An intervention study of the effects of probenecid on the pharmacokinetics and pharmacodynamics of sorafenib (PROSORA-study)

In oncology, the last two decades have seen a transition from the use of
traditional cytotoxic chemotherapy to the emergence of a new paradigm in
rational drug design coupled with an uprising in the development of targeted
agents, including the kinase inhibitors. However, while kinase inhibitors
possibly offer a number of important theoretical advantages over conventional
cytotoxic chemotherapy, they are still afflicted by some of the same problems,
including an extensive interindividual pharmacokinetic variability, the
existence of a rather narrow therapeutic window, and the occurrence of
multiple, debilitating adverse events.

Cutaneous adverse effects are among the most frequently observed toxicities
with many kinase inhibitors, and their intensity can significantly affect both
quality of life and health care economics. A particularly painful complication
seen most frequently during the early weeks of use with multikinase inhibitors
(MKIs), such as sorafenib, sunitinib, and pazopanib, is called hand-foot skin
reaction (HFSR), in which hyperkeratotic plaques develop predominantly over
sites of pressure or friction. These plaques may have significant inflammation
and xerotic hyperkeratosis, often in a bilateral symmetric distribution,
causing pain and debilitation that interfere with activities of daily living.
Sequential biopsy specimens have revealed progressive accumulation of
hyperkeratosis with focal parakeratosis. The clinical incidence of HFSR varies
among MKIs with a particularly high incidence being observed with sorafenib
and does not appear to be related to increased excretion of MKIs through
sweat.


Sorafenib is an orally administered MKI with activity against VEGFR-2, VEGFR-3,
Flt-3, RAF-1 and c-KIT. Phase III clinical trials demonstrated the efficacy of
sorafenib in advanced hepatocellular carcinoma, advanced renal cell carcinoma
as well as iodine-refractory advanced thyroid cancer. After oral
administration sorafenib undergoes CYP3A4 mediated oxidation into its active
metabolite (pyridine-N-oxide) and UGT1A9-mediated glucuronidation into
sorafenib glucoronide. Sorafenib is eliminated for 77% via the feces of which
51% as unchanged drugs. Excretion of glucuronidated metabolites in urine
accounts for 19% of the total elimination.


The pathogenesis of MKI-induced HFSR remains currently unknown, and the only
demonstrably effective treatment options involve dose reduction or
discontinuation of therapy, which have negative effects on disease
management.(7, 8) Furthermore, sorafenib can extensively accumulate into human
epidermal keratinocytes mediated by the organic anion transporter SLC22A20
(OAT6). In vivo research in mice demonstrated that this effect can be reversed
by cotreatment with the OAT6 inhibitor probenecid.
Probenecid is a uricosuric agent indicated for the maintenance treatment of
hyperuricemia associated with gout and gouty arthritis. Sometimes it is used as
an adjuvant for therapy with certain antibiotics as penicillin, ampicillin or
methicillin, because it elevates and prolongs their plasma levels. Probenecid
is usually well tolerated in a dose of 500 mg two times daily and is normally
taken for (many) months. Probenecid also acts as a pan-UGT inhibitor by
inhibiting multiple UDP-glucuronosyltransferase enzymes (UGT1A1, 1A6, 1A7, 1A9,
1A10, 2B7) and therefore potentially could influence sorafenib
pharmacokinetics. The extent of this effect is not yet determined in clinical
studies.

In this study we therefore want to study the safety and pharmacokinetics (PK)
of sorafenib when concomitantly used with probenecid by human objects. If no PK
interactions are observed, this pharmacotherapeutic intervention may provide a
potential treatment strategy for sorafenib-induced HFSR. As a secondary
endpoint we therefore want to look at the incidence of all-grade HFSR and
intracellular concentration of sorafenib in skin.

To demonstrate the bioequivalence of sorafenib with probenecid relative to
sorafenib without probenecid based on the AUC in patients with unresectable
hepatocellular cancer, advanced clear-cell renal cell carcinoma, locally
recurrent or metastatic, progressive, differentiated thyroid carcinoma
refractory to radioactive iodine treatment.

Secondary outcomes are:
1. Other pharmacokinetic outcomes (i.e. clearance, maximum concentration
(Cmax), Maximum steady-state concentration (Cmaxss), Minimal concentration
(Cmin), steady-state volume of distribution (Vss) and half-life (t*)).
2. To evaluate the incidence and severity of side-effects of treatment with
sorafenib in absence and presence of probenecid (in particular HFSR) .
3. To evaluate the intracellular concentration of sorafenib in skin in patients
treated with sorafenib in absence and presence of probenecid.
4. To determine the influence of HFSR on quality of life.

This is a non-randomized, single-center, prospective pharmacokinetic
interventional drug-drug interaction cohort study in patients taking probenecid
and sorafenib to evaluate the pharmacokinetics (PK) and safety of sorafenib
concomitantly used with probenecid in patients with histologically or
cytologically confirmed diagnosis of metastatic renal cell carcinoma,
hepatocellular carcinoma or differentiated thyroid carcinoma. This study will
be performed at the Erasmus MC Cancer Institute in Rotterdam, The Netherlands.
It is anticipated that
sorafenib treatment must have been initiated at least 7 days prior to start of
the study, but no longer than 14 days. to ensure steady-state concentration of
sorafenib during the study period. It is anticipated that the study will be
completed within 12-18 months after approval of the ethical board

Patients will be admitted to the hospital for pharmacokinetic (PK) blood
sampling at Day 1. During this admission blood samples are drawn up to 12 hours
after start of sorafenib administration and a single biopsy of the skin will be
performed. 12 hours after start of sorafenib PK sampling patients will start
with oral administration of probenecid. Patients will be re-admitted to the
hospital for a second PK sampling at Day 15. If patients have given consent for
an additional skin biopsy an extra biopsy of the skin of the hand or an active
HFSR lesion will be performed for pathologic grading.

Probenecid concomitant with sorafenib during 2 consecutive weeks

Patients will be admitted to the hospital for 12 hours on two different PK
days, during which 9 pharmacokinetic blood withdrawals and one biopsy will be
performed. Patients do not benefit individually from this study. Risks to be
expected are *normal* side effects of sorafenib and probenecid for which
patients will be carefully observed .