Studying the metabolism of sorafenib (Nexavar®) by OATP1B blockage in adult cancer patients

Recent pre-clinical experiments demonstrated that sorafenib in Oatp1b2(-/-)
mice had 8-fold increased sorafenib-glucuronide blood concentrations. Organic
anion-transporting polypeptides (OATP) 1B1 and 1B3 are widely acknowledged as
important and rate limiting to the hepatic uptake of many therapeutic agents in
clinical use. OATP1B1 and 1B3 are highly expressed in the human liver and
facilitate the hepatocellular uptake of several substrates before metabolism
and efflux from the liver. Because sorafenib is subject to an enterohepatic
recirculation, OATP1B deficiency in human possibly results in altered sorafenib
(parent drug) concentrations. If rifampicin is used as OATP inhibiter, and not
as CYP3A4 inducer, sorafenib concentrations may increase indirectly. Therefore
we designed a mechanistic human study to evaluate the effects of blockage of
OATP1B (with rifampicin) on the pharmacokinetics of sorafenib. This study
should help to provide further insights into the variability in antitumor
activity and side effects in sorafenib-treated patients.

To determine the influence of OATP1B inhibition, through rifampicin exposure,
on the metabolism and plasma pharmacokinetics of sorafenib and its metabolites.

This is a single center, randomized cross- over pharmacokinetic study intended
to investigate the effects of OATP1B inhibition by rifampicin on the metabolism
and plasma pharmacokinetics of sorafenib and its metabolites. The study will be
performed at the Erasmus MC, Rotterdam, the Netherlands. It is anticipated that
the study will be completed within 12 months. A total of 9 evaluable patients
with solid tumors, who are treated with first- line therapy with a (stable)
daily dose of 400 mg to 800 mg sorafenib will be included in this study.
Randomization is performed to avoid bias in cycle sequence. After registration
patients will be randomized to start in arm A or arm B. Patients in study arm A
will be co-treated with a single dose of rifampicin during two days (1 tablet
of rifampicin 600 mg) after a run- in period of sorafenib for at least 14 days.
PK samples will be taken (according to table 2) as patients are hospitalized on
day 2. After a wash out period of 10 days (as t 1/2 of rifampicin is 3-5 hour,
no inhibitory effects are expected after 5 times t*; t1/2 of sorafenib is 25-48
hour, after a period of 5 times t1/2, a new steady state will be achieved), PK
samples will be taken during a clinical period on day 11. Arm B will be treated
in the opposite cycle order; first PK sampling without co-treatment with
rifampicin, followed by a second PK sampling period with co-treatment with
rifampicin. During both days of PK sampling a midazolam clearance test will be
performed, which includes administration of midazolam and PK blood sampling at
three timepoints to provide insight in CYP3A induction by rifampicin
administration.

As sorafenib has a long half-life, multiple dosing will be required to reach
steady state blood concentration. Thus sorafenib will be dosed twice daily for
14 days in the same dose prior to the start of pharmacokinetic (PK) sampling.
Sorafenib has to be taken daily without food at the same time for at least 1
week before start of the study. Rifampicin has to be taken without food as well
during the intervention period.
Genotyping samples will also be performed once during, before, or after the
study period (MEC 02.1002 protocol).
Patients will be evaluable if crucial pharmacokinetic samples are available, to
calculate the most essential pharmacokinetic parameters, and the patient has
taken the medication at the correct moment in time.

Rifampicin 600 mg once daily during two days and midazolam 2,5 mg intravenously
during two hospital admissions.

Patients do not have any individual benefit in this study. They will be
admitted for a day twice in ten days and will undergo multiple blood
withdrawals during these admissions. The risk on compliciations is negligible
during these procedures. A possible interaction between the different types of
study medication are observed carefully during the hospital admissions and are
evaluated during an interim analysis after four included patients.