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

Nakade, Susumu; Ohno, Tomoya; Kitagawa, Junsaku; Hashimoto, Yoshitaka; Katayama, Masahiro; Awata, Hiroshi; Kodama, Yasuo; Miyata, Yasuyuki

doi:10.1007/s00280-008-0713-y

Cited by 48 publications

(40 citation statements)

References 22 publications

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“…Nakade et al also reported that body weight affected the oral clearance of aprepitant. 10) This inconsistency between the current study and their report on the contribution of body weight to the plasma pharmacokinetics of aprepitant is most likely due to the narrower range of the body weights in our study (40-85 kg) compared to their patients (33-93 kg). earlier studies with various doses of aprepitant indicated some nonlinearity in the disposition of aprepitant, reflecting saturation of metabolism and decreased clearance with an increasing dose.…”

Section: Discussioncontrasting

confidence: 85%

“…Nakade et al reported that ALT affected the oral clearance of aprepitant, 10) although their study did not examine linear correlation. These enzyme activities are affected by not only hepatic function, 19) but also by the extent of liver fat accumulation, 20) insulin resistance, 20,21) inflammation, 22) and oxidative stress.…”

Section: Discussionmentioning

confidence: 94%

“…earlier studies with various doses of aprepitant indicated some nonlinearity in the disposition of aprepitant, reflecting saturation of metabolism and decreased clearance with an increasing dose. 4,10,18) The low oral bioavailability of aprepitant was also reported to be attributed to its slow dissolution rate, poor permeability across the intestinal mucosa, or first-pass metabolism in the gut and liver. 5) Higher T-Bil was correlated with a higher plasma exposure to aprepitant in a univariate analysis.…”

Section: Discussionmentioning

confidence: 99%

“…[6][7][8][9] A population pharmacokinetics study of aprepitant in Japan found that body weight, alanine aminotransferase (ALT), blood urea nitrogen (BUN), and age affected the oral clearance of aprepitant. 10) The authors reported that the changes in aprepitant pharmacokinetics caused by these factors were not clinically significant and they did not examine the linear correlations between aprepitant pharmacokinetics and these factors. The influence of these factors on plasma aprepitant concentrations has not been fully clarified in clinical settings.…”

Section: Interindividual Variations In Aprepitant Plasma Pharmacokinementioning

confidence: 99%

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Interindividual Variations in Aprepitant Plasma Pharmacokinetics in Cancer Patients Receiving Cisplatin-Based Chemotherapy for the First Time

Motohashi

Mino

Hori

et al. 2013

Biological & Pharmaceutical Bulletin

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The pharmacokinetics of aprepitant, a neurokinin-1 receptor antagonist, have not been fully evaluated in clinical settings. The aim of this study was to characterize the plasma pharmacokinetics of aprepitant and reveal their influence of laboratory tests and cytochrome P450 (CYP) 3A5 gene polymorphisms in cancer patients. Forty-four Japanese cancer patients receiving cisplatin-based chemotherapy for the first time following oral aprepitant (125 mg on day 1 and 80 mg on days 2 and 3) were enrolled. The patients did not have gastrointestinal disease and the clinical laboratory values were within their normal reference levels. The plasma concentrations of aprepitant 24 (day 2 predose), 72, and 120 h after the first aprepitant administration were determined using LC-MS/MS. The relationships between plasma exposure to aprepitant and body weight, clinical laboratory values, age, gender, or CYP3A5*3 were investigated. The median and interquartile ranges of the 120-h area under the plasma concentration time curve (AUC) 0-120 of aprepitant were 73215 and 55518-91121 ng h/mL. The coefficient of variation value for aprepitant AUC 0-120 was 53%. The AUC 0-120 of aprepitant was correlated with the levels of total bilirubin and serum albumin, respectively (r=0.454, p<0.01 and r=0.287, p=0.06), but not with other non-genetic factors and CYP3A5 genetic variants in a univariate analysis. The AUC 0-120 of aprepitant was significantly correlated with the level of total bilirubin (adjusted R 2 =0.187, p<0.01) in a multivariate analysis. In conclusion, the plasma pharmacokinetics of aprepitant varied markedly in cancer patients receiving cisplatin-based chemotherapy for the first time and were correlated with the level of total bilirubin. Key words aprepitant; pharmacokinetics; total bilirubin; serum albumin; cytochrome P450 3A5 Aprepitant is a highly selective antagonist of neurokinin-1 (NK 1 ) receptors and developed as a treatment for both acute (during the first 24 h postchemotherapy) and delayed (24 through 120 h postchemotherapy) chemotherapy-induced nausea and vomiting (CINV). The combination of aprepitant, dexamethasone, and a 5-hydroxytryptamine 3 (5-HT 3 ) receptor antagonist has elevated the percentages of patients with a complete response (no vomiting and no rescue medication) during the 5 d after highly and moderately emetogenic chemotherapy by approximately 20% 1,2) and 10% 3) compared to non-aprepitant regimens, respectively.The bioavailability of oral aprepitant capsules is 59% for the 125 mg capsules and 67% for the 80 mg capsules.4) There are no restrictions in the administration of aprepitant with regard to feeding conditions. 4,5) Aprepitant penetrates the blood-brain barrier and binds to a high degree with brain NK 1 receptors, inhibiting emesis via the central nervous system. [6][7][8][9] A population pharmacokinetics study of aprepitant in Japan found that body weight, alanine aminotransferase (ALT), blood urea nitrogen (BUN), and age affected the oral clearance of aprepitant.10) The authors reported that the ...

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Section: Discussioncontrasting

confidence: 85%

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Interindividual Variations In Aprepitant Plasma Pharmacokinementioning

confidence: 99%

See 2 more Smart Citations

Interindividual Variations in Aprepitant Plasma Pharmacokinetics in Cancer Patients Receiving Cisplatin-Based Chemotherapy for the First Time

Motohashi

Mino

Hori

et al. 2013

Biological & Pharmaceutical Bulletin

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“…The final concentrations of the drugs during exposure were 100 nM, 10, 2 and 1 µM for DEX, CDDP, 5-FU and RU-486, respectively. The concentrations of DEX, CDDP and 5-FU were set to mimic clinical conditions (7)(8)(9). To examine the inhibitory effects on DEX-induced Cys C secretion, CDDP, 5-FU and RU-486 were added to the culture medium containing DEX at the abovementioned concentrations for each drug.…”

Section: Methodsmentioning

confidence: 99%

Effect of dexamethasone on extracellular secretion of cystatin C in cancer cell lines

et al. 2012

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Abstract. The aim of the present study was to investigate dexamethasone (DEX)-induced secretion of cystatin C (Cys C) and the effect of cisplatin (CDDP) and 5-fluorouracil (5-FU) on Cys C secretion in human cancer cell lines. KYSE150, A549 and Caki-2 human cancer cell lines were cultured on plastic dishes and treated with DEX (100 nM) for 24, 48 and 72 h. KYSE150 cells were co-treated with DEX, CDDP (10 µM), and 5-FU (2 µM). The effects of DEX, CDDP and 5-FU on cell viability were evaluated. Results showed Cys C secretion levels in the culture medium of DEX-treated KYSE150 cells to be 1.8-to 2.3-fold higher compared to those in the culture medium of control cells. A similar tendency was observed in A549 cells at all the time points, whereas a significant increase in the Cys C secretion by Caki-2 cells was observed only 24 h after DEX treatment. Regarding KYSE150 cells, the secretion of Cys C was also enhanced by co-treatment of CDDP or 5-FU with DEX, although it was not affected by the co-administration of DEX and mifepristone, a glucocorticoid receptor antagonist. At concentrations that are typically used in esophageal cancer chemotherapy, CDDP and 5-FU demonstrated a moderate level of cytotoxicity in KYSE150 cells in contrast to DEX. These findings suggested that DEX has the potential to enhance the extracellular secretion of Cys C in esophageal cancer cells, possibly due to the transcriptional regulation mediated by glucocorticoid receptor activity. IntroductionCystatin C (Cys C) is a non-glycosylated cationic 13.3-kDa protein belonging to the cystatin superfamily of cysteine protease inhibitors (1-3). Cys C is produced by nucleated cells and is secreted into the blood at a constant rate (1-3). It is freely filtered through the glomerular membrane, completely re-absorbed and then catabolized in the proximal tubular cells (1-3). Thus, similarly to creatinine, the biological fate of Cys C is a good endogenous marker of the glomerular filtration rate (GFR).In patients with esophageal cancer, cisplatin (CDDP) is used as a neoadjuvant or as a post-operative adjuvant chemotherapy in combination with continuous infusion of 5-fluorouracil (5-FU) (4,5). When CDDP-based chemotherapy is administered, antiemetic drugs, such as dexamethasone (DEX), 5-HT 3 serotonin receptor antagonists or aprepitant are administered to prevent treatment-associated nausea and vomiting (6). A transient elevation was previously reported in serum Cys C concentration during the perioperative chemotherapy period in patients with esophageal cancer. We suggested that renal function estimates determined on the basis of serum Cys C levels during this treatment period might be misleading (7).To understand the effect of DEX and other drugs in detail, it is crucial to investigate the renal effects associated with serum Cys C concentration. The aim of this study was to investigate the ability of DEX to induce Cys C secretion in human cancer cell lines, as well as the effect of CDDP, 5-FU and mifepristone (RU-486) on Cys C secretion. Materials and metho...

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Intravenous fosaprepitant for the prevention of chemotherapy‐induced vomiting in children: A double‐blind, placebo‐controlled, phase III randomized trial

Radhakrishnan

Joshi

Ramamoorthy

et al. 2018

Pediatric Blood & Cancer

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Background Fosaprepitant is a neurokinin‐1 receptor antagonist, approved for the prevention of chemotherapy‐induced nausea and vomiting. The data on the use of fosaprepitant in children are limited and therefore we conducted a phase III randomized controlled trial. Procedure Children aged 1‐12 years scheduled to receive moderately or highly emetogenic chemotherapy were randomly assigned to arm‐A (fosaprepitant) or arm‐B (placebo). Children recruited to arm‐A received intravenous ondansetron plus dexamethasone followed by fosaprepitant infusion. Children recruited to arm‐B received the same drugs as those given to children in arm‐A, except that fosaprepitant was substituted with a placebo. Ondansetron and dexamethasone were continued for 48 hours after completion of chemotherapy. The primary end point of the study was to determine the proportion of patients who achieved a complete response (CR), defined as no vomiting, no retching, and no use of rescue medication, during the 24‐120 hours (delayed phase) after administration of the last dose of chemotherapy. Secondary end points were the proportion of patients who achieved a CR during the acute phase (0‐24 hours) and overall after administration of the last dose of chemotherapy. Results One‐hundred‐sixty‐three patients were analyzed (81 in the fosaprepitant arm and 82 in the placebo arm). CR rates were significantly higher in the fosaprepitant arm compared to those in the placebo arm during the acute phase (86% vs 60%, P < 0.001), delayed phase (79% vs 51%, P < 0.001), and overall phase (70% vs 41%, P < 0.001). Three (4%) patients in the fosaprepitant arm and sixteen (20%) in the placebo arm required rescue anti‐emetics (P = 0.0017). Conclusion Addition of fosaprepitant to ondansetron and dexamethasone improved chemotherapy‐induced vomiting control in children treated with moderately or highly emetogenic chemotherapy.

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

Cited by 48 publications

References 22 publications

Interindividual Variations in Aprepitant Plasma Pharmacokinetics in Cancer Patients Receiving Cisplatin-Based Chemotherapy for the First Time

Interindividual Variations in Aprepitant Plasma Pharmacokinetics in Cancer Patients Receiving Cisplatin-Based Chemotherapy for the First Time

Effect of dexamethasone on extracellular secretion of cystatin C in cancer cell lines

Intravenous fosaprepitant for the prevention of chemotherapy‐induced vomiting in children: A double‐blind, placebo‐controlled, phase III randomized trial

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