Effectiveness and Safety of Antiemetic Aprepitant in Japanese Patients Receiving High-Dose Chemotherapy Prior to Autologous Hematopoietic Stem Cell Transplantation

Mayako Uchida; Hiroaki Ikesue; Toshihiro Miyamoto; Koji Kato; Kimitaka Suetsugu; Kimiko Ichinose; Hiromi Hiraiwa; Asako Sakurai; Katsuto Takenaka; Tsuyoshi Muta; Hiromi Iwasaki; Takanori Teshima; Motoaki Shiratsuchi; Nobuaki Egashira; Koichi Akashi; Ryozo Oishi

doi:10.1248/bpb.b12-01012

Abstract

For patients receiving high-dose chemotherapy, a 5-hydroxytryptamine 3 receptor antagonist combined with dexamethasone is a standard antiemetic therapy. Despite this prophylactic anti-emetic treatment, many patients still suffer from uncontrollable emesis. In this study, we retrospectively evaluated the antiemetic effectiveness and safety of aprepitant (a neurokinin-1 receptor antagonist) in addition to 5-HT₃ antagonist in Japanese patients with hematologic malignancy receiving high-dose chemotherapy prior to autologous peripheral blood stem cell transplantation (auto-PBSCT). Twenty-six patients received aprepitant and granisetron (the aprepitant group), whereas, 22 patients received granisetron alone (the control group). All patients received 3 mg of granisetron intravenously 30 min before chemotherapy administration. Patients in the aprepitant group additionally received 125 mg of aprepitant 60–90 min before administration of the first moderately to highly emetogenic chemotherapy. On the next day or thereafter, 80 mg of aprepitant was administered in the morning until the last administration of moderately to highly emetogenic anticancer drugs. The percentage of patients who achieved complete response (CR), defined as no emesis with only grade 1–2 nausea, in the aprepitant group was significantly higher than that in the control group (42% vs. 5%, p=0.003). Logistic regression analysis showed that non-prophylactic use of aprepitant was significantly associated with non-CR. The frequencies of adverse drug events (ADEs) were not significantly different between two groups. In conclusion, the results of this study suggest that the addition of aprepitant to granisetron can improve the antiemetic effect without increasing ADEs in patients receiving high-dose chemotherapy prior to auto-PBSCT.

Cancer chemotherapy-induced nausea and vomiting (CINV) is one of the most problematic symptoms for cancer patients. The appropriate use of antiemetics to control CINV is necessary to maintain patients’ quality of life and ensure their adherence to therapy.¹⁾ For patients receiving high-dose chemotherapy prior to hematopoietic stem cell transplantation (HSCT), a 5-hydroxytryptamine 3 (5-HT₃) receptor antagonist combined with dexamethasone is usually used as a standard antiemetic therapy.^2–4) However, a number of recipients still suffer from uncontrollable CINV.^5–10) Therefore, additional options to reduce CINV in these patients are needed.

Aprepitant, a neurokinin-1 receptor antagonist, has been shown to be effective for controlling CINV in the patients receiving (high-dose) chemotherapy.^11–13) According to the latest American Society of Clinical Oncology guidelines,¹⁴⁾ combination anti-emetic therapy with aprepitant in and 5-HT₃ receptor antagonist and dexamethasone should be considered for patients receiving high-dose chemotherapy prior to HSCT. Recently, several studies have reported the antiemetic effect and safety of aprepitant in combination with 5-HT₃ receptor antagonist and dexamethasone for patients receiving high-dose chemotherapy as a pre-transplant conditioning regimen.^15–18) However, since there are a large number of high-dose chemotherapy regimens, the information concerning this matter is still not sufficiently provided. In addition, no study has been reported about the usefulness of aprepitant in Japanese patients receiving high-dose chemotherapy prior to HSCT.

Corticosteroids such as dexamethasone are generally considered safe when used in combination with other antiemetic agents.^4,14) However, since patients with hematological malignancies receiving high-dose chemotherapy followed by HSCT are highly immunosuppressed, dexamethasone is not preferred to use for antiemetic therapy because of increasing risk of infection.^19,20) Thus, it is important to accumulate more evidence about the usefulness and safety of aprepitant in combination with 5-HT₃ receptor antagonist.

At our institution, pharmacists and physicians had discussed the antiemetic treatment for the patients with hematologic malignancies, and introduced aprepitant to conventional chemotherapies²¹⁾ as well as preparative regimens for HSCT since April 2010. In this study, we retrospectively evaluated the antiemetic effect and safety of aprepitant in combination with 5-HT₃ receptor antagonist in such patients undergoing autologous peripheral blood stem cell transplantation (auto-PBSCT).

Materials and Methods

Patients

This study was conducted in accordance with the Declaration of Helsinki and its amendments, and the protocol was approved by the Ethics Committee of Kyushu University Graduate School and Faculty of Medicine (approval No. 24-12 of the institutional review board). Japanese patients included in the study were age 20 years or older and received conditioning high-dose chemotherapies prior to auto-PBSCT for hematologic malignancies at the Department of Hematology, Kyushu University Hospital. Twenty-six consecutive patients received aprepitant and granisetron as an antiemetic prophylaxis (the aprepitant group) between April 1, 2010 and January 31, 2012. Twenty-two consecutive patients received granisetron alone (the control group) between January 1, 2008 and March 31, 2010 before the introduction of aprepitant. No patients were excluded from the present study due to severe toxicity or other reasons.

Treatments

In both groups, i.v. administration of granisetron of 3 mg was started 30 min before the administration of chemotherapy on the first day, and it was given every 12 h while receiving chemotherapy. In the aprepitant group, 125 mg of aprepitant was administered orally 60–90 min before administration of the first moderately to highly emetogenic anticancer drugs (Table 1). On the next day or thereafter, 80-mg oral aprepitant was administered in the morning. The administration schedules of anticancer and antiemetic drugs in representative high-dose chemotherapy regimens are summarized in Table 1. Rescue medication including metoclopramide (in most cases) or hydroxyzine was used for breakthrough nausea or vomiting. Because most patients in this study were already highly immunosuppressed, corticosteroid was not administered for emetic control.^21–23)

Table 1. Administration Schedules of Anticancer and Antiemetic Drugs in Representative Chemotherapy Regimens

	Dosage	Day 1	Day 2	Day 3	Day 4	Day 5	Day 6	Day 7
MCEC±rituximab
Ranimustine	200 mg/m²	↓					↓
Carboplatin	300 mg/m²		↓	↓	↓	↓
Etoposide	500 mg/m²			↓	↓	↓
Cyclophosphamide	50 mg/kg						↓	↓
Granisetron	3 mg	↓↓	↓↓	↓↓	↓↓	↓↓	↓↓	↓↓
Aprepitant ^a)			125 mg	80 mg	80 mg	80 mg	80 mg	80 mg
Melphalan ±bortezomib
Melphalan	100 mg/m^{2 b)}	↓	↓
Granisetron	3 mg	↓↓	↓↓
Aprepitant ^a)		125 mg	80 mg	80 mg
LEED
Etoposide	500 mg/m²	↓	↓	↓
Cyclophosphamide	60 mg/kg		↓	↓
Melphalan	130 mg/m²				↓
Dexamethasone	40 mg/body	↓	↓	↓	↓
Granisetron	3 mg	↓↓	↓↓	↓↓	↓↓
Aprepitant ^a)		125 mg	80 mg	80 mg	80 mg

a) Patients in the control group did not receive aprepitant. b) Patients aged 60 years or over were administered melphalan 70 mg/m².

Data Collection and Assessment

All data were retrospectively collected from the electronic medical record system. The primary endpoint of this study was achievement of complete response [CR; defined as no emesis with only grade 1–2 nausea, using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0]²⁴⁾ during and until five days after the last dose was administered. Secondary endpoints included the percentages of patients without vomiting, without severe nausea, and the frequencies of other adverse drug events (ADEs). Severe nausea was defined grade 3 or higher nausea, using CTCAE version 4.0.²⁴⁾ Nausea and vomiting were evaluated by grading into 4 categories as follows; CR, Major Response (1–2 vomiting and none-to-moderate nausea or no vomiting and moderate nausea), Minor Response (3–5 vomiting and any degree of nausea or 0–2 vomiting and severe nausea), and Failure (6 or more times of vomiting and any degree of nausea).^5,8,18) Nausea, vomiting, and other ADEs were monitored twice daily (morning and evening) mainly by nurses and recorded into electronic medical record system. The severity of ADEs was classified by the CTCAE version 4.0.²⁴⁾ Nurses prepared paper-based ADE monitoring form which was excerpted from CTCAE, and used them for the monitoring of ADEs. The ADEs were informed to physicians and pharmacist, and evaluated by physicians.

Statistical Analysis

Chi-square analysis or Fisher’s exact test was used to compare the categorical data between the aprepitant and control groups. Patients’ age data and severity of nausea and vomiting (CR, major response, minor response and failure) were analyzed using the Mann–Whitney U test.

To identify the factors associated with non-CR and vomiting, patient characteristics were analyzed using chi-square analysis or Fisher’s exact test for categorical variables and with the Mann–Whitney U test for continuous variables. The variables included for univariate analyses were as follows: age (<40 or ≥40), sex, conditioning regimen [ranimustine, carboplatin, etoposide, and cyclophosphamide (MCEC) therapy or other], and aprepitant prophylaxis. Factors of p<0.25 in univariate analyses were evaluated as potential covariates in a stepwise multivariate logistic regression with backward selection. Data were analyzed using JMP 9.0.0.2 (SAS Institute Inc., Cary, NC, U.S.A.), and a p-value of less than 0.05 was considered statistically significant.

Results

Patient Characteristics and Treatment

Patient characteristics are shown in Table 2. There were no significant differences in median age, sex, and diagnosis between in the aprepitant and control groups. In the conditioning regimen, the percentages of patients who received melphalan±bortezomib therapy was higher in the aprepitant group (42.3% vs. 18.2%, p=0.118), but there was no significant difference.

Table 2. Patient Characteristics

Characteristic	Control^a) (n=22)	Aprepitant^b) (n=26)	p-Value
Age
Median, year (range)	50 (20–65)	54 (20–66)	0.336
Gender, No. (%)			0.281
Male	11 (50.0%)	17 (65.4%)
Female	11 (50.0%)	9 (34.6%)
Diagnosis, No. (%)			0.092
Non-Hodgkin lymphoma	16 (72.7%)	13 (50.0%)
Multiple myeloma	3 (13.6%)	11 (42.3%)
Hodgkin’s lymphoma	2 (9.1%)	0 (0%)
Leukemia	1 (4.6%)	2 (7.7%)
Conditioning regimen, No. (%)^c)
MCEC±rituximab	14 (63.6%)	13 (50.0%)	0.393
Melphalan±bortezomib	4 (18.2%)	11 (42.3%)	0.118
LEED	2 (9.1%)	0 (0%)
Other	2 (9.1%)	2 (7.7%)

a) Patients in the control group received granisetron alone. b) Patients in the aprepitant group received aprepitant and granisetron. c) MCEC: ranimustine, carboplatine, etoposide, and cyclophosphamide, LEED: melphalan, etoposide, cyclophosphamide, and dexamethasone.

Antiemetic Effectiveness

In a total, the percentage of patients who achieved CR in the aprepitant group was significantly higher than that in the control group (42.3% vs. 4.5%, p=0.003) (Fig. 1A). Similary, the percentage of patients without vomiting (57.7% vs. 4.5%, p<0.001) and severe nausea (57.7% vs. 22.7%, p=0.020) were also significantly higher in the aprepitant group (Figs. 1B, C). The percentages of patients with major response, minor response and failure in the aprepitant group were 38.5%, 15.4% and 3.8%, respectively, whereas those in the control group were 13.6%, 22.7% and 59.1%, respectively (p<0.001).

Fig. 1. Comparison of the Percentages of Patients with Complete Response (A), without Vomiting (B), and without Severe Nausea (C) between the Aprepitant and Control Groups

Aprepitant was administered according to the schedules shown in Table 1.

When antiemetic effectiveness was analyzed by each regimen including MCEC±rituximab and melphalan±bortezomib, among patients who received MCEC±rituximab therapy, the percentage of patients without vomiting was significantly higher than that in the control group (38.5% vs. 0%, p=0.016) (Table 3).

Table 3. Percentages of Patients without Vomiting in Each Subgroup

Regimens^a)	Without vomiting		p-Value
Regimens^a)	Control (n=22)	Aprepitant (n=26)	p-Value
MCEC±rituximab	0/14 (0%)	5/13 (38.5%)	0.016
Melphalan±bortezomib	1/4 (25.0%)	9/11 (81.8%)	0.077
Others	0/4 (0%)	1/2 (50.0%)	ND ^b)
Total	1/22 (4.5%)	15/26 (57.7%)	<0.001

The numbers and percentages of patients without vomiting were described in each regimen. a) MCEC: ranimustine, carboplatine, etoposide, and cyclophosphamide. b) ND=Not detected.

Risk Factors for Poor Control of CINV

In the univariate analysis, the CR rate was significantly lower in patients without prophylactic use of aprepitant (4.5% vs. 42.3%, p=0.003), and in patients treated with MCEC±rituximab therapy (11.1% vs. 42.9%, p=0.018). Stepwise logistic regression analysis revealed that the predictors significantly associated with non-CR were non-prophylactic use of aprepitant [odds ratio (OR)=14.86; 95% confidence interval (CI), 2.09–312.31; p=0.005] and MCEC±rituximab therapy (OR=5.38; 95% CI, 1.03–35.64, p=0.046) (Table 4).

Table 4. Risk Factors for Poor Emetic Control (Multivariate Analysis)

Variable	Non-CR			Vomiting
Variable	OR	95% CI	p-Value	OR	95% CI	p-Value
Non-prophylactic use of aprepitant	14.86	2.09–312.31	0.005	34.22	4.71–758.03	<0.001
Conditioning regimen (MCEC therapy)	5.38	1.03–35.64	0.046	5.73	1.06–40.54	0.042
Younger age (<40)	5.18	0.61–114.51	0.139	4.28	0.61–41.95	0.146
Female gender	2.35	0.41–16.10	0.342	3.17	0.56–21.79	0.193

CR=complete response; OR=odds ratio; CI=confidence interval; MCEC=ranimustine, carboplatin, etoposide, and cyclophosphamide.

Similarly, the percentage of patients with vomiting was significantly higher in patients without prophylactic use of aprepitant (95.5% vs. 42.3%, p<0.001), and in patients treated with MCEC±rituximab therapy (81.5% vs. 47.6%, p=0.029). The significant predictors associated with vomiting were the non-prophylactic use of aprepitant (OR=34.22; 95% CI, 4.71–758.03; p<0.001) and MCEC therapy (OR=5.73; 95% CI, 1.06–40.54, p=0.042) in multivariate analysis.

Safety

The most common ADE in the aprepitant and control groups was malaise (84.6% vs. 100%, p=0.114, Table 5). The following symptoms appeared in at least 20% of patients: diarrhea, stomatitis, abdominal pain, headache, skin rush and flushing, insomnia, and pharyngeal pain. These ADEs were mostly grade 2 or lower. No patients who discontinued aprepitant due to ADEs. The frequencies of ADEs were similar in both groups.

Table 5. Adverse Drug Events

Adverse drug events	Control^a) (n=22)	Aprepitant^b) (n=26)	p-Value
Malaise	22 (100%)	22 (84.6%)	0.114
Diarrhea	20 (90.9%)	23 (88.5%)	1.000
Stomatitis	15 (68.2%)	12 (46.2%)	0.153
Abdominal pain	12 (54.5%)	14 (53.8%)	1.000
Headache	9 (40.9%)	7 (26.9%)	0.366
Skin rash and flushing	8 (36.4%)	7 (26.9%)	0.543
Insomnia	7 (31.8%)	9 (34.6%)	1.000
Pharyngeal pain	6 (27.3%)	6 (23.1%)	0.751
Light headedness	3 (13.6%)	4 (15.4%)	1.000
Constipation	3 (13.6%)	1 (3.8%)	0.320
Dizziness	1 (4.5%)	3 (11.5%)	0.614
Back pain	1 (4.5%)	0 (0%)	0.458
Hypersensitivity	0 (0%)	1 (3.8%)	1.000

a) Patients in the control group received granisetron alone as antiemetics. b) Patients in the aprepitant group received aprepitant and granisetron as antiemetics.

Discussion

This retrospective study of the antiemetic effect and safety of aprepitant in Japanese patients receiving high-dose chemotherapy prior to auto-PBSCT for hematologic malignancies revealed three findings: (1) the prophylactic administration of aprepitant significantly enhanced the effectiveness of the antiemetic therapy, (2) the addition of aprepitant did not increase the frequencies and severity of ADEs, and (3) MCEC regimen was significantly associated with poor control of CINV.

The percentages of patients with CR and without vomiting were significantly higher in the aprepitant group than that in the control group. Recently, four studies have demonstrated the effectiveness and safety of aprepitant in combination with 5-HT₃ receptor antagonist and dexamethasone for patients receiving high-dose chemotherapy before HSCT.^15–18) This is the first study to evaluate the usefulness of aprepitant in Japanese patients with hematologic malignancy receiving high-dose chemotherapy. Although the conditioning regimens in our study were different from regimens in those studies, the results in this study strongly support their findings that the addition of aprepitant to standard antiemetic therapy significantly improved the control of CINV. Another advantage of this study over other studies is that we evaluated the effectiveness and safety of aprepitant in combination with only a 5-HT₃ receptor antagonist. Corticosteroids such as dexamethasone are generally considered safe when they were used in antiemetic therapy.^4,14) However, patients with hematological malignancies receiving high-dose chemotherapy followed by HSCT are highly immunosuppressed, and dexamethasone is not preferred to use for antiemetic therapy in such patients, because it may increase a risk of infection.^19,20) Therefore, it is important to accumulate information about the usefulness of aprepitant in combination with 5-HT₃ receptor antagonist. All of the previous studies on the effectiveness and safety of aprepitant used triple combination antiemetic therapy composed of aprepitant, a 5-HT₃ receptor antagonist, and dexamethasone.^15–18) The multivariate analyses in this study revealed that the addition of aprepitant to granisetron was significantly associated with CR and without vomiting. Our study provides evidence supporting the effectiveness and safety of aprepitant in combination with 5-HT₃ receptor antagonist in Japanese patients receiving high-dose chemotherapy prior to HSCT.

Aprepitant has been shown to inhibit cytochrome P450 3A4 (CYP3A4) moderately.²⁵⁾ Therefore, drug–drug interactions may occur when aprepitant is administered in combination with anticancer drugs including cyclophosphamide and etoposide.^26–28) However, no study has shown serious drug interactions between aprepitant and etoposide. Bubalo et al.²⁹⁾ reported that the area under the concentration–time curve (AUC) of 4-hydroxycy clophosphamide, the active metabolite of cyclophosphamide, decreased by approximately 5% in the presence of aprepitant in patients who underwent cyclophosphamide therapy (1.5 g/m²/d×4 d) as pre-transplant conditioning regimen, and this was not clinically significant. In another study, Walko et al.³⁰⁾ reported that aprepitant did not influence the AUC of cyclophosphamide in patients with breast cancer. Recently, we reported that the addition of aprepitant to granisetron improved antiemetic control without influencing ADEs in patients with hematologic malignancies receiving multiday conventional chemotherapy.²¹⁾ In the present study, the frequencies of ADEs in the control and aprepitant groups were similar. Based on these results, aprepitant can be safely incorporated into the conditioning regimen for auto-HSCT as an effective antiemetic drug.

Multivariate analyses in this study revealed that MCEC therapy was significantly associated with non-CR and vomiting. MCEC conditioning represent one of the chemotherapy regimens and actually induce highly emetogenesis.¹⁴⁾ Nevertheless, aprepitant improved the control of CINV in the MCEC-treated group; the percentage of patients without vomiting in the aprepitant group was significantly higher than that in the control group (39% vs. 0%, p=0.016; Table 3). This suggests the usefulness of aprepitant to control of CINV especially in this therapy. Otherwise, prolonged administration of aprepitant might be useful to control of CINV in the MCEC-treated group, as other clinical trials conducted a long-term administration of aprepitant for HSCT recipients.^18,29)

This study had some limitations. Because we did not evaluate the pharmacokinetics of anticancer drugs, we could not confirm that the addition of aprepitant would not affect the clinical outcomes associated with anticancer drugs. In addition, the appropriate duration of aprepitant therapy was not obtained from this study design. Finally, the adequate sample size to reach the power of detecting the true different on treatment outcomes between the two groups was not calculated in this study.

In conclusion, the results of this study suggest that the addition of aprepitant to granisetron increased the antiemetic effect without influencing ADEs in Japanese patients receiving high-dose chemotherapy prior to auto-PBSCT for hematologic malignancies.

Acknowledgment

This study was supported by MEXT KAKENHI Grant Number 24928027.

REFERENCES

1) Hesketh PJ. Chemotherapy-induced nausea and vomiting. N. Engl. J. Med., 358, 2482–2494 (2008).
2) Roila F, Herrstedt J, Aapro M, Gralla RJ, Einhorn LH, Ballatori E, Bria E, Clark-Snow RA, Espersen BT, Feyer P, Grunberg SM, Hesketh PJ, Jordan K, Kris MG, Maranzano E, Molassiotis A, Morrow G, Olver I, Rapoport BL, Rittenberg C, Saito M, Tonato M, Warr D, ESMO/MASCC Guidelines Working Group. Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference. Ann. Oncol., 21 (Suppl. 5), v232–v243 (2010).
3) National Comprehensive Cancer Network (NCCN). “NCCN Clinical Practice Guidelines in Oncology. Antiemesis. V.1.2012.”: ‹http://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf›, cited 9 October, 2012.
4) Einhorn LH, Grunberg SM, Rapoport B, Rittenberg C, Feyer P. Antiemetic therapy for multiple-day chemotherapy and additional topics consisting of rescue antiemetics and high-dose chemotherapy with stem cell transplant: review and consensus statement. Support. Care Cancer, 19 (Suppl. 1), S1–S4 (2011).
5) Abbott B, Ippoliti C, Hecth D, Bruton J, Whaley B, Champlin R. Granisetron (Kytril) plus dexamethasone for antiemetic control in bone marrow transplant patients receiving highly emetogenic chemotherapy with or without total body irradiation. Bone Marrow Transplant., 25, 1279–1283 (2000).
6) Ballen KK, Hesketh AM, Heyes C, Becker PS, Emmons RV, Fogarty K, LaPointe J, Liu Q, Hsieh CC, Hesketh PJ. Prospective evaluation of antiemetic outcome following high-dose chemotherapy with hematopoietic stem cell support. Bone Marrow Transplant., 28, 1061–1066 (2001).
7) Matsuoka S, Okamoto S, Watanabe R, Mori T, Nagayama H, Hamano Y, Yokoyama K, Takayama N, Ikeda Y. Granisetron plus dexamethasone versus granisetron alone in the prevention of vomiting induced by conditioning for stem cell transplantation: a prospective randomized study. Int. J. Hematol., 77, 86–90 (2003).
8) Walsh T, Morris AK, Holle LM, Callander N, Bradshaw P, Valley AW, Clark G, Freytes CO. Granisetron vs. ondansetron for prevention of nausea and vomiting in hematopoietic stem cell transplant patients: results of a prospective, double-blind, randomized trial. Bone Marrow Transplant., 34, 963–968 (2004).
9) Musso M, Scalone R, Crescimanno A, Bonanno V, Polizzi V, Porretto F, Bianchini C, Perrone T. Palonosetron and dexamethasone for prevention of nausea and vomiting in patients receiving high-dose chemotherapy with auto-SCT. Bone Marrow Transplant., 45, 123–127 (2010).
10) Giralt SA, Mangan KF, Maziarz RT, Bubalo JS, Beveridge R, Hurd DD, Mendoza FL, Rubenstein EB, DeGroot TJ, Schuster MW. Three palonosetron regimens to prevent CINV in myeloma patients receiving multiple-day high-dose melphalan and hematopoietic stem cell transplantation. Ann. Oncol., 22, 939–946 (2011).
11) de Wit R, Herrstedt J, Rapoport B, Carides AD, Carides G, Elmer M, Schmidt C, Evans JK, Horgan KJ. Addition of the oral NK1 antagonist aprepitant to standard antiemetics provides protection against nausea and vomiting during multiple cycles of cisplatin-based chemotherapy. J. Clin. Oncol., 21, 4105–4111 (2003).
12) Poli-Bigelli S, Rodrigues-Pereira J, Carides AD, Julie Ma G, Eldridge K, Hipple A, Evans JK, Horgan KJ, Lawson F, Aprepitant Protocol 054 Study Group. Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapy-induced nausea and vomiting. Results from a randomized, double-blind, placebo-controlled trial in Latin America. Cancer, 97, 3090–3098 (2003).
13) Gralla RJ, de Wit R, Herrstedt J, Carides AD, Ianus J, Guoguang-Ma J, Evans JK, Horgan KJ. Antiemetic efficacy of the neurokinin-1 antagonist, aprepitant, plus a 5HT3 antagonist and a corticosteroid in patients receiving anthracyclines or cyclophosphamide in addition to high-dose cisplatin: analysis of combined data from two Phase III randomized clinical trials. Cancer, 104, 864–868 (2005).
14) Basch E, Prestrud AA, Hesketh PJ, Kris MG, Feyer PC, Somerfield MR, Chesney M, Clark-Snow RA, Flaherty AM, Freundlich B, Morrow G, Rao KV, Schwartz RN, Lyman GH, American Society of Clinical Oncology. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J. Clin. Oncol., 29, 4189–4198 (2011).
15) Paul B, Trovato JA, Thompson J, Badros AZ, Goloubeva O. Efficacy of aprepitant in patients receiving high-dose chemotherapy with hematopoietic stem cell support. J. Oncol. Pharm. Pract., 16, 45–51 (2010).
16) Jordan K, Jahn F, Jahn P, Behlendorf T, Stein A, Ruessel J, Kegel T, Schmoll HJ. The NK-1 receptor-antagonist aprepitant in high-dose chemotherapy (high-dose melphalan and high-dose T-ICE: paclitaxel, ifosfamide, carboplatin, etoposide): efficacy and safety of a triple antiemetic combination. Bone Marrow Transplant., 46, 784–789 (2011).
17) Pielichowski W, Barzal J, Gawronski K, Mlot B, Oborska S, Wasko-Grabowska A, Rzepecki P. A triple-drug combination to prevent nausea and vomiting following BEAM chemotherapy before autologous hematopoietic stem cell transplantation. Transplant. Proc., 43, 3107–3110 (2011).
18) Stiff PJ, Fox-Geiman MP, Kiley K, Rychlik K, Parthasarathy M, Fletcher-Gonzalez D, Porter N, Go A, Smith SE, Rodriguez TE. Prevention of nausea and vomiting associated with stem cell transplantation: results of a prospective, randomized trial of aprepitant used with highly emetogenic preparative regimens. Biol. Blood Marrow Transplant., 19, 49–55 (2013).
19) Schimmer BP, Parker KL. Adrenocorticotropic hormone; Adrenocortical steroids and their synthetic analogs; Inhibitors of the synthesis and actions of adrenocortical hormones. Goodman & Gilman’s the pharmacological basis of therapeutics. (Brunton LL, Lazo JS, Parker K ed.) Vol. 11, McGraw-Hill, New York, pp. 1587–1612 (2006).
20) Holmberg LA, Boeckh M, Hooper H, Leisenring W, Rowley S, Heimfeld S, Press O, Maloney DG, McSweeney P, Corey L, Maziarz RT, Appelbaum FR, Bensinger W. Increased incidence of cytomegalovirus disease after autologous CD34-selected peripheral blood stem cell transplantation. Blood, 94, 4029–4035 (1999).
21) Uchida M, Ikesue H, Kato K, Ichinose K, Hiraiwa H, Sakurai A, Takenaka K, Iwasaki H, Miyamoto T, Teshima T, Egashira N, Akashi K, Oishi R. Antiemetic effectiveness and safety of aprepitant in patients with hematologic malignancy receiving multiday chemotherapy. Am. J. Health Syst. Pharm., 70, 343–349 (2013).
22) López-Jiménez J, Martín-Ballesteros E, Sureda A, Uralburu C, Lorenzo I, del Campo R, Fernández C, Calbacho M, García-Belmonte D, Fernández G. Chemotherapy-induced nausea and vomiting in acute leukemia and stem cell transplant patients: results of a multicenter, observational study. Haematologica, 91, 84–91 (2006).
23) Mattiuzzi GN, Cortes JE, Blamble DA, Bekele BN, Xiao L, Cabanillas M, Borthakur G, O’Brien S, Kantarjian H. Daily palonosetron is superior to ondansetron in the prevention of delayed chemotherapy-induced nausea and vomiting in patients with acute myelogenous leukemia. Cancer, 116, 5659–5666 (2010).
24) Japan Clinical Oncology Group (JCOG). “Common Terminology Criteria for Adverse Events (CTCAE), version 4.0-JCOG.”: ‹http://www.jcog.jp/doctor/tool/CTCAEv4J_20111217.pdf›, cited 9 October, 2012.
25) Majumdar AK, McCrea JB, Panebianco DL, Hesney M, Dru J, Constanzer M, Goldberg MR, Murphy G, Gottesdiener KM, Lines CR, Petty KJ, Blum RA. Effects of aprepitant on cytochrome P450 3A4 activity using midazolam as a probe. Clin. Pharmacol. Ther., 74, 150–156 (2003).
26) Aapro MS, Walko CM. Aprepitant: drug–drug interactions in perspective. Ann. Oncol., 21, 2316–2323 (2010).
27) Glotzbecker B, Duncan C, Alyea E 3rd, Campbell B, Soiffer R. Important drug interactions in hematopoietic stem cell transplantation: what every physician should know. Biol. Blood Marrow Transplant., 18, 989–1006 (2012).
28) Ono Pharmaceutical. EMEND (aprepitant) package insert. Osaka, Japan (2012).
29) Bubalo JS, Cherala G, McCune JS, Munar MY, Tse S, Maziarz R. Aprepitant pharmacokinetics and assessing the impact of aprepitant on cyclophosphamide metabolism in cancer patients undergoing hematopoietic stem cell transplantation. J. Clin. Pharmacol., 52, 586–594 (2012).
30) Walko CM, Combest AJ, Spasojevic I, Yu AY, Bhushan S, Hull JH, Hoskins J, Armstrong D, Carey L, Collicio F, Dees EC. The effect of aprepitant and race on the pharmacokinetics of cyclophosphamide in breast cancer patients. Cancer Chemother. Pharmacol., 69, 1189–1196 (2012).

責任著者(Corresponding author)

J-STAGEへの登録はこちら（無料）