Aprepitant (Emend) Significantly Increases Sirolimus Levels

Home , Sirolimus

LETTER TO THE EDITOR Aprepitant (Emend) signiﬁcantly increases sirolimus levels in patients undergoing allogeneic hematopoietic SCT

Bone Marrow Transplantation (2012) 47, 291–293; prior to administration of melphalan on day À4. Oral doi:10.1038/bmt.2011.42; published online 7 March 2011 aprepitant was administered as a three-day course of 125 mg on day 1 and 80 mg on days 2 and 3. The first dose of aprepitant was administered between days À4 and À2 of transplant in all patients. Patients Aprepitant (Emend, Merck and Co. Inc., Whitehouse Station, NJ, USA) is a potent antagonist of substance P/neurokinin-1 (NK1) receptors effective for treatment of Table 1 Patient, disease and treatment characteristics chemotherapy-induced nausea and vomiting in patients Characteristic Cases Controls P-valueb receiving highly emetogenic chemotherapy regimens. Even (n ¼ 14)a (n ¼ 71)a though the role of aprepitant in the context of hemato- Age at transplant (years) 54 (20–68) 56 (22–71) 0.52 poietic SCT (HSCT) has not been clearly defined, national Patient gender 0.08 antiemetic guidelines recommend addition of this drug Female 9 (64.3) 27 (38.0) to standard antiemetic regimens.1,2 Aprepitant is both a Male 5 (35.7) 44 (62.0) substrate and a moderate inhibitor of human cytochrome Female donor to 2 (14.3) 10 (14.1) 0.99 P450 (CYP450), specifically CYP3A4. Use of aprepitant in male patient the context of SCT presents multiple opportunities for drug Matched donor type 0.77 interactions.3,4 Sibling 6 (42.9) 27 (38.0) Sirolimus and tacrolimus are immunosuppressive agents Unrelated 8 (57.1) 44 (62.0) used for prevention of GVHD5,6 that are also substrates for 7,8 Stem cell source 0.99 CYP3A4 isoenzyme and P-glycoprotein. Drugs known to BM 1 (7.1) 5 (7.0) inhibit CYP3A4, such as aprepitant, have the potential Peripheral blood 11 (92.9) 70 (93.0) to increase the bioavailability of these two agents, leading to overt toxicity. Disease diagnosis In this retrospective study, we present data on a conse- AML 4 22 NHL/HL 3/1 16/1 cutive case series of 85 patients (aprepitant group: n ¼ 14, MDS 3 13 control group: n ¼ 71) treated with a tacrolimus/sirolimus- MPD/MF 0 7 based GVHD prophylactic regimen, some of whom also ALL 0 4 received aprepitant during conditioning for an allogeneic CLL/PLL 0 4 CML 2 1 HSCT. Patients were transplanted between May 2008 and Multiple myeloma 0 1 July 2009 at City of Hope. We explored the nature and significance of the potential drug–drug interactions between Undifferentiated aprepitant and initial doses of tacrolimus/sirolimus. Leukemia 0 2 Patients were included in the study if they underwent Aplastic anemia 1 0 reduced-intensity HSCT from a sibling or a matched Conditioning regimen unrelated donor (MUD). All patients received a conditioning Flu/Mel 12 (85.7) 66 (93.0) regimen of fludarabine 25 mg/m2 daily for five days starting Flu/Mel/Rituxan 1 (7.1) 3 (4.2) on day À9 and melphalan 140 mg/m2 on day À4. The Flu/Mel/ Zevalin 0 (0.0) 2 (2.8) GVHD prophylaxis regimen consisted of sirolimus 12 mg Clofarabine/Mel 1 (7.1) 0 (0.0) orally on day À3 (loading dose), followed by 4 mg daily. GVHD prophylaxis Tacrolimus was administered initially as 0.02 mg/kg intrave- Tacro/Siro 11 (78.6) 56 (78.9) nously daily, starting on day À3. Both drugs were Tacro/Siro/MTX 2 (14.3) 11 (15.5) subsequently dose adjusted to maintain serum levels between Tacro/Siro/ATG 1 (7.1) 4 (5.6) Baseline creatinine 0.65 (0.45–0.97) 0.80 (0.44–1.20) o0.01 5–10 ng/mL or to mitigate toxicity. A select few patients (mg/dL) undergoing MUD HSCT also received mini-MTX (14.3% in study group vs 15.5% in the control group) or antithymocyte ATG ¼ antithymocyte globulin; PLL ¼ prolymphocytic leukemia; Flu/ globulin (7.1% in study group and 5.6% in the control arm). Mel ¼ fludarabine/melphalan; HL ¼ Hodgkin’s lymphoma; MDS ¼ myelo- The standard antiemetic regimen consisted of ondanse- dysplastic syndrome; MPD/MF ¼ myeloproliferative disorder/myelofibro- sis; NHL ¼ non-Hodgkin’s lymphoma; Tacro/Siro ¼ tacrolimus/sirolimus. tron (Zofran, GlaxoSmithKline, Philadelphia, PA, USA) aReported as number of patients (percent) or median (range). 24 mg i.v. daily starting on day À4 for three days. Patients bP-values are determined using the Wilcoxon rank-sum test (continuous also received dexamethasone 10 mg and lorazepam 1 mg i.v. variables) or Fisher’s exact test (categorical variables). Letter to the Editor 292 received supportive care measures per institutional guide- All but five patients experienced neutrophil engraftment lines. Azole antifungals were not administered during the (ANC 4500) with a median time to engraftment of 14 days conditioning regimen. in both groups. There were no significant differences in the Descriptive statistics were used to summarize baseline cumulative incidence of acute GVHD or 100-day survival characteristics. Fisher’s exact test was used to examine (Table 2). We observed no TMA in the aprepitant group. possible differences in baseline characteristics and outcome Drug interactions may lead to overt toxicity/complications data between the aprepitant group and control group, and or treatment failure, especially in patients undergoing Wilcoxon rank sum was used for analysis of continuous/ HSCT. Our data demonstrate the drug interaction between numeric data. The following end points were examined: sirolimus and aprepitant, in which concomitant administra- sirolimus and tacrolimus serum drug levels (loading and tion leads to a twofold increase in sirolimus levels. This median of first 30 days post HSCT), acute GVHD, observation was consistent with the fact that both drugs are thrombotic microangiopathy (TMA) and vital status. substrates for CYP3A4. However, we did not observe any Baseline patient characteristics were generally similar significant impact of coadministration of sirolimus and for the two cohorts (Table 1) with the exception of gender aprepitant on clinical outcomes such as survival, GVHD or and baseline creatinine levels. The first set of tacrolimus TMA in this cohort. As we constantly adjust the drug doses and sirolimus levels were drawn one to three days after according to the serum levels, the difference in sirolimus initiation of the immunosuppressive regimen (days À2to levels was not observed over the duration of first 30 days 0 of HSCT). The median numbers of sampling points post HSCT. for tacrolimus/sirolimus levels over the first 30 days were We observed no significant differences in tacrolimus 8.5/8.5 for the aprepitant group and 9/8 for the control levels between the two groups. Although Ibrahim et al.4 group, respectively. had reported previously that i.v. tacrolimus trough concen- The post-loading sirolimus levels (drawn one to three trations may be affected by aprepitant, the observed days after loading dose) were significantly higher in the interaction was not clinically significant and most of the aprepitant group (29.2 vs 13.5 ng/mL, P ¼ 0.003, Table 2), tacrolimus levels were within the therapeutic range. while the levels were not different for tacrolimus (9.2 vs While coadministration of sirolimus with strong inhibi- 8.6 ng/mL, P ¼ 0.13). There was a trend toward higher tors of CYP3A4 and/or P-glycoproteins is not recom- median tacrolimus levels over the first 30 days for the mended, recent studies have demonstrated that some of patients in the control group (8.2 vs 7.3 ng/mL, P ¼ 0.05). these agents, including azole antifungal agents may be In response to elevated post-loading sirolimus levels administered concomitantly if careful monitoring and dose clinicians drastically reduced the sirolimus dose, which led adjustment of sirolimus is employed.9,10 to subtherapeutic sirolimus levels (o5 ng/mL) in six Our data must be interpreted with caution since the patients in the aprepitant group. study was retrospective, with a small number of patients

Table 2 Outcomes

Variable Cases (n ¼ 14) Controls (n ¼ 71) P-value

First tacrolimus level, ng/mL 9.2 (6.4–26.4) 8.6 (4.3–46.8) 0.13 1 Day after loading, ng/mL 8.8 (6.4–26.4, n ¼ 10) 11.2 (4.3–15.1, n ¼ 56) 2 Days after loading, ng/mL 9.8 (8.3–11.2, n ¼ 2) 11.1 (7.3–46.8, n ¼ 8) 3 Days after loading, ng/mL 20.2 (14.3–26.2, n ¼ 2) 18.1 (9.1–44.4, n ¼ 6) Median tacrolimus level over 30 days post HSCT, ng/mL 7.3 (3.6–9.8) 8.2 (4.1–12.8) 0.05 Median number of labs collected over 30 days 8.5 (3–9) 9 (1–9) First sirolimus level, ng/mL 29.2 (8.5–53.3) 13.5 (3.7–59.0) 0.003 1 Day after loading, ng/mL 31.7 (11.6–53.3, n ¼ 10) 14.3 (3.7–49.7, n ¼ 58) 2 Days after loading, ng/mL 21.2 (8.5–33.8, n ¼ 2) 10.5 (5.1–12.1, n ¼ 8) 3 Days after loading, ng/mL 26.9 (24.0–29.7, n ¼ 2) 10.5 (6.6–59.0, n ¼ 5) Median sirolimus level over 30 days post HSCT, ng/mL 6.7 (4.6–9.5) 7.3 (4.3–15.0) 0.54 Median number of labs collected over 30 days 8.5 (6–9) 8 (1–15)

Acute GVHD Yes 9 (64.3) 35 (50.0) Grade I 4 (44.4) 12 (30.0) Grade II 4 (44.4) 22 (55.0) Grade III 1 (11.1) 3 (7.5) Grade IV 0 (0.0) 3 (7.5) No 4 (28.6) 35 (46.7) Non-evaluable 1 (7.1) 4 (5.7) Time to acute GVHD (days) 29 (7–69) 25 (7–87)

Vital status Alive 9 (64.3) 63 (84.0) Dead 5 (35.7) 12 (16.0) Follow-up (months) 4.5 (0.4–11.9) 5.9 (0.1–12.6)

P-values are determined using Wilcoxon rank-sum tests.

Bone Marrow Transplantation Letter to the Editor 293 analyzed. There are likely to be other factors not examined guideline for antiemetics in oncology: update 2006. J Clin in this study that may exert an impact on the drug levels Oncol 2006; 24: 2932–2947. such as genetic variation in drug-metabolism genes includ- 2 NCCN Practice Guidelines in Oncologyt Antiemetics ing CYP3A4. In summary our data demonstrate the drug Version. 2010. http://www.nccn.org/professionals/physician_gls/ interaction between sirolimus and aprepitant, and strongly f_guidelines.asp. suggest that lowering the current 12 mg loading dose on 3 McCrea JB, Majumdar AK, Goldberg MR, Iwamoto M, Gargano C, Panebianco DL et al. Effects of the neurokinin-1 day À3 should be considered, and that serum levels should receptor antagonist aprepitant on the pharmacokinetics of be closely monitored. dexamethasone and methylprednisolone. Clin Pharmacol Ther 2003; 74: 17–24. Conflict of interest 4 Ibrahim RB, Abidi MH, Ayash LJ, Cronin SM, Cadotte C, Mulawa J et al. Effect of aprepitant on intravenous tacrolimus disposition in reduced intensity hematopoietic stem cell The authors declare no conflict of interest. transplantation. J Oncol Pharm Pract 2008; 14: 113–121. 5 Cutler C, Kim H, Hochberg E, Ho V, Alyea E, Lee S et al. Acknowledgements Sirolimus and tacrolimus without methotrexate as graft- versus-host disease prophylaxis after matched related donor peripheral blood stem cell transplantation. Biol Blood and We acknowledge our transplant coordinators and transplant Marrow Transplant 2004; 10: 328–336. nurses for their dedicated care of our patients, and all the 6 Rodriguez R, Nakamura R, Palmer J, Parker P, Shayani S, members of the Hematopoietic Cell Transplant Team for their Nademanee A et al. A phase II pilot study of tacrolimus/ constant support of the program. We also thank clinical research sirolimus GVHD prophylaxis for sibling donor hematopoietic associates and statistical assistants for their support on data stem cell transplantation using 3 different conditioning management and collections. We also thank Dr Sandra Thomas regimens. Blood 2010; 115: 1098–1105. for her critical reading of the manuscript. 7 Vicari-Christensen N, Repper S, Basile S, Young D. S Shayani1, JM Palmer2, T Stiller2, H Chan1, S Keuylian1, Tacrolimus: review of pharmacokinetics, pharmacodynamics, P Parker3, S Thomas3, V Pullarkat3, A Nademanee3, and pharmacogenetics to facilitate practitioner’s understand- SJ Forman3 and R Nakamura3 ing and offer strategies for educating patients and promoting 1Department of Pharmacy, City of Hope, Duarte, CA, USA; adherence. Progr Transplant 2009; 19: 277–284. 8 Sattler M, Guengerich FP, Yun CH, Christians U, Sweing K. 2Division of Biostatistics, City of Hope, Duarte, CA, USA 3 Cytochrome P-450 3A enzymes are responsible for bio- and Department of Hematology & Hematopoietic Cell transformation of FK506 and rapamycin in man and rat. Transplantation, City of Hope, Duarte, CA, USA Drug Metab Dispos 1992; 20: 753–761. E-mail: [email protected] 9 Marty FM, Lowry CM, Cutler CS, Campbell BJ, Fiumara K, Baden LR et al. Voriconazole and sirolimus coadministration after allogeneic hematopoietic stem cell transplantation. Biol References Blood Marrow Transplant 2006; 12: 552–559. 10 Sadaba B, Campanero MA, Quetglas EG, Azanza JR. Clinical 1 Kris MG, Hesketh P, Somerfield M, Feyer P, Clark-Snow R, relevance of sirolimus drug interactions in transplant patients. Koeller J et al. American Society of Clinical Oncology Transplant Proc 2004; 36: 3226–3228.

Bone Marrow Transplantation