The Experts below are selected from a list of 4368 Experts worldwide ranked by ideXlab platform
Alexandra D Carides - One of the best experts on this subject based on the ideXlab platform.
-
a phase 3 randomized double blind study of single dose fosAprepitant for prevention of cisplatin induced nausea and vomiting results of an indian population subanalysis
Indian Journal of Cancer, 2013Co-Authors: Anish Maru, V P Gangadharan, C J Desai, R K Mohapatra, Alexandra D CaridesAbstract:Context: Currently, there is limited data on the prevention of chemotherapy-induced nausea and vomiting (CINV) in Indian patients. Aims: This post hoc study assessed the efficacy and safety of fosAprepitant compared with Aprepitant for prevention of CINV in the Indian population. A subgroup analysis was performed from data collected in a phase 3 study of intravenous (IV) fosAprepitant or oral Aprepitant, plus the 5-HT 3 antagonist ondansetron and the corticosteroid dexamethasone, in cisplatin-naοve patients with solid malignancies. Materials and Methods: Patients scheduled to receive cisplatin (≥70 mg/m 2 ) were administered a single IV dose of fosAprepitant dimeglumine (150 mg) on day 1 or a 3-day dosing regimen of oral Aprepitant (day 1:125 mg, days 2 and 3:80 mg) with standard doses of ondansetron and dexamethasone. Patients recorded nausea and/or vomiting episodes and their use of rescue medication and were monitored for adverse events (AEs) and tolerability. Statistical Analysis Used: Differences in response rates between fosAprepitant and Aprepitant were calculated using the Miettinen and Nurminen method. Results: In the Indian subpopulation ( n = 372), efficacy was similar for patients in both the fosAprepitant or Aprepitant groups; complete response in the overall, acute, and delayed phases and no vomiting in all phases were approximately 4 percentage points higher in the fosAprepitant group compared with the Aprepitant group. FosAprepitant was generally well-tolerated; common AEs were similar to oral Aprepitant. Conclusions: IV fosAprepitant is as safe and effective as oral Aprepitant in the Indian subpopulation and offers an alternative to the oral formulation.
-
single dose fosAprepitant for the prevention of chemotherapy induced nausea and vomiting associated with cisplatin therapy randomized double blind study protocol ease
Journal of Clinical Oncology, 2011Co-Authors: Steven M Grunberg, Anish Maru, Suzanne Devandry, Judith A Boice, James Hardwick, Elizabeth Beckford, Arlene Taylor, Daniel Chua, Jose Dinis, Alexandra D CaridesAbstract:Purpose Addition of Aprepitant, a neurokinin-1 receptor antagonist (NK1RA), to an ondansetron and dexamethasone regimen improves prevention of chemotherapy-induced nausea/vomiting (CINV), particularly during the delayed phase (DP; 25 to 120 hours). Therefore, recommended antiemetic regimens include multiple-day NK1RA administration. Preliminary data suggested that single-dose Aprepitant before chemotherapy could provide CINV protection throughout the overall risk phase (OP; 0 to 120 hours). This study compared a 3-day oral Aprepitant schedule to a regimen containing a single dose of the intravenous NK1RA fosAprepitant. Patients and Methods A randomized, double-blind, active-control design was used to test whether fosAprepitant is noninferior to Aprepitant. Patients receiving cisplatin ≥ 70 mg/m2 for the first time received ondansetron and dexamethasone with a standard Aprepitant regimen (125 mg on day 1, 80 mg on day 2, 80 mg on day 3) or a single-dose fosAprepitant regimen (150 mg on day 1). The primary ...
-
Aprepitant in adolescent patients for prevention of chemotherapy induced nausea and vomiting a randomized double blind placebo controlled study of efficacy and tolerability
Pediatric Blood & Cancer, 2009Co-Authors: Lia Gore, Alexandra D Carides, Suzanne Devandry, Arlene Taylor, Sant P Chawla, A Petrilli, Molly Hemenway, D Schissel, J Valentine, Judith K EvansAbstract:Background The neurokinin-1 receptor antagonist Aprepitant, plus a 5HT3 antagonist and corticosteroid is well-tolerated and effective in preventing chemotherapy-induced nausea and vomiting in adults but has not been formally assessed in adolescents. Procedure Patients age 11–19 years old receiving emetogenic chemotherapy were randomized 2:1 to Aprepitant triple therapy (Aprepitant [A] 125 mg p.o., dexamethasone [D] 8 mg p.o., and ondansetron [O] 0.15 mg/kg i.v. t.i.d. day 1; A 80 mg, D 4 mg, and O 0.15 mg/kg t.i.d. day 2; A 80 mg and D 4 mg day 3; and D 4 mg day 4) or a control regimen (D 16 mg and O 0.15 mg/kg t.i.d. day 1; D 8 mg and O 0.15 mg/kg t.i.d. day 2; and D 8 mg days 3 and 4). The primary endpoint was the difference in drug-related adverse events during and for 14 days following treatment. Efficacy and Aprepitant pharmacokinetics were assessed. Results Baseline characteristics were similar between Aprepitant (N = 28) and control (N = 18) groups. Febrile neutropenia was more frequent in the Aprepitant group (25% vs. 11.1%). Complete response (CR) rates were 35.7% for Aprepitant triple therapy versus 5.6% for the control group. Mean plasma Aprepitant AUC0–24 hr and Cmax on day 1 and mean trough concentrations on days 2 and 3 were consistently lower compared to historical data obtained from healthy adults; however, the differences were not clinically significant. Conclusion Aprepitant triple therapy was generally well tolerated; CR were greater with Aprepitant, although not statistically significant. Pharmacokinetics suggest that the adult dosing regimen is appropriate for adolescents. Pediatr Blood Cancer 2009;52:242–247. © 2008 Wiley-Liss, Inc.
-
single dose Aprepitant vs ondansetron for the prevention of postoperative nausea and vomiting a randomized double blind phase iii trial in patients undergoing open abdominal surgery
BJA: British Journal of Anaesthesia, 2007Co-Authors: Pierre Diemunsch, Alexandra D Carides, Tong J. Gan, Beverly K Philip, Manoel Joao Batista Castello Girao, L H J Eberhart, M G Irwin, J Pueyo, Jacques E Chelly, T ReissAbstract:Background The neurokinin1 antagonist Aprepitant is effective for prevention of chemotherapy-induced nausea and vomiting. We compared Aprepitant with ondansetron for prevention of postoperative nausea and vomiting. Methods Nine hundred and twenty-two patients receiving general anaesthesia for major abdominal surgery were assigned to receive a single preoperative dose of oral Aprepitant 40 mg, oral Aprepitant 125 mg, or i.v. ondansetron 4 mg in a randomized, double-blind trial. Vomiting episodes, use of rescue therapy, and nausea severity (verbal rating scale) were documented for 48 h after surgery. Primary efficacy endpoints were complete response (no vomiting and no use of rescue therapy) 0–24 h after surgery and no vomiting 0–24 h after surgery. The secondary endpoint was no vomiting 0–48 h after surgery. Results Aprepitant at both doses was non-inferior to ondansetron for complete response 0–24 h after surgery (64% for Aprepitant 40 mg, 63% for Aprepitant 125 mg, and 55% for ondansetron, lower bound of 1-sided 95% CI > 0.65), superior to ondansetron for no vomiting 0–24 h after surgery (84% for Aprepitant 40 mg, 86% for Aprepitant 125 mg, and 71% for ondansetron; P Conclusions Aprepitant was non-inferior to ondansetron in achieving complete response for 24 h after surgery. Aprepitant was significantly more effective than ondansetron for preventing vomiting at 24 and 48 h after surgery, and in reducing nausea severity in the first 48 h after surgery. Aprepitant was generally well tolerated.
-
a randomized double blind comparison of the nk1 antagonist Aprepitant versus ondansetron for the prevention of postoperative nausea and vomiting
Anesthesia & Analgesia, 2007Co-Authors: Christian C Apfel, Alexandra D Carides, Beverly K Philip, Anthony L Kovac, Neil Singla, Harold S Minkowitz, Ashraf S Habib, Jennifer Knighton, Hong Zhang, Kevin J HorganAbstract:BACKGROUND: Antiemetics currently in use are not totally effective. Neurokinin-1 receptor antagonists are a new class of antiemetic that have shown promise for chemotherapy-induced nausea and vomiting. This is the first study evaluating the efficacy and tolerability of the neurokinin-1 receptor antagonist, Aprepitant, for the prevention of postoperative nausea and vomiting. METHODS: In this multicenter, double-blind trial, we randomly assigned 805 patients receiving general anesthesia for open abdominal surgery to a preoperative dose of Aprepitant 40 mg orally, Aprepitant 125 mg orally, or ondansetron 4 mg IV. Vomiting, nausea, and use of rescue therapy were assessed over 48 h after surgery. Treatments were compared using logistic regression. RESULTS: Incidence rates for the primary end point (complete response [no vomiting and no use of rescue] over 0-24 h after surgery, tested for superiority of Aprepitant) were not different across groups (45% with Aprepitant 40 mg, 43% with Aprepitant 125 mg, and 42% with ondansetron). The incidence of no vomiting (0-24 h) was higher with Aprepitant 40 mg (90%) and Aprepitant 125 mg (95%) versus ondansetron (74%) (P < 0.001 for both comparisons), although between-treatment use of rescue and nausea control was not different. Both Aprepitant doses also had higher incidences of no vomiting over 0-48 h (P < 0.001). No statistically significant differences were seen among the side effect profiles of the treatments. CONCLUSIONS: Aprepitant was superior to ondansetron for prevention of vomiting in the first 24 and 48 h, but no significant differences were observed between Aprepitant and ondansetron for nausea control, use of rescue, or complete response.
Nicole R Leboeuf - One of the best experts on this subject based on the ideXlab platform.
-
Aprepitant for refractory cutaneous t cell lymphoma associated pruritus 4 cases and a review of the literature
BMC Cancer, 2017Co-Authors: Johanna S Song, Marianne Tawa, Nicole G Chau, Thomas S Kupper, Nicole R LeboeufAbstract:Aprepitant is an FDA-approved medication for chemotherapy-induced nausea and vomiting. It blocks substance P binding to neurokinin-1; substance P has been implicated in itch pathways both as a local and global mediator. We report a series of four patients, diagnosed with cutaneous T-cell lymphoma, who experienced full body pruritus recalcitrant to standard therapies. All patients experienced rapid symptom improvement (within days) following Aprepitant treatment. Aprepitant has been shown in small studies to be efficacious for treating chronic and malignancy-associated pruritus. Prior studies have shown no change in clinical efficacy of chemotherapeutics with concurrent Aprepitant administration. These cases further demonstrate that Aprepitant can be considered as a therapeutic option in malignancy-associated pruritus and further support the need for larger clinical trials.
-
Aprepitant for refractory cutaneous T-cell lymphoma-associated pruritus: 4 cases and a review of the literature
BMC Cancer, 2017Co-Authors: Johanna S Song, Marianne Tawa, Nicole G Chau, Thomas S Kupper, Nicole R LeboeufAbstract:Background Aprepitant is an FDA-approved medication for chemotherapy-induced nausea and vomiting. It blocks substance P binding to neurokinin-1; substance P has been implicated in itch pathways both as a local and global mediator. Case presentations We report a series of four patients, diagnosed with cutaneous T-cell lymphoma, who experienced full body pruritus recalcitrant to standard therapies. All patients experienced rapid symptom improvement (within days) following Aprepitant treatment. Conclusion Aprepitant has been shown in small studies to be efficacious for treating chronic and malignancy-associated pruritus. Prior studies have shown no change in clinical efficacy of chemotherapeutics with concurrent Aprepitant administration. These cases further demonstrate that Aprepitant can be considered as a therapeutic option in malignancy-associated pruritus and further support the need for larger clinical trials.
Koichiro Tsugawa - One of the best experts on this subject based on the ideXlab platform.
-
infusion site adverse events in breast cancer patients receiving highly emetic chemotherapy with prophylactic anti emetic treatment with Aprepitant and fosAprepitant a retrospective comparison
Current Opinion in Clinical Nutrition and Metabolic Care, 2016Co-Authors: Takashi Tsuda, Chisato Kyomori, Takuro Mizukami, Tomoko Taniyama, Yoshiki Horie, Mami Hirakawa, Takako Eguchi Nakajima, Naoki Izawa, Takashi Ogura, Koichiro TsugawaAbstract:The incidences of infusion site adverse events in chemotherapy regimens, including anthracyclines with either fosAprepitant or Aprepitant as the anti-emetic, were not highlighted in the randomized trial comparing Aprepitant and fosAprepitant. The present retrospective analysis was performed in breast cancer patients receiving anthracycline-containing chemotherapy, a combination of epirubicin and cyclophosphamide with or without 5-fluorouracil as the adjuvant or neoadjuvant, at the outpatient infusion center of St. Marianna University Hospital (Kawasaki, Japan). Infusion site adverse events were retrospectively compared between the 3 months prior to and three months following switching from 3 day oral administration of Aprepitant to intravenous infusion of fosAprepitant. A total of 62 patients were included in the Aprepitant group and 38 in the fosAprepitant group. Of these patients, 26 (42%) in the Aprepitant group and 36 patients (96%) in the fosAprepitant group experienced any grade of infusion site adverse events at least once (P<0.001). As an anti-emetic treatment for chemotherapy using anthracyclines, fosAprepitant may be associated with a higher risk of infusion site adverse events compared with Aprepitant.
-
Infusion site adverse events in breast cancer patients receiving highly emetic chemotherapy with prophylactic anti‑emetic treatment with Aprepitant and fosAprepitant: A retrospective comparison
Molecular and Clinical Oncology, 2016Co-Authors: Takashi Tsuda, Chisato Kyomori, Takuro Mizukami, Tomoko Taniyama, Yoshiki Horie, Mami Hirakawa, Takako Eguchi Nakajima, Naoki Izawa, Takashi Ogura, Koichiro TsugawaAbstract:The incidences of infusion site adverse events in chemotherapy regimens, including anthracyclines with either fosAprepitant or Aprepitant as the anti-emetic, were not highlighted in the randomized trial comparing Aprepitant and fosAprepitant. The present retrospective analysis was performed in breast cancer patients receiving anthracycline-containing chemotherapy, a combination of epirubicin and cyclophosphamide with or without 5-fluorouracil as the adjuvant or neoadjuvant, at the outpatient infusion center of St. Marianna University Hospital (Kawasaki, Japan). Infusion site adverse events were retrospectively compared between the 3 months prior to and three months following switching from 3 day oral administration of Aprepitant to intravenous infusion of fosAprepitant. A total of 62 patients were included in the Aprepitant group and 38 in the fosAprepitant group. Of these patients, 26 (42%) in the Aprepitant group and 36 patients (96%) in the fosAprepitant group experienced any grade of infusion site adverse events at least once (P
Sjoerd Rodenhuis - One of the best experts on this subject based on the ideXlab platform.
-
Aprepitant inhibits cyclophosphamide bioactivation and thiotepa metabolism
Cancer Chemotherapy and Pharmacology, 2005Co-Authors: Milly E. De Jonge, Alwin D. R. Huitema, Jos H. Beijnen, Marjo J. Holtkamp, Sjoerd RodenhuisAbstract:Background : Patients receiving the highly emetogenic high-dose chemotherapy regimen with cyclophosphamide, thiotepa and carboplatin (CTC) may benefit from the neurokin-1 receptor antagonist Aprepitant in addition to standard anti-emetic therapy. As Aprepitant has been shown to be a moderate inhibitor of the cytochrome P450 (CYP) 3A4 isoenzyme, its effect on the pharmacokinetics and metabolism of cyclophosphamide and thiotepa was evaluated. Moreover, preliminary results on the clinical efficacy of Aprepitant in the CTC regimen are reported. Patients and methods : Six patients were enrolled in a protocol that employed a 4-day course of CTC high-dose chemotherapy with cyclophosphamide (1,500 mg/m^2/day), thiotepa (120 mg/m^2/day) and carboplatin (AUC 5 mg min/ml/day). Two patients received the tCTC protocol, which comprises two-third of the dose of CTC. In addition to standard anti-emetic therapy, the patients received Aprepitant from one day before the start of their course until 3 days after chemotherapy. Blood samples were collected on days one and three of the course and analyzed for cyclophosphamide and its activated metabolite 4-hydroxycyclophosphamide, thiotepa and its main active metabolite tepa. The influence of Aprepitant on the pharmacokinetics of cyclophosphamide and thiotepa was analyzed using a population pharmacokinetic analysis including a reference population of 49 patients receiving the same chemotherapy regimen without Aprepitant and sampled under the same conditions. The frequency of nausea and vomiting in the six patients receiving CTC was compared with those of the last 22 consecutive patients receiving CTC chemotherapy without Aprepitant. Inhibitory activity of Aprepitant on cyclophosphamide and thiotepa metabolism was also tested in human liver microsomes. Results : In our patient population, the rate of autoinduction of cyclophosphamide ( P =0.040) and the formation clearance of tepa ( P
-
Aprepitant inhibits cyclophosphamide bioactivation and thiotepa metabolism
Cancer Chemotherapy and Pharmacology, 2005Co-Authors: Milly E. De Jonge, Alwin D. R. Huitema, Jos H. Beijnen, Marjo J. Holtkamp, Selma M Van Dam, Sjoerd RodenhuisAbstract:Background: Patients receiving the highly emetogenic high-dose chemotherapy regimen with cyclophosphamide, thiotepa and carboplatin (CTC) may benefit from the neurokin-1 receptor antagonist Aprepitant in addition to standard anti-emetic therapy. As Aprepitant has been shown to be a moderate inhibitor of the cytochrome P450 (CYP) 3A4 isoenzyme, its effect on the pharmacokinetics and metabolism of cyclophosphamide and thiotepa was evaluated. Moreover, preliminary results on the clinical efficacy of Aprepitant in the CTC regimen are reported. Patients and methods: Six patients were enrolled in a protocol that employed a 4-day course of CTC high-dose chemotherapy with cyclophosphamide (1,500 mg/m2/day), thiotepa (120 mg/m2/day) and carboplatin (AUC 5 mg min/ml/day). Two patients received the tCTC protocol, which comprises two-third of the dose of CTC. In addition to standard anti-emetic therapy, the patients received Aprepitant from one day before the start of their course until 3 days after chemotherapy. Blood samples were collected on days one and three of the course and analyzed for cyclophosphamide and its activated metabolite 4-hydroxycyclophosphamide, thiotepa and its main active metabolite tepa. The influence of Aprepitant on the pharmacokinetics of cyclophosphamide and thiotepa was analyzed using a population pharmacokinetic analysis including a reference population of 49 patients receiving the same chemotherapy regimen without Aprepitant and sampled under the same conditions. The frequency of nausea and vomiting in the six patients receiving CTC was compared with those of the last 22 consecutive patients receiving CTC chemotherapy without Aprepitant. Inhibitory activity of Aprepitant on cyclophosphamide and thiotepa metabolism was also tested in human liver microsomes. Results: In our patient population, the rate of autoinduction of cyclophosphamide (P=0.040) and the formation clearance of tepa (P<0.001) were reduced with 23% and 33% when Aprepitant was co-administered, respectively. Exposures to the active metabolite 4-hydroxycyclophosphamide and tepa were therefore reduced (5% and 20%, respectively) in the presence of Aprepitant. In human liver microsomes, the 50% inhibitory concentrations (IC50) of Aprepitant for inhibition of cyclophosphamide (IC50=1.3 μg/ml) and thiotepa (IC50=0.27 μg/ml) metabolism were within the therapeutic range. Patients receiving Aprepitant experienced less frequently CINV both during and after the CTC course compared with the reference population (nausea 3.7 days vs. 5.8 days, P=0.052; vomiting 0.5 days vs. 4.8 days, P<0.001). Conclusion: Aprepitant inhibited both cyclophosphamide and thiotepa metabolism, most probably due to inhibition of the CYP 3A4 and/or 2B6 isoenzymes. The effects of this interaction are, however, small compared to the total variability. Addition of Aprepitant may provide superior protection against vomiting in patients receiving the highly emetogenic high-dose CTC chemotherapy.
Robert A. Blum - One of the best experts on this subject based on the ideXlab platform.
-
a single dose bioequivalence and food effect study with Aprepitant and fosAprepitant dimeglumine in healthy young adult subjects
Clinical pharmacology in drug development, 2012Co-Authors: Craig R Shadle, Gail M Murphy, Maureen Ho, Daniel Tatosian, Susie Xiujiang Li, Robert A. BlumAbstract:Abstract FosAprepitant dimeglumine, a lyophilized prodrug, is rapidly converted to Aprepitant, a substance P/neurokinin 1 (NK1 ) receptor antagonist. Intravenous (IV) fosAprepitant and oral Aprepitant are used in combination with other antiemetics to prevent chemotherapy-induced nausea and vomiting. This randomized, phase 1 study was designed to assess the Aprepitant area under the curve (AUC0-∞ ) equivalence of a single, oral 165-mg or 185-mg dose of Aprepitant to a single 150-mg fosAprepitant IV dose infused over 20 minutes, and to evaluate the effect of food on the bioavailability of the oral 165-mg and 185-mg Aprepitant doses. Plasma samples were analyzed for Aprepitant, and linear mixed-effects models were applied to natural log-transformed Aprepitant AUC data. A 2 one-sided tests procedure was used to evaluate bioequivalence; the adjusted P values for the AUC0-∞ of both oral doses versus the IV dose were < .05, supporting the hypothesis that each single, oral dose of Aprepitant is equivalent to the AUC0-∞ of a single IV infusion of fosAprepitant. Food effect results suggest that dose adjustment would not be necessary with a single oral dose of Aprepitant. Single-dose administration of oral 165 mg and 185 mg Aprepitant and IV 150 mg fosAprepitant was generally well tolerated.
-
A Single‐Dose Bioequivalence and Food Effect Study With Aprepitant and FosAprepitant Dimeglumine in Healthy Young Adult Subjects
Clinical pharmacology in drug development, 2012Co-Authors: Craig R Shadle, Maureen Ho, Daniel Tatosian, Susie Li, M Gail Murphy, Robert A. BlumAbstract:Abstract FosAprepitant dimeglumine, a lyophilized prodrug, is rapidly converted to Aprepitant, a substance P/neurokinin 1 (NK1 ) receptor antagonist. Intravenous (IV) fosAprepitant and oral Aprepitant are used in combination with other antiemetics to prevent chemotherapy-induced nausea and vomiting. This randomized, phase 1 study was designed to assess the Aprepitant area under the curve (AUC0-∞ ) equivalence of a single, oral 165-mg or 185-mg dose of Aprepitant to a single 150-mg fosAprepitant IV dose infused over 20 minutes, and to evaluate the effect of food on the bioavailability of the oral 165-mg and 185-mg Aprepitant doses. Plasma samples were analyzed for Aprepitant, and linear mixed-effects models were applied to natural log-transformed Aprepitant AUC data. A 2 one-sided tests procedure was used to evaluate bioequivalence; the adjusted P values for the AUC0-∞ of both oral doses versus the IV dose were < .05, supporting the hypothesis that each single, oral dose of Aprepitant is equivalent to the AUC0-∞ of a single IV infusion of fosAprepitant. Food effect results suggest that dose adjustment would not be necessary with a single oral dose of Aprepitant. Single-dose administration of oral 165 mg and 185 mg Aprepitant and IV 150 mg fosAprepitant was generally well tolerated.
-
evaluation of potential inductive effects of Aprepitant on cytochrome p450 3a4 and 2c9 activity
The Journal of Clinical Pharmacology, 2004Co-Authors: Craig R Shadle, Anup Majumdar, Judith K Evans, Kevin J Petty, Cynthia Gargano, Thomas E Bradstreet, Robert A. BlumAbstract:: The NK(1) receptor antagonist Aprepitant (EMEND(R)), developed for use in combination with a 5HT(3) receptor antagonist and a corticosteroid to prevent highly emetogenic chemotherapy-induced nausea and vomiting (CINV), has been shown to have a moderate inhibitory effect as well as a possible inductive effect on cytochrome P450 (CYP) 3A4. Aprepitant has been noted to produce modest decreases in plasma S(-)-warfarin concentrations, suggesting potential induction of CYP2C9. Because metabolism of some chemotherapeutic agents may involve CYP3A4, the potential inductive effect of the CINV dosing regimen of Aprepitant on this metabolic pathway was evaluated using intravenous midazolam, a sensitive probe substrate of CYP3A4. The time course of induction of CYP2C9 by Aprepitant was also evaluated using oral tolbutamide, a probe substrate of CYP2C9. In this double-blind, randomized, placebo-controlled, single-center study, 24 healthy subjects were randomized (12 subjects per group) to receive either an Aprepitant 3-day regimen (Aprepitant 125 mg p.o. on day 1 and Aprepitant 80 mg p.o. on days 2 and 3) or matching placebo. All subjects also received probe drugs (midazolam 2 mg i.v. and tolbutamide 500 mg p.o.) once prior to Aprepitant dosing (baseline) and again on days 4, 8, and 15. The ratio (Aprepitant/placebo) of the geometric mean area under the plasma concentration curve (AUC) fold-change from baseline for midazolam was 1.25 on day 4 (p < 0.01), 0.81 on day 8 (p < 0.01), and 0.96 on day 15 (p = 0.646). The ratio (Aprepitant/placebo) of the geometric mean AUC fold-change from baseline for tolbutamide was 0.77 on day 4 (p < 0.01), 0.72 on day 8 (p < 0.001), and 0.85 on day 15 (p = 0.05). Assessed using intravenous midazolam as a probe, Aprepitant 125/80 mg p.o. administered over days 1 to 3 produced clinically insignificant weak inhibition (day 4) and induction (day 8) of CYP3A4 activity and no effect on CYP3A4 activity on day 15. Assessed using oral tolbutamide as a probe, the Aprepitant regimen also produced modest induction of CYP2C9 activity on days 4 and 8, which resolved nearly to baseline by day 15. Thus, the Aprepitant regimen for CINV results in modest, transient induction of CYPs 3A4 and 2C9 in the 2 weeks following administration.
-
effects of Aprepitant on the pharmacokinetics of ondansetron and granisetron in healthy subjects
Clinical Therapeutics, 2003Co-Authors: Robert A. Blum, Anup Majumdar, Deborah Panebianco, Kevin J Petty, Jacqueline B Mccrea, Michael R Goldberg, Michael Hesney, Laura H. Orlowski, John Busillo, Gail M MurphyAbstract:Abstract Background: The neurokinin-1-receptor antagonist Aprepitant, when given in combination with a corticosteroid and a 5-hydroxytryptamine type 3 (5-HT 3 )-receptor antagonist, has been shown to be effective for the prevention of acute and delated chemotherapy-induced nausea and vomiting (CINV). Objective: Two studies were conducted to determine whether concomitant administration of Aprepitant altered the pharmacokinetic profiles of ondansetron and granisetron, two 5-HT 3 -receptor antagonists commonly used as antiemetic therapy for CINV. Methods: The 2 studies were randomized, open-label, crossover trials conducted in healthy subjects aged between 18 and 46 years. Study 1 involved the following 2 treatment regimens: Aprepitant 375 mg PO, dexamethasone 20 mg PO, and ondansetron 32 mg IV on day 1, followed by Aprepitant 250 mg PO and dexamethasone 8 mg PO on days 2 through 5; and dexamethasone 20 mg PO and ondansetron 32 mg IV on day 1, followed by dexamethasone 8 mg PO on days 2 through 5. Study 2 involved the following 2 treatment regimens: Aprepitant 125 mg PO with granisetron 2 mg PO on day 1, followed by Aprepitant 80 mg PO on days 2 and 3; and granisetron 2 mg PO on day 1 only. Individual plasma samples were used to estimate area under the plasma concentration-time curve from time zero to infinity (AUC 0−∞ ), peak plasma concentration, and apparent terminal elimination half-life (t12) of both ondansetron and granisetron. Results: Study 1 included 19 subjects (10 women, 9 men), and study 2 included 18 subjects (11 men, 7 women). Coadministration of Aprepitant 375 mg produced a small but statistically significant increase in the AUC 0−∞ for intravenous ondansetron (from 1268.3 to 1456.5 ng·h/mL; P = 0.019), with no significant effect on peak concentration at the end of the infusion (360.8 ng/mL with Aprepitant vs 408.4 ng/mL without) or t12 (5.0 vs 4.5 hours, respectively). Coadministration of Aprepitant 125 mg/80 mg did not alter the mean pharmacokinetic characteristics of oral granisetron (AUC 0−∞ , 101.4 ng·h/mL with Aprepitant vs 92.2 ng·h/mL without; maximum plasma concentration, 9.0 ng/mL with and without Aprepitant; time to maximum plasma concentration, both 3.0 hours; t12, 6.5 vs 6.9 hours, respectively). Conclusion: Concomitant administration of Aprepitant had no clinically significant effect on the mean pharmacokinetic characteristics of either ondansetron or granisetron in these healthy subjects.