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 Therefore, in accordance with the 2012 US FDA Draft Guidance on DDIs, orteronel can be labeled a 'non-inhibitor' and further clinical DDI evaluation is not required.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.

Development and validation of a high-performance liquid chromatography-tandem mass spectrometry method for the determination of the novel inhibitor of angiogenesis E-3810 in human plasma and its application in a clinical pharmacokinetic study.

E-3810, 6-[[7-[(1-aminocyclopropyl)methoxy]-6-methoxy-4-quinolyl]oxy]-N-methyl-naphthalene-1-carboxamide, is a novel, potent, dual inhibitor of vascular endothelial growth factor and fibroblast growth factor receptors with antiangiogenic properties, now under early clinical evaluation as an anticancer agent. To investigate its clinical pharmacokinetics, a high-performance liquid chromatography-tandem mass spectrometry method was developed and validated to measure the drug in human plasma on the basis of simple protein precipitation with methanol after addition of deuterated E-3810 as internal standard. The method requires a small volume of sample (100 µl) and is rapid and selective, allowing good resolution of peaks in 5 min. It is sensitive, precise, and accurate, with overall precision, expressed as CV%, always ≤7.1%, accuracy in the range 92.7%-104.4%, and high recovery, close to 100%. The limit of detection is 0.01 ng/ml, and the lower limit of quantitation is 2.0 ng/ml. The assay was validated in the range from the lower limit of quantitation up to 500.0 ng/ml. This is the first method developed and validated for analyzing E-3810 in human plasma. The method has been successfully applied to study E-3810 pharmacokinetics in cancer patients with solid tumors who are receiving daily oral doses of the drug during the phase I trial.

Terbinafine quantification in human plasma by high-performance liquid chromatography coupled to electrospray tandem mass spectrometry: application to a bioequivalence study.

A method based on liquid chromatography with positive ion electrospray ionization and tandem mass spectrometry is described for the determination of terbinafine in human plasma using naftifine as internal standard. The method has a chromatographic run time of 5 minutes and was linear in the range 1.0 to 2000 ng/mL. The limit of quantification was 1.0 ng/mL; the intraday precision was 3.6%, 3.8%, 3.5%, and 4.1%; and the intraday accuracy was -2.7%, 7.7%, 4.8%, and -2.7% for 5.0, 80.0, 250.0, and 1500.0 ng/mL, respectively. The interday precision was 4.9%, 1.7%, 2.4%, and 4.6% and the interday accuracy was 0.3%, 5.8%, 6.5%, and -1.4% for the same concentrations. This method was used in a bioequivalence study of two tablet formulations of terbinafine. Twenty-four healthy volunteers (both sexes) received a single oral dose of terbinafine (250 mg) in an open, randomized, two-period crossover study. The 90% CI of geometric mean ratios between Terbinafina (Medley S/A Indústria Farmacêutica, Campinas, Brazil) and Lamisil (Novartis Biociências S/A, São Paulo, Brazil) were 90.5% to 110.0% for C max, 92.2% to 108.1% for AUC last, and 91.3% to 107.5% for AUC 0-inf. Because the 90% CI for the above-mentioned parameters were included in the 80% to 125% interval proposed by the US FDA, the two formulations were considered bioequivalent in terms of rate and extent of absorption.