NCT02621047

Effect of Hepatic Impairment on the Pharmacokinetics of Alectinib

Completed Phase 1 Results posted Last updated 24 August 2018

What this trial tests

Phase 1 trial testing Alectinib in Hepatic Impairment in 28 participants. Completed in 8 December 2016.

Timeline

4 December 2015

Primary endpoint
8 December 2016

8 December 2016

Quick facts

Lead sponsor	Hoffmann-La Roche
Phase	Phase 1
Status	Completed
Study type	INTERVENTIONAL
Allocation	non randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	28
Start date	4 December 2015
Primary completion	8 December 2016
Estimated completion	8 December 2016
Sites	2 locations across Slovakia, Czechia

Drugs / interventions tested

• Alectinib — full drug profile →

Conditions studied

• Hepatic Impairment — all drugs for Hepatic Impairment →

Sponsor

Hoffmann-La Roche — full company profile →

Who can join

Adults 18 to 70, any sex, with Hepatic Impairment. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Maximum Observed Plasma Concentration (Cmax) of Total Alectinib Primary · Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1)

Total alectinib = unbound alectinib plus alectinib bound to plasma proteins

Group	Value	95% CI
Alectinib: Moderate Hepatic Impairment	107	± 35.9
Alectinib: Normal Moderate Matched Control	83.6	± 58.4
Alectinib: Severe Hepatic Impairment	85.5	± 54.4
Alectinib: Normal Severe Matched Control	85.1	± 85.0

Cmax of Unbound Alectinib Primary · Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1)

Group	Value	95% CI
Alectinib: Moderate Hepatic Impairment	24.0	± 35.3
Alectinib: Normal Moderate Matched Control	16.2	± 38.7
Alectinib: Severe Hepatic Impairment	16.1	± 33.1
Alectinib: Normal Severe Matched Control	12.3	± 87.0

Area Under the Plasma Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUC 0-inf) for Total Alectinib Primary · Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1)

Total alectinib = unbound alectinib plus alectinib bound to plasma proteins. AUC 0-inf = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC 0-t plus AUC t-inf.

Group	Value	95% CI
Alectinib: Moderate Hepatic Impairment	2920	± 60.5
Alectinib: Normal Moderate Matched Control	1830	± 40.4
Alectinib: Severe Hepatic Impairment	3850	± 54.1
Alectinib: Normal Severe Matched Control	1750	± 64.0

AUC 0-inf for Unbound Alectinib Primary · Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1)

AUC 0-inf = AUC from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC 0-t plus AUC t-inf.

Group	Value	95% CI
Alectinib: Moderate Hepatic Impairment	659	± 60.5
Alectinib: Normal Moderate Matched Control	355	± 27.4
Alectinib: Severe Hepatic Impairment	725	± 37.8
Alectinib: Normal Severe Matched Control	254	± 70.6

Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measureable Concentration (AUC 0-last) for Total Alectinib Primary · Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1)

Total alectinib = unbound alectinib plus alectinib bound to plasma proteins

Group	Value	95% CI
Alectinib: Moderate Hepatic Impairment	2820	± 63.7
Alectinib: Normal Moderate Matched Control	1740	± 45.1
Alectinib: Severe Hepatic Impairment	3710	± 56.6
Alectinib: Normal Severe Matched Control	1630	± 74.8

AUC 0-last for Unbound Alectinib Primary · Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1)

Group	Value	95% CI
Alectinib: Moderate Hepatic Impairment	636	± 63.3
Alectinib: Normal Moderate Matched Control	337	± 31.9
Alectinib: Severe Hepatic Impairment	699	± 38.9
Alectinib: Normal Severe Matched Control	236	± 80.2

Cmax of Total Metabolite of Alectinib (M4) Secondary · Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1)

Total M4 = unbound M4 plus M4 bound to plasma proteins

Group	Value	95% CI
Alectinib: Moderate Hepatic Impairment	19.3	± 62.0
Alectinib: Normal Moderate Matched Control	29.8	± 89.3
Alectinib: Severe Hepatic Impairment	17.5	± 114
Alectinib: Normal Severe Matched Control	28.7	± 99.5

Cmax of Unbound M4 Secondary · Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1)

Group	Value	95% CI
Alectinib: Moderate Hepatic Impairment	17.6	± 51.3
Alectinib: Normal Moderate Matched Control	20.6	± 45.4
Alectinib: Severe Hepatic Impairment	8.26	± 39.6
Alectinib: Normal Severe Matched Control	14.0	± 82.7

Cmax of Total Combined Alectinib and M4 (Alectinib + M4) Secondary · Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1)

Total alectinib + M4 = unbound alectinib + M4 plus alectinib + M4 bound to plasma proteins

Group	Value	95% CI
Alectinib: Moderate Hepatic Impairment	266	± 23.3
Alectinib: Normal Moderate Matched Control	229	± 65.6
Alectinib: Severe Hepatic Impairment	214	± 61.3
Alectinib: Normal Severe Matched Control	218	± 90.5

Cmax of Unbound Alectinib + M4 Secondary · Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1)

Group	Value	95% CI
Alectinib: Moderate Hepatic Impairment	87.0	± 24.4
Alectinib: Normal Moderate Matched Control	75.9	± 39.5
Alectinib: Severe Hepatic Impairment	48.9	± 36.1
Alectinib: Normal Severe Matched Control	50.6	± 86.4

AUC 0-inf of Total M4 Secondary · Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1)

Total M4 = unbound M4 plus M4 bound to plasma proteins. AUC 0-inf = AUC from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC 0-t plus AUC t-inf.

Group	Value	95% CI
Alectinib: Moderate Hepatic Impairment	583	± 14.8
Alectinib: Normal Moderate Matched Control	718	± 70.5
Alectinib: Severe Hepatic Impairment	465	± 147
Alectinib: Normal Severe Matched Control	709	± 92.4

AUC 0-inf of Unbound M4 Secondary · Predose (0 hour), and at 1, 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, and 240 hours postdose (Dosing day = Day 1)

AUC 0-inf = AUC from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC 0-t plus AUC t-inf.

Group	Value	95% CI
Alectinib: Moderate Hepatic Impairment	516	± 27.3
Alectinib: Normal Moderate Matched Control	497	± 33.7
Alectinib: Severe Hepatic Impairment	220	± 71.1
Alectinib: Normal Severe Matched Control	345	± 77.8

Adverse events — posted to ClinicalTrials.gov

Time frame: Baseline up to Day 21. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Alectinib: Moderate Hepatic Impairment

Serious: 0/8 (0%)

Deaths: —

Alectinib: Severe Hepatic Impairment

Serious: 0/8 (0%)

Deaths: —

Alectinib: Normal Hepatic Function

Serious: 1/12 (8%)

Deaths: —

Serious adverse events (1 terms)

Reaction	System	Alectinib: Moderate Hepati…	Alectinib: Severe Hepatic …	Alectinib: Normal Hepatic …
Angina unstable	Cardiac disorders	—	—	—

Other adverse events (1 terms — click to expand)

Reaction	System	Alectinib: Moderate Hepati…	Alectinib: Severe Hepatic …	Alectinib: Normal Hepatic …
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—

Most-reported serious reactions: Angina unstable.

Data from ClinicalTrials.gov NCT02621047 adverse events section.

Sponsor's own description

This is a multicenter, non-randomized, single-dose, open-label study conducted in male and surgically sterile or post-menopausal female participants with stable chronic hepatic impairment and in healthy participants matched by age, gender, and body weight to assess the effect of hepatic impairment on the pharmacokinetics of alectinib.

Publications & conference data

2 peer-reviewed publications reference this trial (live from Europe PMC):

1. Reviewing the role of healthy volunteer studies in drug development.
   Karakunnel JJ, Bui N, Palaniappan L, Schmidt KT, et al · · 2018 · cited 33× · PMID 30509294 · DOI 10.1186/s12967-018-1710-5
2. Effect of Hepatic Impairment on the Pharmacokinetics of Alectinib.
   Morcos PN, Cleary Y, Sturm-Pellanda C, Guerini E, et al · · 2018 · cited 18× · PMID 30052269 · DOI 10.1002/jcph.1286