Effect of Moderate Hepatic Impairment on the Pharmacokinetics and Pharmacodynamics of Roxadustat, an Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor.

BACKGROUND AND OBJECTIVE: Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor in phase III development for the treatment of anaemia associated with chronic kidney disease. This study evaluated the effects of moderate hepatic impairment on roxadustat pharmacokinetics, pharmacodynamics and tolerability. METHODS: This was an open-label study in which eight subjects with moderate hepatic impairment (liver cirrhosis Child-Pugh score 7-9) and eight subjects with normal hepatic function (matched for body mass index, age and sex) received a single oral 100 mg roxadustat dose under fasted conditions. Blood samples were collected until 144 h post-dose in subjects with moderate hepatic impairment and until 96 h post-dose in subjects with normal hepatic function. RESULTS: In subjects with moderate hepatic impairment, area under the concentration-time curve (AUC) from the time of drug administration to infinity (AUC∞) and observed maximum concentration (C max) were 23 % higher [geometric least-squares mean ratio (GMR) 123 %; 90 % CI 86.1-175] and 16 % lower (GMR 83.6 %; 90 % CI 67.5-104), respectively, than in subjects with normal hepatic function. Mean terminal half-life (t ½) appeared to be longer (17.7 vs. 12.8 h) in subjects with moderate hepatic impairment, however intersubject variability on apparent total systemic clearance after single oral dosing (CL/F), apparent volume of distribution at equilibrium after oral administration (V z/F) and t ½ was approximately twofold higher. Erythropoietin (EPO) baseline-corrected AUC from administration to the last measurable EPO concentration (AUCE,last) and maximum effect (E max) were 31 % (GMR 68.95 %; 90 % CI 29.29-162.29) and 48 % (GMR 52.29 %; 90 % CI 28.95-94.46) lower, respectively, than in subjects with normal hepatic function. The single oral roxadustat dose was generally well tolerated. CONCLUSIONS: This study demonstrated the effect of moderate hepatic impairment on the pharmacokinetics and pharmacodynamics of roxadustat relative to subjects with normal hepatic function. These differences are not expected to be of clinical significance.

Pharmacokinetic Drug Interaction Studies with Enzalutamide.

BACKGROUND AND OBJECTIVES: Two phase I drug interaction studies were performed with oral enzalutamide, which is approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). METHODS: A parallel-treatment design (n = 41) was used to evaluate the effects of a strong cytochrome P450 (CYP) 2C8 inhibitor (oral gemfibrozil 600 mg twice daily) or strong CYP3A4 inhibitor (oral itraconazole 200 mg once daily) on the pharmacokinetics of enzalutamide and its active metabolite N-desmethyl enzalutamide after a single dose of enzalutamide (160 mg). A single-sequence crossover design (n = 14) was used to determine the effects of enzalutamide 160 mg/day on the pharmacokinetics of a single oral dose of sensitive substrates for CYP2C8 (pioglitazone 30 mg), CYP2C9 (warfarin 10 mg), CYP2C19 (omeprazole 20 mg), or CYP3A4 (midazolam 2 mg). RESULTS: Coadministration of gemfibrozil increased the composite area under the plasma concentration-time curve from time zero to infinity (AUC∞) of enzalutamide plus active metabolite by 2.2-fold, and coadministration of itraconazole increased the composite AUC∞ by 1.3-fold. Enzalutamide did not affect exposure to oral pioglitazone. Enzalutamide reduced the AUC∞ of oral S-warfarin, omeprazole, and midazolam by 56, 70, and 86 %, respectively; therefore, enzalutamide is a moderate inducer of CYP2C9 and CYP2C19 and a strong inducer of CYP3A4. CONCLUSIONS: If a patient requires coadministration of a strong CYP2C8 inhibitor with enzalutamide, then the enzalutamide dose should be reduced to 80 mg/day. It is recommended to avoid concomitant use of enzalutamide with narrow therapeutic index drugs metabolized by CYP2C9, CYP2C19, or CYP3A4, as enzalutamide may decrease their exposure.

Expression and induction potential of cytochromes P450 in human cryopreserved hepatocytes.

Fresh human hepatocytes are still considered as the "gold standard" to screen in vitro for cytochrome P450 (P450) induction. However, sparse availability of good quality human liver tissue for research purposes and the demand for standardized cell populations, together with the need for proper storage of the cells not immediately required, have resulted in the development of cryopreservation techniques that provide adequate viability and plateability of hepatocytes after thawing. This study aimed at validating cryopreserved human hepatocytes as a model to investigate P450 induction. Cryopreserved cells from four different donors were plated and cultured for 48 h, followed by incubation in the presence of typical P450 inducers. During the experiments, quality of the cultured cells was monitored both physiologically and morphologically. Concomitantly, the activity of CYP1A2, 2B6, 2C9, 2E1, and 3A4 was measured together with their mRNA and protein expression. Determination of CYP1A2, 2B6, 2C9, 2E1, and 3A4 activity in control versus prototypical inducer-treated hepatocytes revealed a maximal significant mean 11.6-, 2.8-, 1.9-, 1.5-, and 9.0-fold induction over their basal expression, respectively. Protein expression analysis of these P450s confirmed these results. Moreover, a mean 44.9-, 3.5-, 3.2-, and 13.8-fold induction of CYP1A2, 2B6, 2C9, and 3A4 mRNA was observed. Our data demonstrate that cryopreserved human hepatocytes are a valuable tool to study the induction of CYP1A2, 2B6, 2C9, 2E1, and 3A4.