Pharmacokinetics and statistical analysis
A sample size of 18 evaluable patients was selected to provide
reasonable precision for the estimation of the effect of capmatinib on
pharmacokinetics of digoxin and rosuvastatin, assuming the intra-patient
coefficient of variation (CV) of digoxin (44.7%) and rosuvastatin
(31.5%). Using these intra-patient CV% estimates and a sample size of
18, the half-width of the 90% confidence intervals (CIs) for treatment
difference comparison (capmatinib + digoxin vs. digoxin alone;
capmatinib + rosuvastatin vs. rosuvastatin alone) on the log scale was
0.247 for digoxin and 0.178 for rosuvastatin. These calculations were
based on t-distribution with one-sided α-level of 0.05 and N-1 degrees
of freedom. Due to the strict evaluability criteria and the requirement
to conduct the DDI test at steady state, the total number of patients
enrolled was expected to be approximately 32.
The pharmacokinetic analysis was based on patients in the
pharmacokinetic analysis set. Three separate sets were considered; one
for each of the probe drugs (digoxin and rosuvastatin) and one for
capmatinib. For each of the probe drugs, all patients who provided an
evaluable pharmacokinetic profile for all periods (first period after
the cocktail administration and second period after administration of
cocktail + capmatinib) were included for analysis. A profile was
considered evaluable if patient received the planned dose of capmatinib
on Day 22 and at least 3 consecutive days prior to co-administration
with probe drugs; received planned dose of probe drugs, did not vomit
within 4 hours after receiving capmatinib or probe drugs and provided at
least one primary pharmacokinetic parameter (AUCinf,
AUClast, or Cmax) for probe drugs.
Pharmacokinetic analysis set for capmatinib included all patients who
provided at least one evaluable concentration for capmatinib; a
concentration was evaluable if patients received the same dose of
capmatinib at least 3 consecutive days prior to sampling, did not vomit
within 4 hours after receiving capmatinib, and had pre-dose samples
collected before the next dose administration and 9 to 15 hours after
the last dose administration.
Pharmacokinetic parameters were estimated by a non-compartmental method
using Phoenix WinNonlin 6.4 (Pharsight, Mountain View, CA). The
log-transformed pharmacokinetic parameters (AUClast,
AUCinf and Cmax) were analyzed using a
linear mixed model to assess the effect of multiple doses of capmatinib
on the pharmacokinetics of a single oral dose of each of the probe drugs
separately. The model included treatment (probe + capmatinib and probe
alone) as a fixed effect and patient as a random effect. Point estimates
of treatment differences and the corresponding 90% CIs were calculated
and anti-logged to obtain the point estimates and 90% CI for the
geometric means ratio of the probe + capmatinib versus probe alone on
the original scale.