Assessment of cytochrome P450-mediated drug-drug interaction potential of orteronel and exposure changes in patients with renal impairment using physiologically based pharmacokinetic modeling and simulation.

Orteronel is a nonsteroidal, selective inhibitor of 17,20-lyase that was recently in phase 3 clinical development as a treatment for castration-resistant prostate cancer. In humans, the primary clearance route for orteronel is renal excretion. Human liver microsomal studies indicated that orteronel weakly inhibits CYP1A2, 2C8, 2C9 and 2C19, with IC50 values of 17.8, 27.7, 30.8 and 38.8 µm, respectively, whereas orteronel does not inhibit CYP2B6, 2D6 or 3A4/5 (IC50 > 100 µm). Orteronel also does not exhibit time-dependent inhibition of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 or 3A4/5. The results of a static model indicated an [I]/Ki ratio >0.1 for CYP1A2, 2C8, 2C9 and 2C19. Therefore, a physiologically based pharmacokinetic (PBPK) model was developed to assess the potential for drug-drug interactions (DDIs) between orteronel and theophylline, repaglinide, (S)-warfarin and omeprazole, which are sensitive substrates of CYP1A2, 2C8, 2C9 and 2C19, respectively. Simulation of the area under the plasma concentration-time curve (AUC) of these four CYP substrates in the presence and absence of orteronel revealed geometric mean AUC ratios <1.25. Therefore, in accordance with the 2012 US FDA Draft Guidance on DDIs, orteronel can be labeled a 'non-inhibitor' and further clinical DDI evaluation is not required. In PBPK models of moderate and severe renal impairment, the AUC of orteronel was predicted to increase by 52% and 83%, respectively. These results are in agreement with those of a clinical trial in which AUC increases of 38% and 87% were observed in patients with moderate and severe renal impairment, respectively.

[Isoamylases and isolipases values in the serum from patients wtih renal insufficiency]. / Valoración de isoamilasas e isolipasas en el suero de pacientes con insuficiencia renal.

OBJECTIVE: The aim of this study is to test the utility os serum isoamylases and isolipases as determined from patients with renal insufficiency. MATERIAL AND METHODS: Serum levels of isoamylases and isolipases were determined in a group of sixty-eight patients with renal disease, 32 of them suffering acute insufficiency and 36 with chronic renal failure undergoing regular hemodialysis, results obtained were compared from a population of 44 healthy adults. We used a new method for isolipases determination in serum based on its separation on agarose gel. Two forms of lipase, L1 and L2, were identified by this method and quantitated by densitometry. RESULTS: Were found a significant increase of pancreatic isoamylase P2 and P/S isoenzymatic ratio in acute patients (p < 0.001) as chronic (p < 0.05). In both groups, the isolipase L1 activity and L1/L2 isoform ratio were showed significantly elevated (p < 0.01). We studied the relationship between isoamylases and isolipases establishing the P2/L2 ratio (normal range < 0.6) showing, in the two pathologic groups, significantly elevated values compared with the control group (p < 0.001) and a positive and significant correlation between the P2/L2 and P/S isoform ratios (r = 0.76, p < 0.05 in acute patients; r = 0.58, p < 0.05 in chronic patients). CONCLUSION: The combined study of serum levels of isoamylases and isolipases could be an effective marker for diagnosis and evolution of associated pancreatitis with acute or chronic renal failure.