Purpose VS-6063 (also known as defactinib or PF-04554878) is a second-generation inhibitor of focal adhesion kinase and proline-rich tyrosine kinase-2. This phase 1 study evaluated the safety and tolerability, pharmacokinetics, and clinical activity of VS-6063 in Japanese subjects with advanced solid tumor malignancies in a first-in-Asian study setting.MethodsVS-6063 was administered orally twice daily (b.i.d.) in 21-day cycles to cohorts of three subjects each with a standard 3 + 3 dose-escalation design until disease progression or unacceptable toxicity. Blood samples for pharmacokinetics were collected on Day 1 and 15. The assessments were performed using CTCAE v4.0 for adverse events (AEs), and the Response Evaluation Criteria In Solid Tumors, version v1.1 (RECIST v1.1) for tumor response.ResultsNine patients were treated across three dose levels (200–600 mg BID). No dose-limiting toxicities were observed at any dose level. Most frequent treatment-related AEs were Grade 1/2 unconjugated hyperbilirubinemia, fatigue, decreased appetite, and diarrhea. Only one subject in the 200 mg BID cohort experienced reversible and transient Grade 3 unconjugated hyperbilirubinemia. PK analyses confirmed that the exposure at the recommended Phase 2 dose (RP2D) of 400 mg BID was comparable with exposures previously reported in non-Japanese subjects. Durable stable disease of approximately 24 weeks was confirmed in two subjects (malignant mesothelioma and rectal cancer).ConclusionsVS-6063 was well tolerated at all dose levels investigated in this first-in-Asian study. These data support the administration of VS-6063 to Japanese subjects at the RP2D in clinical trials involving solid tumor malignancies.
Ivacaftor is approved in the USA for the treatment of cystic fibrosis (CF) in patients with a G551D-CFTR mutation or one of eight other CFTR mutations. A series of in vitro experiments conducted early in the development of ivacaftor indicated ivacaftor and metabolites may have the potential to inhibit cytochrome P450 (CYP) 2C8, CYP2C9, CYP3A, and CYP2D6, as well as P-glycoprotein (P-gp). Based on these results, a series of clinical drug-drug interaction (DDI) studies were conducted to evaluate the effect of ivacaftor on sensitive substrates of CYP2C8 (rosiglitazone), CYP3A (midazolam), CYP2D6 (desipramine), and P-gp (digoxin). In addition, a DDI study was conducted to evaluate the effect of ivacaftor on a combined oral contraceptive, as this is considered an important comedication in CF patients. The results indicate ivacaftor is a weak inhibitor of CYP3A and P-gp, but has no effect on CYP2C8 or CYP2D6. Ivacaftor caused non-clinically significant increases in ethinyl estradiol and norethisterone exposure. Based on these results, caution and appropriate monitoring are recommended when concomitant substrates of CYP2C9, CYP3A and/or P-gp are used during treatment with ivacaftor, particularly drugs with a narrow therapeutic index, such as warfarin.
Vadadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor in development for the treatment of anemia of chronic kidney disease. This phase 1, open-label, parallel-group, single-dose study evaluated the pharmacokinetics of 450mg vadadustat in adults with moderate hepatic impairment (Child-Pugh class B) vs those with normal hepatic function. Primary end points were area under the plasma concentration-time curve (AUC) from dosing to last concentration and to infinity, as well as maximum concentration (C max ); additional pharmacokinetic parameters included time to C max (T max ) and half-life. Safety and tolerability were also assessed. All enrolled participants (n = 16) completed the study. Demographics were similar in both groups (overall, 100% White; 62.5% female; mean age, 59.2 years). Vadadustat plasma exposure was higher in the moderate hepatic impairment group, whereas maximum concentration was similar between groups. Point estimates of the hepatic impairment : normal geometric mean ratios (90% confidence interval) for AUC from dosing to last concentration, AUC from dosing to infinity, and C max were 1.05 (0.82-1.35), 1.06 (0.82-1.36), and 1.02 (0.79-1.32), respectively. Mean elimination half-life was 5.8 and 7.8 hours in the normal and hepatic impairment groups, respectively. Treatment-emergent adverse events were mostly mild in severity, and vadadustat was generally well tolerated. In conclusion, moderate hepatic impairment did not significantly impact vadadustat systemic exposure, and mild hepatic impairment is unlikely to alter vadadustat exposure.
Background Patients with rheumatoid arthritis (RA) often receive multiple medications to manage the signs and symptom of comorbidities. It is therefore important to understand the potential for drug-drug interactions (DDI). VX-509 is an oral selective JAK3 inhibitor being evaluated for the treatment of RA. In vitro studies suggested that VX-509 was a potential inhibitor of transporter P-glycoprotein (P-gp) and that VX-509 had an inactive metabolite that inhibited CYP3A4, a major drug-metabolizing enzyme. Midazolam, a sensitive CYP3A4 substrate, and digoxin, a substrate of P-gp, are commonly used as probes to study DDI potential of CYP3A4 and P-gp inhibitors, respectively. Objectives To assess the drug-drug interactions between VX-509 and midazolam, digoxin, atorvastatin, pravastatin, rosuvastatin, prednisone and methyl-prednisolone. Methods Ninety-eight healthy male and female volunteers were enrolled into 7 groups (N=14 per group). A single oral dose of midazolam (2 mg), digoxin (0.5 mg), atorvastatin (10 mg), rosuvastatin (20 mg), pravastatin (40 mg), prednisone (10 mg), and methyl-prednisolone (8 mg) was given alone and together with VX-509 200 mg once daily (QD) at steady state. Full pharmacokinetic profiles of these drugs were obtained with and without co-administration of VX-509. Geometric least-squares mean (GLSM) ratios (and associated 90% confidence intervals) of AUC and Cmax of the substrates with/without co-administration of VX-509 were calculated to evaluate the level of interaction. Results VX-509 increased the AUC for midazolam, atorvastatin, and methyl-prednisolone by 12.0-, 2.7-, and 4.3-fold, respectively. VX-509 did not affect the exposure of digoxin, rosuvastatin, pravastatin, and prednisone to a clinically meaningful degree (Table). The drug was generally well tolerated. Conclusions The increase in exposure of midazolam when given with VX-509 suggests that VX-509's major metabolite is a strong CYP3A4 inhibitor in humans. Dose modifications of certain medicines commonly used in patients with RA (e.g. atorvastatin and methyl-prednisolone) or restrictions of certain medicines (e.g. p.o. midazolam) may therefore be required with VX-509. No dose adjustment would be needed for prednisone, or for pravastatin and rosuvastatin. The absence of an effect on digoxin exposure by VX-509 indicates that no dose adjustments are needed for P-gp substrates. Disclosure of Interest : J. Huang Employee of: Vertex Pharmaceuticals Incorporated, A. Chavan Employee of: Vertex Pharmaceuticals Incorporated, L. Viswanathan Employee of: Vertex Pharmaceuticals Incorporated, X. Luo Employee of: Vertex Pharmaceuticals Incorporated, V. Garg Employee of: Vertex Pharmaceuticals Incorporated, Y. Zhang Employee of: Vertex Pharmaceuticals Incorporated, Y. Xi Employee of: Vertex Pharmaceuticals Incorporated, N. Kinnman Employee of: Vertex Pharmaceuticals Incorporated, L. Mahnke Employee of: Vertex Pharmaceuticals Incorporated DOI 10.1136/annrheumdis-2014-eular.1184
Vadadustat is a hypoxia-inducible factor prolyl-hydroxylase inhibitor being developed for the treatment of anemia in patients with chronic kidney disease. Sequelae of chronic kidney disease include hyperphosphatemia and anemia, which are frequently treated with phosphate binders and iron supplements, respectively. Two studies evaluating the pharmacokinetics, safety, and tolerability of a single oral dose of vadadustat coadministered with a phosphate binder or iron supplement were conducted in healthy adult participants. In study 1, 54 healthy women and men were administered vadadustat (300 mg) alone and 1 hour before, concurrently with, or 2 hours after a phosphate binder (sevelamer carbonate 1600 mg, calcium acetate 1334 mg, or ferric citrate 2000 mg). In study 2, 10 healthy men were administered vadadustat (450 mg) alone and concomitantly with the oral iron supplement ferrous sulfate (325 mg [equivalent to 65 mg of elemental iron]). Vadadustat exposure was reduced by coadministration with sevelamer carbonate, calcium acetate, ferric citrate, or ferrous sulfate. Geometric least squares mean ratios for area under the concentration-time curve from time 0 to infinity were reduced 37% to 55% by phosphate binders and 46% by ferrous sulfate. However, when vadadustat was administered 1 hour before phosphate binders, 90% confidence intervals for vadadustat exposure were within the no-effect boundaries of +50% to -33%, indicating that drug-drug interactions can be reduced by administering vadadustat 1 hour before phosphate binders. Vadadustat was well tolerated when administered in conjunction with phosphate binders or an iron supplement.
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