Cancer Chemotherapy and Pharmacology (2018) 81:529–537
Eﬀects of posaconazole (a strong CYP3A4 inhibitor), two new tablet
formulations, and food on the pharmacokinetics of idasanutlin,
an MDM2 antagonist, in patients with advanced solid tumors
· Annie Young
· Samuel Ejadi
· Wilson Miller
· Lin‑Chi Chen
· Gwen Nichols
· Steven Blotner
· Jianguo Zhi
· Albiruni Razak
Received: 22 December 2017 / Accepted: 10 January 2018 / Published online: 24 January 2018
© Springer-Verlag GmbH Germany, part of Springer Nature 2018
Purpose Idasanutlin, a selective small-molecule MDM2 antagonist in phase 3 testing for refractory/relapsed AML, is a
non-genotoxic oral p53 activator. To optimize its dosing conditions, a number of clinical pharmacology characteristics were
examined in this multi-center trial in patients with advanced solid tumors.
Method This was an open-label, single-dose, crossover clinical pharmacology study investigating the eﬀects of strong
CYP3A4 inhibition with posaconazole (Part 1), two new oral formulations (Part 2), as well as high-energy/high-fat and low-
energy/low-fat meals (Part 3) on the relative bioavailability of idasanutlin. After completing Part 1, 2, or 3, patients could have
participated in an optional treatment with idasanutlin. Clinical endpoints were pharmacokinetics (PK), pharmacodynamics
(PD) of MIC-1 elevation (Part 1 only), and safety/tolerability.
Results The administration of posaconazole 400 mg BID × 7 days with idasanutlin 800 mg resulted in a slight decrease
(7%) in C
and a modest increase (31%) in AUC for idasanutlin, a marked reduction in C
(~ 60%) and AUC0 (~ 50%)
for M4 metabolite, and a minimal increase (~ 24%) in serum MIC-1 levels. C
and AUC were both 45% higher for the
SDP formulation. While the low-fat meal caused a less than 20% increase in all PK exposure parameters with the 90% CI
values just outside the upper end of the equivalence criteria (80–125%), the high-fat meal reached bioequivalence with dos-
ing under fasting.
Conclusion In patients with solid tumors, multiple doses of posaconazole, a strong CYP3A4 inhibitor, minimally aﬀected
idasanutlin PK and PD without clinical signiﬁcance. The SDP formulation improved rBA/exposures by ~ 50% without major
Keywords Idasanutlin · MDM2 antagonist · Drug–drug interaction · Food eﬀect · Formulation change · External factors
Cancer remains a major cause of morbidity and mortality
worldwide despite recent successes with drugs providing
survival beneﬁt to patients. There remains a high unmet
medical need for new, eﬀective, and safe treatments that can
be used in all phases of cancer treatment.
The tumor suppressor gene encoded by the TP53 gene (p53)
plays a pivotal role in protection from cancer development.
It is a transcription factor that is activated following cellular
stress and regulates multiple downstream genes implicated
in cell cycle control, apoptosis, DNA repair, and senescence.
In non-stressed cells, the level of p53 is controlled tightly by
murine double minute-2 (MDM2). However, in cancer cells
overexpressing MDM2, this feedback loop is dysregulated.
* Jianguo Zhi
Mary Crowley Cancer Research Center, Dallas, TX, USA
Roche Innovation Center of Welwyn, Welwyn Garden City,
Scottsdale Healthcare Hospitals DBA HonorHealth,
Scottsdale, AZ, USA
Jewish General Hospital/McGill University, Montreal,
Roche Innovation Center of New York, New York,
NY 10016, USA
Medical Oncology and Haematology, Princess Margaret
Hospital, Toronto, Canada