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg	14
Part D: Dabrafenib 75 mg + Trametinib 2 mg	15
Part D: Dabrafenib 150 mg + Trametinib 2 mg	15

Reported measurements

Day 1

Values in ng/mL · Interval/dispersion: 95% Confidence Interval
Group	Value	Spread	Lower	Upper	Comment
Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg	1117	Not reported	914	1365	Not reported
Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg	1669	Not reported	1059	2631	Not reported
Part D: Dabrafenib 75 mg + Trametinib 2 mg	1227	Not reported	924	1764	Not reported
Part D: Dabrafenib 150 mg + Trametinib 2 mg	2289	Not reported	1622	3231	Not reported

Day 21

Values in ng/mL · Interval/dispersion: 95% Confidence Interval
Group	Value	Spread	Lower	Upper	Comment
Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg	1050	Not reported	811	1358	Not reported
Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg	1746	Not reported	1344	2269	Not reported
Part D: Dabrafenib 75 mg + Trametinib 2 mg	1217	Not reported	895	1654	Not reported
Part D: Dabrafenib 150 mg + Trametinib 2 mg	2052	Not reported	1472	2860	Not reported

Source statistical analyses

Group order, estimate direction, methods and comments are retained. No treatment ranking is inferred.

ci Lower Limit
1.10
ci Num Sides
TWO_SIDED
ci Pct Value
90
ci Upper Limit
2.08
estimate Comment
Geometric mean ratio (HPMC/Gelatin) and the corresponding 90% CI were provided for BRAF dose level 150 mg BID.
group Ids
OG001
OG003
non Inferiority Comment
Following loge tranformation, Cmax 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 or 2 mg QD). Geometric mean ratio (HPMC/Gelatin) and the corresponding 90% CI were provided for BRAF dose level 150 mg BID.
non Inferiority Type
NON_INFERIORITY_OR_EQUIVALENCE
param Type
Geometric Mean Ratio
param Value
1.51

Complete source fields

analyses

ci Lower Limit
1.10
ci Num Sides
TWO_SIDED
ci Pct Value
90
ci Upper Limit
2.08
estimate Comment
Geometric mean ratio (HPMC/Gelatin) and the corresponding 90% CI were provided for BRAF dose level 150 mg BID.
group Ids
OG001
OG003
non Inferiority Comment
Following loge tranformation, Cmax 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 or 2 mg QD). Geometric mean ratio (HPMC/Gelatin) and the corresponding 90% CI were provided for BRAF dose level 150 mg BID.
non Inferiority Type
NON_INFERIORITY_OR_EQUIVALENCE
param Type
Geometric Mean Ratio
param Value
1.51

classes

categories
measurements
group Id
OG000
lower Limit
914
upper Limit
1365
value
1117
group Id
OG001
lower Limit
1059
upper Limit
2631
value
1669
group Id
OG002
lower Limit
924
upper Limit
1764
value
1227
group Id
OG003
lower Limit
1622
upper Limit
3231
value
2289
title
Day 1
categories
measurements
group Id
OG000
lower Limit
811
upper Limit
1358
value
1050
group Id
OG001
lower Limit
1344
upper Limit
2269
value
1746
group Id
OG002
lower Limit
895
upper Limit
1654
value
1217
group Id
OG003
lower Limit
1472
upper Limit
2860
value
2052
title
Day 21

denoms

counts
group Id
OG000
value
15
group Id
OG001
value
14
group Id
OG002
value
15
group Id
OG003
value
15
units
Participants

description

dispersion Type

95% Confidence Interval

groups

description
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.
id
OG000
title
Part D: Dabrafenib (DAB) 75 mg to DAB 75 mg + Trametinib 2 mg
description
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.
id
OG001
title
Part D: Dabrafenib 150 mg to DAB 150 mg + Trametinib 2 mg
description
Participants received dabrefinib 75 mg HPMC capsules BID and trametinib 2 mg tablets QD.
id
OG002
title
Part D: Dabrafenib 75 mg + Trametinib 2 mg
description
Participants received dabrefinib 150 mg HPMC capsules BID and trametinib 2 mg tablets QD.
id
OG003
title
Part D: Dabrafenib 150 mg + Trametinib 2 mg

param Type

GEOMETRIC_MEAN

population Description

PK Population: all participants who received at least one dose of either dabrafenib or trametinib and for whom a PK sample was obtained and analyzed

reporting Status

POSTED

time Frame

Day 1 and Day 21

title

Part D (Analyte=GSK2118436): Maximum Plasma Concentration (Cmax) of a Single and Repeat Dose of Dabrafenib Alone and in Combination With Trametinib

type

PRIMARY

unit Of Measure

ng/mL

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Preserved source evidence · Independent clinical review pending · Not medical advice