Simultaneous physiologically-based pharmacokinetic (PBPK) modeling of parent and active metabolites to investigate complex CYP3A4 drug-drug interaction potential: a case example of midostaurin

Midostaurin (PKC412) is being investigated for the treatment of acute myeloid leukemia (AML) and advanced systemic mastocytosis (ASM). It is extensively metabolized by cytochrome P450 (CYP) 3A4 to form 2 major active metabolites, CGP52421 and CGP62221. In vitro and clinical drug-drug interaction (DDI) studies indicated that midostaurin and its metabolites are substrates, reversible and time-dependent inhibitors, and inducers of CYP3A4. A simultaneous pharmacokinetic model of parent and active metabolites was initially developed by incorporating data from in vitro, preclinical, and clinical pharmacokinetic studies in healthy volunteers and in patients with AML or ASM. The model reasonably predicted changes in midostaurin exposure after single-dose administration with ketoconazole (5.8-fold predicted increase vs 6.1-fold observed) and rifampicin (90% predicted reduction vs 94% observed), as well as changes in midazolam exposure (1.0 predicted ratio vs 1.2 observed) with midostaurin after daily dosing for four days. The qualified model was then applied to predict the DDI effect with other CYP3A4 inhibitors/inducers as well as DDI potential with midazolam under steady-state conditions. The simulated midazolam AUC ratio of 0.54 and the accompanying 1.9-fold increase in the CYP3A4 activity biomarker, 4β-hydroxycholesterol, indicated a weak-to-moderate CYP3A4 induction by midostaurin and its metabolites at steady-state in ASM patients. In conclusion, a simultaneous parent and metabolite modeling approach allowed predictions under steady-state conditions that were not possible to achieve in healthy subjects. Furthermore, endogenous biomarker data enabled evaluation of the net effect of midostaurin and its metabolites on CYP3A4 activity at steady-state and increased confidence in DDI predictions

Safety, tolerability and anti-tumour activity of the androgen biosynthesis inhibitor ASP9521 in patients with metastatic castration-resistant prostate cancer : multi-centre phase I/II study

BACKGROUND: ASP9521 is a first-in-class orally available inhibitor of the enzyme 17 β-hydroxysteroid dehydrogenase type 5 (17 βHSD5; AKR1C3), catalysing the conversion of dehydroepiandrosterone and androstenedione into 5-androstenediol and testosterone. It has demonstrated anti-tumour activity in in vitro and in vivo preclinical models. MATERIAL AND METHODS: This first-in-man phase I/II study utilised a 3 + 3 dose escalation design starting at 30 mg ASP9521/day, with the aim of defining a maximum tolerated dose, as defined by the incidence of dose-limiting toxicities. Eligible patients received ASP9521 orally for 12 weeks. Safety, tolerability, pharmacokinetics (PK), pharmacodynamics and anti-tumour activity were assessed. RESULTS: Thirteen patients (median age: 68 years; range 52-76) with metastatic castration-resistant prostate cancer (mCRPC) progressing after chemotherapy were included; 12 patients discontinued treatment at or before week 13, mainly due to disease progression. The most common adverse events were grade 1/2 and included asthenia (N = 5), constipation (N = 4), diarrhoea (N = 3), back pain (N = 3) and cancer pain (N = 3). PK demonstrated a half-life (t1/2) ranging from 16 to 35 h, rapid absorption and dose proportionality. No biochemical or radiological responses were identified; neither endocrine biomarker levels nor circulating tumour cell counts were altered by ASP9521. Given the lack of observable clinical activity, the study was terminated without implementing a planned 12-week dose expansion part at selected doses or a planned food-effect study part. CONCLUSIONS: In patients with mCRPC, ASP9521 demonstrated dose-proportional increase in exposure over the doses evaluated, with an acceptable safety and tolerability profile. However, the novel androgen biosynthesis inhibitor showed no relevant evidence of clinical activity