Pharmacokinetics of- and interaction between aprepitant and dexamethasone

Rationale:
Prophylaxis on chemotherapy induced nausea and vomiting (CINV) is still a major problem in patients receiving highly emetogenic therapy, which has important consequences for quality of life during chemotherapy administration. Despite standardized prophylaxis patients receiving highly emetogenic therapy achieve a variable complete response rate (no vomiting and no rescue treatment) of 70-90%.6–8 One of the possible explanations could be that the interaction between oral dexamethasone and aprepitant is different from the interaction between iv dexamethasone and aprepitant. Aprepitant and dexamethasone show a mutual drug-drug interaction, which has been studied in adults. As a rule of thumb a 50% dose-reduction of dexamethasone is applied with treatment is combined with aprepitant. However, the difference in interaction between these dosage forms has not been studied yet. From pharmacological perspective, it can be expected that the interaction is stronger for orally given dexamethasone, since aprepitant can inhibit CYP3A4-enzymes in the GI-tract as well, which can alter the absorption of dexamethasone. With the results of this proposed study the differences in the interaction between oral dexamethasone and aprepitant and the interaction between iv dexamethasone and aprepitant will be studied.

Primary objective:
The primary objective of this study is to define the differences in the interaction between oral dexamethasone and aprepitant and the interaction between iv dexamethasone and aprepitant.

Secondary objective:
The secondary objective of this study is to describe the PK of aprepitant and dexamethasone together with the results of an ongoing study in pediatric patients (in the Princess Maxima Center for pediatric oncology), to describe the age dependent differences in PK of dexamethasone and aprepitant.

Study design:
Prospective observational study

Study population:
All patients treated in the NKI who will receive intravenously administered chemotherapy and dexamethasone with or without aprepitant as standard of care antiemetic agents.
Two different patient groups will be enrolled in the study: 1) Stratum A: dexamethasone only (n=10); 2) Stratum B: dexamethasone and aprepitant (n=10). In both strata, we include 10 patients. These patients will be sampled twice: one course where dexamethasone is given orally and another course where dexamethasone is given intravenously.

Main study parameters/ endpoints:
Pharmacokinetic parameters (i.e. clearance and volume of distribution) will be assessed using non-linear mixed effects modelling (NONMEM). Influence of relevant co-variates will be assessed by standard model building methods.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness:
The patient has no direct benefit from participating in this study. The data obtained in this
study will be used to assess the population PK of aprepitant and dexamethasone, and their interaction in patients with cancer. Insight in the PK of these antiemetic drugs may result in improved dosing guidelines and/or individualized dosing regimens based on therapeutic drug monitoring, ultimately resulting better anti-emetic control. The only consequence of study participation is that additional blood samples will be withdrawn. The here applied sampling strategy is minimally invasive. The volume of blood that is withdrawn for the study does not exceed the recommended maximum; see 6.3.3 Blood sampling for pharmacokinetics. Sampling, using a flexible time scheme, will only be requested during regular hospital visits.

We will measure 6 blood samples of 4 ml each per patient on the first treatment day allowing population pharmacokinetic modelling. Drug-levels of aprepitant and dexamethasone will be measured in each sample using a validated LC-MS/MS method.

Sample times:
Sample 1 (4 ml): t = 0.5 hour after first administration of dexamethasone and aprepitant
Sample 2 (4 ml): t = 1-2 hours after first administration of dexamethasone and aprepitant
Sample 3 (4 ml): t = 4 hours after first administration of dexamethasone and aprepitant
Sample 4 (4 ml): t = 6 hours after first administration of dexamethasone and aprepitant
Sample 5 (4 ml): t = 12 hours after first administration of dexamethasone and aprepitant
Sample 6 (4 ml): t = 24 hours, just before the second administration of dexamethasone and aprepitant

Interaction between oral dexamethasone and aprepitant is different than the interaction between iv dexamethasone and aprepitant.

Start date
2020-Nov-01

Stop date
2021-Apr-01