Lack of effect of aprepitant on the pharmacokinetics of docetaxel in cancer patients

Background Aprepitant is a selective neurokinin-1 receptor antagonist that is effective for the prevention of nausea and vomiting caused by highly emetogenic chemotherapy. In vitro, aprepitant is a moderate inhibitor of the CYP3A4 enzyme, which is involved in the clearance of several chemotherapeutic agents. In this study we examined the potential for aprepitant to affect the pharmacokinetics and toxicity of intravenously administered docetaxel, a chemotherapeutic agent that is primarily metabolized by CYP3A4.Methods A total of 11 cancer patients (4 male, 7 female, aged 50–68 years) were enrolled in this multicenter, randomized, open-label, two-period, crossover study. Patients received a single infusion of docetaxel monotherapy, 60–100 mg/m², on two occasions at least 3 weeks apart. During one of the cycles (treatment A), patients received docetaxel alone. During the alternate cycle (treatment B), they also received aprepitant 125 mg orally 1 h prior to docetaxel infusion (day 1), and a single oral dose of aprepitant 80 mg on days 2 and 3. The pharmacokinetic profile of docetaxel was assessed over 30 h following docetaxel infusion. Blood counts were monitored on days 1, 4, 7, and 14.Results Ten patients completed the study. Concomitant administration of aprepitant did not cause any statistically or clinically significant changes in docetaxel pharmacokinetics. Values for docetaxel alone (treatment A) versus docetaxel with aprepitant (treatment B) were as follows: geometric mean AUC_0–last was 3.26 vs 3.17 g h/ml (P>0.25; ratio B/A 0.97); geometric mean AUC_0– 3.51 vs 3.39 g h/ml (P>0.25; ratio B/A 0.96); geometric mean C_max was 3.53 vs 3.37 g/ml (P>0.25; ratio B/A 0.95); and geometric mean plasma clearance was 23.3 vs 24.2 l/h/m² (P>0.25; ratio B/A 1.04). The corresponding harmonic mean half-life values were 10.1 and 8.5 h. The two treatment regimens had similar tolerability profiles; the median absolute neutrophil count nadirs were 681/mm³ during treatment with docetaxel alone and 975/mm³ during aprepitant coadministration.Conclusions Aprepitant had no clinically significant effect on either the pharmacokinetics or toxicity of standard doses of docetaxel in cancer patients. Aprepitant at clinically recommended doses may have a low potential to affect the pharmacokinetics of intravenous chemotherapeutic agents metabolized by CYP3A4.     

Population pharmacokinetics of aprepitant and dexamethasone in the prevention of chemotherapy-induced nausea and vomiting

Purpose  To develop a population pharmacokinetic model of aprepitant and dexamethasone in Japanese patients with cancer, explore the factors that affect the pharmacokinetics of aprepitant, and evaluate the effect of aprepitant on the clearance of intravenous dexamethasone. Methods  A total of 897 aprepitant concentration measurements were obtained from 290 cancer patients and 25 healthy volunteers. For dexamethasone, a total of 847 measurements were obtained from 440 patients who were co-administered aprepitant (40, 125 mg, or placebo). Plasma concentration of aprepitant and dexamethasone were determined by liquid chromatography connected with a tandem mass spectrometer and analyzed by a population approach using NONMEM software. Results  The plasma concentration time course of aprepitant was described using a one-compartment model with first-order absorption and lag time. Oral clearance (CL/F) of aprepitant was changed by aprepitant dose at doses of 40 or 125 mg. Body weight was the most influential intrinsic factor to CL/F of aprepitant. Age, ALT, and BUN also had mild effects on the CL/F. Typical population estimates of CL/F, apparent distribution volume (V _d/F), absorption constant (K _a) and absorption lag time were 1.54 L/h, 72.1 L, 0.893/h and 0.295 h, respectively. Inter-individual variability in CL/F, V _d/F and K _a were 53.9, 21.0, and 141%, respectively; intra-individual variability was 27.7%. The plasma concentration time course of intravenous dexamethasone was also described using a one-compartment model. Clearance of dexamethasone was decreased 24.7 and 47.5% by co-administration of aprepitant 40 and 125 mg. All final model estimates of aprepitant and dexamethasone fell within 10% of the bootstrapped mean. Conclusions  A pharmacokinetic model for aprepitant has been developed that incorporates body weight, age, ALT, BUN and aprepitant dose to predict the CL/F. The results of population pharmacokinetic analysis of dexamethasone support dose adjustment of dexamethasone in the case of co-administration with aprepitant.     

Aprepitant exerts anti-fibrotic effect via inhibition of TGF-β/Smad3 pathway in bleomycin-induced pulmonary fibrosis in rats

Bleomycin is a well-recognized antineoplastic drug. However, pulmonary fibrosis (PF) is considered to be the principal drawback that greatly limits its use. Here, we sought to investigate ability of the neurokinin receptor 1 blocker, aprepitant, to prevent PF caused by bleomycin. Male adult Wistar rat groups were given a single intratracheal injection of bleomycin, either alone or in combination with aprepitant therapy for 3 or 14 days. Collagen deposition and a rise in transforming growth factor beta (TGF-β) immunoreactivity in lung tissue serve as evidence of bleomycin-induced PF. The serum levels of lactate dehydrogenase, alkaline phosphatase, and total antioxidant improved after aprepitant therapy.Additionally, it reduced the protein expressions of interferon alpha, tumor necrosis factor alpha, and lung lipid peroxidation. Moreover, aprepitant treatment led to an increase in the antioxidant indices glutathione, glutathione peroxidase, and catalase. Aprepitant is postulated to protect against bleomycin-induced PF by decreasing TGF-β, phosphorylating Smad3, and increasing interleukin 37, an anti-fibrotic cytokine, and G Protein-coupled Receptor Kinase 2. Aprepitant for 14 days considerably exceeded aprepitant for 3 days in terms of improving lung damage and having an anti-fibrotic impact. In conclusion, aprepitant treatment for 14 days may be used as an adjuvant to bleomycin therapy to prevent PF, mostly through inhibiting the TGF-/p-Smad3 fibrotic pathway.     

隔物灸联合阿瑞匹坦及昂丹司琼对晚期肺癌含顺铂方案化疗所致恶心呕吐的预防效果研究

目的:探讨隔物灸联合阿瑞匹坦、昂丹司琼预防晚期肺癌患者顺铂化疗胃肠道毒副反应的临床效果。方法:对80例晚期肺癌化疗患者临床资料进行回顾性分析,单纯服用阿瑞匹坦及昂丹司琼者纳入对照组（n=46）,在其基础上联合采取隔物灸治疗者纳入观察组（n=34）。比较化疗第1周期（T₁）、化疗第2周期（T₂）、化疗第3周期（T₃）、化疗第4周期（T₄）结束时,两组患者中医症状积分（嗳气反酸、饮食减少、疲乏无力）变化,分析化疗4周期内,两组患者恶心呕吐及非化疗药物不良反应发生情况。结果:T₁结束时,两组各项中医症状积分比较,差异无统计学意义（P>0.05）。T₂、T₃、T₄结束时,观察组嗳气反酸、饮食减少、疲乏无力中医症状积分与T₁结束时比较,差异无统计学意义（P>0.05）,但明显低于同一时间对照组（P<0.05）。化疗4周期内,观察组发生恶心呕吐严重程度明显较对照组更轻,中重度率显著低于对照组（P<0.05）;两组肝功能损害、腹胀/便秘、皮疹、呃逆、眩晕/嗜睡等非化疗药物不良反应发生率比较,差异无统计学意义（P>0.05）。结论:隔物灸联合阿瑞匹坦及昂丹司琼能有效减轻晚期肺癌患者在顺铂化疗方案中出现的恶心呕吐症状,药物安全性良好且不易于产生耐药性,对改善其预后生存质量有利。     

Aprepitant when added to a standard antiemetic regimen consisting of ondansetron and dexamethasone does not affect vinorelbine pharmacokinetics in cancer patients

Purpose Aprepitant, a selective neurokinin-1 (NK-1) receptor antagonist approved for the treatment and prevention of emesis caused by moderately and highly emetogenic chemotherapy, is an inhibitor, inducer, and substrate of the cytochrome P450 3194 pathway. The CYP3A4 pathway is the major pathway of the metabolism of vinorelbine, a vinca alkaloid frequently used in combination with cisplatin. Therefore, we studied the potential interaction of the aprepitant 3-day antiemetic regimen on the pharmacokinetics of vinorelbine. Patients and methods Fourteen patients with metastatic solid tumors were included in this open-label, balanced, 2-period crossover study. In treatment arm A, vinorelbine (25 mg/m² weekly) was administered alone, while in treatment arm B the same dose of vinorelbine was administered following the administration of the aprepitant antiemetic regimen on day 1 and alone on day 8. The antiemetic regimen of aprepitant was comprised of the following; on day 1: 125 mg aprepitant, 12 mg dexamethasone, and 32 mg ondansetron; on days 2 and 3: 80 mg aprepitant and 8 mg dexamethasone and on day 4: 8 mg dexamethasone. Blood samples for vinorelbine pharmacokinetic analysis were collected over 96 h. Results Two patients discontinued the study due to adverse events that were judged not to be drug-related. Complete pharmacokinetic data of vinorelbine administered alone and with the aprepitant antiemetic regimen were obtained in 12 patients. The mean plasma concentration profile of vinorelbine administered with aprepitant was identical to that following vinorelbine administered alone, with geometric mean vinorelbine plasma AUC ratios of treatment B day 1/treatment A day 1 and of treatment B day 8/treatment A day of 1.01 (0.93, 1.10) and 1.00 (0.92, 1.08), respectively. Conclusion As the aprepitant antiemetic regimen has no detectable inhibitory or inductive effect on the pharmacokinetics of vinorelbine, aprepitant when added to a standard antiemetic regimen consisting of ondansetron and dexamethasone can be safely combined with vinorelbine at clinically recommended doses.     

Simultaneous determination of Aprepitant and two metabolites in human plasma by high-performance liquid chromatography with tandem mass spectrometric detection

A method for the simultaneous determination of Aprepitant, I (5-[[2(R)-[1(R)-(3,5-bistrifluoromethylphenyl)ethoxy]-3(S)-(4-fluorophenyl) morpholin-4-yl]methyl]-2,4-dihydro-[1,2,4]triazol-3-one) and two active metabolites (II and III) in human plasma has been developed. The method was based on high-performance liquid chromatography (HPLC) with atmospheric pressure chemical ionization tandem mass spectrometric (APCI-MS-MS) detection in positive ionization mode using a heated nebulizer interface. The analytes and internal standard (IV) (Fig. 1) were isolated from basified plasma using liquid–liquid extraction. The organic extracts were dried, reconstituted in mobile phase and injected into the HPLC-MS/MS system.

The analytes were chromatographed on a narrow bore (50 mm×2.0 mm, 3 μm) Keystone Scientific’s Prism R.P. analytical column, with mobile phase consisting of acetonitrile (ACN):water containing trifluoroacetic acid with pH adjusted to 3 (40:60, v/v) pumped at a flow rate of 0.5 ml/min. The MS-MS detection was performed on a Sciex API 3000 tandem mass spectrometer operated in selected reaction monitoring mode. The precursor→product ion combinations of m/z 535→277, 438→180, 452→223 and 503→259 were used to quantify I, II, III, and IV, respectively, after chromatographic separation of the analytes. The assay was validated in the concentration range of 10–5000 ng/ml for I and II and 25–5000 ng/ml for III when 1 ml of plasma was processed. The precision of the assay (expressed as coefficient of variation, CV) was less than 10% at all concentrations within the standard curve range, with adequate assay accuracy. Matrix effect experiments were performed to demonstrate the absence of any significant change in ionization of the analytes when comparing neat standards to analytes in the presence of plasma matrix. This assay was utilized to support a clinical study where multiple oral doses of I were administered to healthy subjects to investigate the pharmacokinetics, safety, and tolerability of Aprepitant. Concentrations of the two most active metabolites, which if present in high concentrations would increase the neurokinin-1 (NK₁) receptor occupancy level and therefore potentially contribute to the antiemetic action of Aprepitant, were determined.     

Cost-effectiveness analysis of aprepitant in the prevention of chemotherapy-induced nausea and vomiting in Belgium

OBJECTIVES: Chemotherapy-induced nausea and vomiting (CINV) remains a major adverse effect of cancer chemotherapy which may increase morbidity, reduce quality of life and threaten the success of cancer therapy. Aprepitant is effective in preventing CINV, achieving higher complete response (no emesis and no rescue therapy) compared to standard prevention, in patients receiving either highly (HEC) or moderately emetogenic chemotherapy (MEC; absolute reduction = 11 and 13%, respectively). We assessed the cost effectiveness of aprepitant-based vs standard prevention in these indications in Belgium. MATERIALS AND METHODS: A decision analytical model was developed in MS Excel (Fig. 1). To estimate resource use, two approaches were used. The first is based on the preventive regimens applied in randomized controlled trials comparing aprepitant-based CINV prevention (for HEC: aprepitant days 1-3, ondansetron 32 mg i.v. day 1, oral placebo twice daily days 2-4, oral dexamethasone days 1-4; for MEC: aprepitant days 1-3, ondansetron 16 mg p.o. day 1, placebo on days 2-3, oral dexamethasone day 1), vs a standard regimen (for HEC: oral placebo days 1-3, ondansetron 32 mg i.v. day 1 and 16 mg p.o. days 2-4, oral dexamethasone days 1-4; for MEC: oral placebo, ondansetron 16 mg p.o. days 1-3, dexamethasone day 1) The second analysis is based on current real-world resource use in the Belgian setting in the prevention of CINV using a longitudinal Hospital Database. CINV-specific utility values were used to calculate quality-adjusted life years (QALYs). Drug costs were obtained from official reimbursement listings. Treatment costs for CINV were obtained from a German study and adapted to Belgium. RESULTS: The aprepitant-based regimen is associated with 0.003 and 0.014 more QALYs in HEC and MEC, respectively and with per patient savings of 66.84 (trial based) and 74.62 (real-life based) for HEC and 17.95 (trial based) and 21.70 (real-life based) for MEC. Hence, aprepitant is both more effective and less expensive (=dominant). One-way sensitivity analyses were performed on treatment cost of emesis, the clinical benefit of aprepitant and the cost of ondansetron and showed that the results were robust on the first two parameters but sensitive on the decrease in cost of ondansetron for the moderately emetogenic chemotherapy regimens. CONCLUSIONS: In both approaches, the aprepitant-based strategy is more effective and less expensive compared to standard care.