| I havent posted on here much lately since there hasn't been much going on. So here's a paper I just finished for Drug Literature Evaluation... The Use of Aprepitant For Treatment and Prophylaxis of Chemotherapy-Induced Nausea and Vomiting
by Luke Glarum Chemotherapy-induced nausea and vomiting, or CINV, is described as nausea and vomiting, caused by chemotherapy, with an upset stomach which may trigger a strong urge to forcefully eliminate what is in the stomach.1 This occurs due to the emetogenic properties of some chemotherapy regimens including; cisplatin, CHOP (cyclophosphamide + doxorubicin + vincristine + prednisone), AC (doxorubicin + cyclophosphamide), carboplatin, ABVD (doxorubicin + bleomycin + vinblastine + dacarbazine), and FOLFOX/FOLFIRI (oxaliplatin + leucovorin + 5-fluorouracil/irinotrecan + leucovorin + 5-flurouracil). CINV can also be attributed to a short IV infusion time, repeated cycles of chemotherapy, being a female, age >50 years, history of low alcohol intake (<1.5oz/day), history of motion sickness, and prior history of CINV. 2 Overall, 60-80% of patients who are not given prophylactic antiemetic treatment are at risk to develop CINV.3 There have been three types of CINV identified, acute, delayed, and anticipatory. Acute CINV has been defined as symptoms occurring within 24 hours of chemotherapy administration with most symptoms occurring during the first 4 hours post dose. Delayed CINV is described as symptoms showing up more than 24 hours post dose with effects that may last for many days. The last type of CINV is called anticipatory and is a conditioned response to chemotherapy that is triggered by neutral stimuli that normally would not cause symptoms. These stimuli can be related to the smells, sights and sounds of the clinic where the chemotherapy is being administered. Also, in patients who have previously experienced uncontrolled CINV, anticipatory CINV often starts prior to starting a new cycle of chemotherapy. 3 There are two biological pathways that have been identified as causes of CINV. The first pathway that has been implicated is a pathway called the peripheral pathway. This pathway involves the binding of serotonin to 5-HT3 receptors located in the gut. The 5-HT3 receptors were thought to be solely responsible for CINV, but as time went on it was discovered that they are really only half of the reason. Another pathway, the central pathway, involves a compound called Substance P that binds to NK-1 receptors that are highly concentrated in the emetic center of the brain. 2 Aprepitant is a neurokinin-1(NK-1) receptor antagonist which gives it the ability to inhibit the emetic effects of the central pathway in the brain. It is not a drug that can be used by itself to combat CINV but in combination with ondansetron, a 5-HT3 antagonist that helps block the peripheral emetic pathway, and dexamethasone which potentiates the effect of ondansetron. A study on ferrets, an animal that exhibits human-type NK1 receptor pharmacology, was conducted to observe the pharmacokinetic, metabolism, and brain penetration of the drug. It was not known whether or not the lengthy antiemetic activity was due to aprepitant itself, any of its many metabolites, or a combination of the two. For the pharmacokinetic study, the ferrets were dosed with oral aprepitant (1mg/kg) by gavage, or a feeding tube, and blood was taken at predose, 5, 15, and 30 min as well as 1, 2, 4, 6, 8, 10, 24, 32, 48, 56, and 72hrs post dose. For the brain penetration study, two groups of ferrets were dosed orally, 2mg/kg and 4mg/kg respectively, and blood samples were taken from anesthetized ferrets at 1, 2, 4, 10, and 24 hrs post dose. The brains were collected and stored at -70°C while the plasma was separated from all blood samples and stored at -20°C until analysis could be conducted.4 Previous studies had shown that cisplatin administration caused vomiting in ferrets just as it does in humans. The results of this study showed that complete prevention of retching and vomiting occurred for 72 hrs when ferrets were challenged with cisplatin after being dosed with aprepitant.4 This strengthens the idea that this drug is a good choice for limiting the effects of emetogenic chemotherapy in humans. The study also showed that the prevention of CINV in ferrets was due to aprepitant itself and not the metabolites, mainly due to the fact that aprepitant has a ~4-7000 fold higher affinity for the NK1 receptor than any of its metabolites.4 A study was conducted in an attempt to determine that the antiemetic effect occurring during delayed CINV wasn’t due to a carryover antiemetic effect from the acute CINV treatment. This study tested the relationship of acute (AV) and delayed vomiting (DV) and was conducted using data that had been pooled from two randomized, double-blind, phase III studies with identical designs. In this study 1034 patients who were being treated with a high-dose cisplatin regimen were given either a standard antiemetic regimen (SAR) or an aprepitant based regimen (ApAR). The SAR consisted of ondansetron 32mg IV and dexamethasone 20mg PO on day 1, and dexamethasone 8mg PO BID on days 2-4. The ApAR consisted of aprepitant 125mg PO, ondansetron 32mg IV, and dexamethasone 12mg on day 1, aprepitant 80mg PO and dexamethasone 8mg PO on days 2-3, and dexamethasone 8mg PO on day 4. Results showed conclusively that the drugs effect on DV is not a carryover effect from the prevention of AV, but is an actual pharmacological effect in and of itself.5 In most cases a single chemotherapeutic dose is not sufficient for treatment and multiple cycles must be endured. A study by de Wit, et al. evaluating whether or not aprepitant can sustain its antiemetic effect over multiple cycles of chemotherapy was conducted using three groups with different dosing regimens. Group 1 was given 375mg aprepitant 1hr before cisplatin on day 1 and 250mg aprepitant on days 2-5. Group 2 was given 125mg aprepitant before cisplatin on days 2-5. Group 3 was given placebo before cisplatin on days 2-5. In addition to the aprepitant or placebo, all groups were given ondansetron 32mg and dexamethasone 20mg before cisplatin on day 1 and dexamethasone 8mg on days 2-5. Results were measured as complete response to therapy over five days after cisplatin dosing for up to six chemotherapeutic cycles. Response after the first cycle was 64% in the aprepitant groups and 49% in the standard treatment group. After the sixth cycles the aprepitant groups still showed a 59% response with the standard group’s response had dropped to 34%. This confirms the fact that aprepitant provides a more sustained effect against CINV over multiple cycles vs. standard therapy.6 A separate study was conducted using a similar study model with the results agreeing with those found by Herrstedt, et al.7 In regards to the economic aspect of adding aprepitant to the existing standard antiemetic treatment, one would think that an increase in health care cost would be evident. A study evaluating the cost difference between standard therapy and aprepitant based therapy was conducted using standard dosing regimens which were based on clinical results and utilization of healthcare resources observed in a large clinical trial testing aprepitant in patients undergoing moderately-emetogenic chemotherapy. Again, an SAR and ApAR were used consisting of: the SAR using ondansetron 8mg PO BID and dexamethasone 20mg PO on day 1, and ondansetron 8mg PO BID on days 2-3, and the ApAR consisting of aprepitant 125mg PO, ondansetron 8mg PO BID, and dexamethasone 12mg on day 1, and aprepitant 80mg PO on days 2-3. The study showed that 51.3% in the aprepitant group were complete responders over the entire chemotherapy cycle vs. 42.7% showing complete response in the standard regimen. While the increased cost of the additional aprepitant in the ApAR might increase overall cost, the decreased amount of ondansetron used nearly offsets the entire aprepitant cost. This is a good finding that shows the positive effects of aprepitant can be had with nearly no additional cost to the patient.8 Another study testing the effect that antiemetic therapy had on the daily lives of the patients was conducted. What was being tested is called the functional relevance in regards to a set of 9 questions asking the patient how the nausea and vomiting, separately, has affected activities in their daily life, this is called the Functional Living Index-Emesis. The first item asks how much nausea or vomiting they have experienced over the last 5 days. The following 8 questions ask the patient how the nausea or vomiting has affected these aspects of their life: ability to enjoy meals/liquids, prepare meals/do household tasks, perform daily functions, perform usual recreation/leisure activities, willingness to spend time with family and friends, and the extent to which the side-effect has caused personal hardship and hardship on others. Each item is answered on a 100mm visual scale labeled from 1 on the far left to 7 on the far right, dividing the scale into 6 equal sections. The scores are summed up with higher scores indicating a lesser effect of the nausea and vomiting on daily life and a more effective drug regimen. Complete response is defined as a score >6 on the scale. Results showed that 65% of patients dosed with varying levels of aprepitant showed a complete response with only 44% showing complete response in the standard therapy group. This study again shows the efficacy of aprepitant against standard therapy for CINV.9 Results of previously reviewed studies along with other data shows that CINV can be controlled in ~60% of patients receiving highly emetogenic chemotherapy and ~60-80% of patients being treated with moderately emetogenic therapy.3 This, along with the nearly identical drug cost, leads me to believe that the NK1 receptor antagonist aprepitant when given with a 5-HT3 receptor antagonist is currently the best available treatment for CINV.
References 1. CancerNausea. Hoffman-LaRoche, Inc. Available at: www.CancerNausea.com. 2. Emend. Merck & Co., Inc. Available at: www.emend.com. 3. manageCINV. MGI Pharma, Inc. Available at: www.manageCINV.com. 4. Huskey S, Dean B, Bakhtiar R, et al. Brain penetration of aprepitant, a substance P receptor antagoinist, in ferrets. ASPET. 2003;31:785-791. 5. Horgan K, Grunburg S, Hesketh P, et al. Analysis of pooled data from two Phase III studies of the NK-1 antagonist aprepitant to assess relationships between the incidence and control of cisplatin-induced acute vomiting and delayed vomiting. EJCS. September 2003;1:S284-285. 6. de Wit R, Herrstedt J, Rapoport B, Carides AD, Carides G, Elmer M, Schmidt C, et al . 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 2003;21:4105-11. 7. Herrstedt J, Muss HB, Warr DG, Hesketh PJ, Eisenberg PD, Raftopoulos H, et al. Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and emesis over multiple cycles of moderately emetogenic chemotherapy. Cancer 2005;104:1548-55. 8. Pellissier J, Briand Y, Davies G, Souchet T, Deuson R. Economic analysis of aprepitant in patients receiving antiemetic prophylaxis with moderately emetogenic chemotherapy in France – results of a decision-analytic model. EJCS. October 2005;3:370. 9. Martin A R, Carides A D, Pearson J D, et al. Functional relevance of antiemetic control: experience using the FLIE questionnaire in a randomised study of the NK-1 antagonist aprepitant. EJC. 2003;39:1395-1401. LBG |
