What literature is there on the interaction between dexamethasone and NK1 inhibitors (e.g., fosaprepitant, aprepitant)? Should the dexamethasone dose be reduced when used concomitantly?

Comment by InpharmD Researcher

Current literature suggests that fosaprepitant and aprepitant can significantly affect the pharmacokinetics of dexamethasone. When coadministered with dexamethasone, aprepitant and fosaprepitant have been found to act as moderate and weak inhibitors of CYP3A4, respectively. Coadministration with aprepitant resulted in a 2.2-fold increase in dexamethasone exposure. This heightened exposure may increase the risk of adverse effects associated with high doses of dexamethasone. To address this concern, it is recommended to reduce the dexamethasone dose by 50%. Additionally, Tables 1 and 2 provide comprehensive dose adjustments derived from fosaprepitant and aprepitants prescribing information.

Background

A 2017 systematic review describing aprepitant and fosaprepitant drug interactions indicates a clinically significant pharmacokinetic interaction with dexamethasone. Aprepitant and fosaprepitant are moderate and weak inhibitors of CYP3A4, respectively, and may influence the toxicity and efficacy of concomitantly administered CYP3A4 substrates such as dexamethasone. Reduced clearance or measures indicating reduced clearance have been observed for victim drugs which are CYP3A4 substrates including dexamethasone intravenous. A reduction of dexamethasone clearance by approximately 25% and 50% in the presence of aprepitant 40 mg or 125 mg, respectively, was observed in population pharmacokinetic studies. [1], [2], [3]

A 2018 review investigates the effect of aprepitant on the metabolism of various drugs commonly used during chemotherapy. When co-administered with dexamethasone, aprepitant was found to act as a moderate inhibitor of the CYP3A4 enzyme, leading to a 2.2-fold increase in the area under the concentration-time curve (AUC) of dexamethasone. This increase in dexamethasone exposure can potentially lead to a higher risk of serious adverse effects associated with high doses of dexamethasone, such as infections and mental disturbances. Evaluated pharmacokinetic studies with aprepitant also found that this interaction remains consistent whether dexamethasone is administered orally or intravenously. To mitigate this risk, it is recommended to reduce the dose of dexamethasone by 50% when it is used in conjunction with aprepitant. [4]

Similarly, a 2010 literature review examined potential drug-drug interactions involving aprepitant, primarily in the context of chemotherapy-induced nausea and vomiting prevention. The addition of aprepitant to both standard and modified oral dexamethasone regimens was found to result in an increase in dexamethasone exposure, leading to the same recommendation to reduce the oral dexamethasone dose by 50% when coadministered with aprepitant. However, it was noted that while oral dexamethasone should be reduced, a similar reduction may not be necessary for IV dexamethasone due to less CYP3A4 gut effect involvement. [4], [5]

References:

[1] Patel P, Leeder JS, Piquette-Miller M, Dupuis LL. Aprepitant and fosaprepitant drug interactions: a systematic review. Br J Clin Pharmacol. 2017;83(10):2148-2162. doi:10.1111/bcp.13322
[2] Nakade S, Ohno T, Kitagawa J, et al. Population pharmacokinetics of aprepitant and dexamethasone in the prevention of chemotherapy-induced nausea and vomiting. Cancer Chemother Pharmacol. 2008;63(1):75-83. doi:10.1007/s00280-008-0713-y
[3] Takahashi T, Nakamura Y, Tsuya A, Murakami H, Endo M, Yamamoto N. Pharmacokinetics of aprepitant and dexamethasone after administration of chemotherapeutic agents and effects of plasma substance P concentration on chemotherapy-induced nausea and vomiting in Japanese cancer patients. Cancer Chemother Pharmacol. 2011;68(3):653-659. doi:10.1007/s00280-010-1519-2
[4] Schoffelen R, Lankheet AG, van Herpen CML, van der Hoeven JJM, Desar IME, Kramers C. Drug-drug interactions with aprepitant in antiemetic prophylaxis for chemotherapy. Neth J Med. 2018;76(3):109-114.
[5] Aapro MS, Walko CM. Aprepitant: drug-drug interactions in perspective. Ann Oncol. 2010;21(12):2316-2323. doi:10.1093/annonc/mdq149
Relevant Prescribing Information

DRUG INTERACTIONS
Aprepitant is a substrate, a weak-to-moderate (dose-dependent) inhibitor, and an inducer of CYP3A4.
CYP3A4 Substrates: Dexamethasone
Increased dexamethasone exposure; reduce the oral dose of dexamethasone by approximately 50%. [6]

DRUG INTERACTIONS
When administered intravenously, fosaprepitant, a prodrug of aprepitant, is converted to aprepitant within 30 minutes. Therefore, drug interactions following administration of EMEND for injection are likely to occur with drugs that interact with oral aprepitant.
Fosaprepitant, given as a single 150-mg dose, is a weak inhibitor of CYP3A4, and the weak inhibition of CYP3A4 continues for 2 days after single dose administration. Single dose fosaprepitant does not induce CYP3A4. Aprepitant is a substrate, an inhibitor, and an inducer of CYP3A4.
CYP3A4 Substrates: Dexamethasone
Increased dexamethasone exposure; reduce the dose of oral dexamethasone by approximately 50%. [7]

References:

[6] Emend (aprepitant). Prescribing information. Merck Sharpe & Dohme LLC; 2022.
[7] Emend (fosaprepitant dimeglumine injection). Prescribing information. Merck Sharp & Dohm LLC; 2022.
Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

What literature is there on the interaction between dexamethasone and NK1 inhibitors (e.g., fosaprepitant, aprepitant)? Should the dexamethasone dose be reduced when used concomitantly?

Please see Tables 1-3 for your response.

 

Recommended Dexamethasone Dosing in Adults and Pediatric Patients 12 Years of Age and Older Receiving Aprepitant for Prevention of Nausea and Vomiting Associated with Chemotherapy

Highly Emetogenic Chemotherapy
Population

Day 1

 Day 2 Day 3 Day 4

Adults

 12 mg orally 8 mg orally 8 mg orally 8 mg orally

Pediatric Patients 12 Years and Older

 If a corticosteroid, such as dexamethasone, is co-administered, administer 50% of the recommended corticosteroid dose on Days 1 through 4.

Moderately Emetogenic Chemotherapy

Population

 Day 1 Day 2 Day 3 -

Adults

 12 mg orally None None -

Pediatric Patients 12 Years and Older

 If a corticosteroid, such as dexamethasone, is co-administered, administer 50% of the recommended corticosteroid dose on Days 1 through 4.

 

References:

Adapted from: Emend (aprepitant). Prescribing information. Merck Sharpe & Dohme LLC; 2022.

 

Recommended Dexamethasone Dosing in Adults and Pediatric Patients Receiving Fosaprepitant Dimeglumine for Prevention of Nausea and Vomiting Associated with Chemotherapy

Adults - Highly Emetogenic Chemotherapy:

Day 1: 12 mg orally

Day 2: 8 mg orally

Day 3: 8 mg orally twice daily

Day 4: 8 mg orally twice daily

Adults - Moderately Emetogenic Chemotherapy: 12 mg orally

Pediatrics 6 Months to 17 Years - Single-Day Regimens of Highly or Moderately Emetogenic Chemotherapy: If a corticosteroid, such as dexamethasone, is co-administered, administer 50% of the recommended corticosteroid dose on Days 1 and 2.

Pediatric Patients 6 Months to 17 Years - Single- or Multi-Day Regimens of Highly or Moderately Emetogenic Chemotherapy: If a corticosteroid, such as dexamethasone, is co-administered, administer 50% of the recommended corticosteroid dose on Days 1 through 4.

 

References:

Adapted from: Emend (fosaprepitant dimeglumine injection). Prescribing information. Merck Sharp & Dohm LLC; 2022.

 

Clinical interaction between dexamethasone and aprepitant in chemotherapy for lymphoma

Design

Retrospective, single-center, observational, cohort study

N= 62

Objective

To compare the antitumor effect of dexamethasone for lymphoma when dexamethasone dose was reduced in combination with aprepitant to that when dexamethasone was used in a standard dose without aprepitant

Study Groups

No aprepitant; standard-dose dexamethasone  (n= 29)

Concomitant; reduced-dose dexamethasone (n= 33)

Inclusion Criteria

 Patients taking R-DHAP (rituximab, dexamethasone, high-dose cytarabine, and cisplatin) for follicular lymphoma or diffuse large B cell lymphoma (DLBCL)

Exclusion Criteria

 None reported

Methods

This was a retrospective study of lymphoma patients at a single-center in Japan. All patients received DHAP with cisplatin (100 mg/m2 on day 1), cytarabine (2 g/m2 on day 2), and dexamethasone. Rituximab 375 mg/m2 was added before or after DHAP.

The dexamethasone dose depended on whether the patient also received aprepitant. For patients who did not receive aprepitant, the dexamethasone dose was 40 mg/kg on days 1-4; patients who received aprepitant got dexamethasone 20 mg/kg on days 1-4. The dose of aprepitant used was not reported.

The groups were partially stratified by treatment year, since the institution started using aprepitant in 2010.

Duration

December 2005 to February 2017

Outcome Measures

Primary: response rate after first R-DHAP course (per RECIST)

Secondary: overall survival rate, lymphocyte reduction rate (lymphocyte count)

Baseline Characteristics

  

No aprepitant (n= 29)

Concomitant (n= 33)

 p-value

Median age, years (range)

 57 (29-69) 63 (38-73) 0.005

Male

 51.7% 60.6% 0.61

Histology

Follicular lymphoma

DLBCL

 

31%

69%

 

9.1%

90.9%

 0.051

Stage

Stage 1-2

Stage 3-4

 

37.9%

62.1%

 

24.2%

75.8%

 0.28

Disease status

Refractory

Relapsed

 

62.1%

37.9%

 

36.4%

63.6%

 0.074
There was a significant difference in the time patients were treated, with all of the concomitant aprepitant and dexamethasone patients being treated between 2010-2017; only 20.7% who did not receive aprepitant were treated during that period.

Results

Endpoint

No aprepitant (n= 29)

Concomitant (n= 33)

p-value

Response

DLBCL

18 (62.1%)

11/20 (55%)

18 (54.5%)

16/30 (53.3%)

0.61

0.908

Overall survival

2-year

5-year

 

65%

55%

 

70%

70%

0.304

As a surrogate endpoint to evaluate the effect of dexamethasone, serial relative changes in the peripheral blood lymphocyte count over 10 days were measured. A greater reduction in the lymphocyte count was observed in patients who received aprepitant and reduced-dose dexamethasone.

Adverse Events

A higher severity of thrombocytopenia was reported in patients who received aprepitant and reduced-dose dexamethasone (grade3; 6 [18.2%] patients, grade 4; 26 [78.8%] patients) compared to patients who did not receive aprepitant (grade 3; 12 [41.4%] patients, grade 4; 12 [41.4%] patients) (p= 0.0012). No other significant differences in adverse events were noted.
While not significant, the incidence of febrile neutropenia was higher in patients who received aprepitant and reduced-dose dexamethasone (24.2%) compared to patients who did not receive aprepitant (10.3%) (p= 0.159).

Study Author Conclusions

 The effect of treatment with dexamethasone was not impaired by reducing the dose of dexamethasone associated with the addition of aprepitant. Considering the safety profile of this regimen, however, the addition of aprepitant without reducing the dose of dexamethasone should be evaluated in the future.

InpharmD Researcher Critique

 The major limitation of this study is the small sample size from a single Japanese institute. Because most of the aprepitant/reduced-dose dexamethasone patients were from 2010 onward, more recent advances in medicine (e.g. supportive management) may have affected outcomes. Most patients had DLBCL, so the results may not be as applicable for follicular lymphoma; the difference in lymphoma types was large between the groups.



References:

Hatano K, Fujiwara SI, Umino K, et al. Clinical interaction between dexamethasone and aprepitant in chemotherapy for lymphoma. Ann Hematol. 2022;101(6):1211-1216. doi:10.1007/s00277-022-04832-9