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Review of oral fixed-dose combination netupitant and palonosetron (NEPA) for the treatment of chemotherapy-induced nausea and vomiting Vito Lorusso*,1, Meinolf Karthaus2 & Matti Aapro3
Abstract Current guidelines recommend the combination of a neurokinin-1 (NK1) receptor antagonist (RA) and a 5-hydroxytryptamine-3 (5-HT3) RA, together with corticosteroids, in order to prevent chemotherapy-induced nausea and vomiting with anthracycline–cyclophosphamide and highly emetogenic chemotherapy, and it is to be considered with moderately emetogenic chemotherapy. Netupitant and palonosetron (NEPA) is a fixed-dose combination of netupitant, a novel, highly selective NK1 RA, and palonosetron, a new-generation 5-HT3 RA, targeting two major emetic pathways in a single oral capsule. In clinical trials, NEPA administered on day 1 together with dexamethasone was highly effective and well tolerated in the prevention of chemotherapy-induced nausea and vomiting in patients with solid tumors undergoing moderately emetogenic chemotherapy or highly emetogenic chemotherapy. NEPA offers maximal convenience, and as a simple guideline-based regimen, has the potential to improve adherence to guidelines. Chemotherapy-induced nausea and vomiting (CINV) is a frequent and debilitating clinical complication in patients undergoing emetogenic chemotherapy. The availability of effective antiemetic treatments is critical since inadequately controlled CINV impairs daily functioning and quality of life, can compromise adherence to treatment and increases the use of healthcare resources [1] . Unfortunately, more than 75% of nurses and physicians underestimate the incidence of CINV in the delayed phase (25–120 h postchemotherapy) after both highly emetogenic chemotherapy (HEC) and moderately emetogenic chemotherapy (MEC) [2] . In fact, patient self-reports of nausea and vomiting are routinely discordant with physician reports, and CINV is often underreported [3,4] . Patients who receive any emetogenic chemotherapy with a prior CINV episode are at increased risk of subsequent CINV [5,6] ; therefore, an optimal antiemetic prophylaxis should be adopted from the first cycle. The mechanisms of CINV are still not completely understood, but are thought to be primarily mediated through neurotransmitters, such as serotonin, dopamine and substance P. Chemotherapeutic agents can cause vomiting by activating neurotransmitter receptors in the chemoreceptor trigger zone, the vomiting center and the GI tract [1] . Whereas serotonin mediates early emesis through the activation of the 5-hydroxytryptamine-3 (5-HT3) receptor, delayed emesis occurring more than 24 h after chemotherapy appears to be mostly mediated by substance P, which acts on the neurokinin-1 (NK1) receptor [7] . The most commonly used antiemetic drug classes are therefore the 5-HT3 receptor antagonists (RAs), corticosteroids and NK1 RAs. Medical Oncology Unit, National Cancer Institute Giovanni Paolo II, 70124 Bari, Italy Hematology & Oncology, Staedt. Klinikum Neuperlach & Harlaching, Munich, Germany 3 Institut Multidisciplinaire d’Oncologie, Genolier, Switzerland *Author for correspondence: Tel.: +39 0805 555 909; [email protected]
Keywords
• antiemetic • chemotherapy-induced nausea and vomiting • NEPA • netupitant • palonosetron
1 2
10.2217/FON.14.260 © 2015 Future Medicine Ltd
Future Oncol. (Epub ahead of print)
part of
ISSN 1479-6694-0794
Drug Evaluation Lorusso, Karthaus & Aapro The Multinational Association of Supportive Care in Cancer (MASCC) [8] , the European Society for Medical Oncology (ESMO) [9] , the American Society of Clinical Oncology (ASCO) [10] and the National Comprehensive Cancer Network (NCCN) [11] , among others, have developed antiemetic prophylaxis recommendations. For patients receiving HEC or anthracycline–cyclophosphamide (AC)-based chemotherapy, the guidelines unanimously suggest that a combination of a 5-HT3 RA, dexamethasone and a NK1 RA be used for acute (day 1) CINV; for MEC, the guidelines endorse a combination of a 5-HT3 RA (palonosetron is preferred) and dexamethasone for acute CINV, although the NCCN and ASCO guidelines state that the addition of aprepitant to the combination may be considered in some patients (reviewed by Jordan et al. [12]). Treatment recommendations in the delayed phase are more variable, although guidelines suggest the combination of dexamethasone and aprepitant for HEC, and following MEC, dexamethasone is the favored agent. Most national guidelines endorse at least one of these evidence-based guideline associations; for example, the Association Francophone pour les Soins Oncologiques de Support (Frenchspeaking Association for Supportive Care in Cancer [AFSOS]) supports the joint MASCC and ESMO recommendations [13] . Most guidelines are conservative in their recommendations and require that any changes are accompanied by high-level evidence. A Phase III trial comparing both intravenous (iv.) palonosetron with granisetron, both with corticosteroids has been influential in this regard, since it showed that palonosetron provides greater protection against CINV compared with granisetron [14] . Indeed, this advantage demonstrated with palonosetron has been noted compared with all first-generation 5-HT3 RAs [15,16] . Consequently, palonosetron is now specifically recommended as a preferred 5-HT3 RA for patients receiving MEC in the MASCC, ESMO, ASCO and NCCN guidelines [8–11,17,18] . Although increased adherence to antiemetic guidelines reduces the incidence of CINV following chemotherapy, these guidelines are frequently not followed [19–21] . The simplification of antiemetic regimens would be beneficial in improving guideline adherence. This article reviews the emerging treatment of CINV with netupitant and palonosetron (NEPA), which targets dual antiemetic pathways with a single administration of an oral fixed-dose
10.2217/FON.14.260
Future Oncol. (Epub ahead of print)
combination of netupitant, a new highly selective NK1 RA, and palonosetron. Palonosetron & other 5-HT3 RAs The first generation of 5-HT3 RAs, comprising dolasetron, granisetron, ondansetron, tropisetron, azasetron and ramosetron, have similar efficacy and toxicities when used at the recommended doses [22] . Their introduction resulted in an improvement in supportive care with regard to the prevention of CINV [16,23] . However, they have not been as effective in the delayed phase (25–120 h) after single-day HEC or MEC as they have been against acute (0–24 h) CINV [24–26] . Palonosetron is a new-generation 5-HT 3 RA with a longer half-life and higher receptor binding affinity, and it appears to be the most effective agent in its class [16] . Palonosetron has demonstrated distinct pharmacologic characteristics compared with the first-generation 5-HT3 RAs, such as triggering receptor internalization and 5-HT3/NK1 receptor cross-talk inhibition [27] . The chemistry of palonosetron hydrochloride – (3aS)-2-(3S)-1-azabicyclo[2.2.2] oct-3-yl]-2,3,3a,4,5,6-hexahydro-1H-benz[de] isoquinolin-1-one (Figure 1) – has been reviewed elsewhere [22] . In a pooled analysis of data from four randomized, double-blind Phase III trials comparing iv. palonosetron 0.25 or 0.75 mg with ondansetron 32 mg, dolasetron 100 mg or granisetron 40 μg/kg, rates of complete response (CR; no emesis and no rescue antiemetics) and complete control (no emesis, no rescue antiemetics and no more than mild nausea) were significantly higher for palonosetron compared with these older 5-HT3 RAs, both in the delayed and overall (0–120 h) phases [28] . In addition, nausea severity was significantly lower for palonosetron in the delayed and overall phases, and emetic episodes were significantly fewer in all three periods (acute, delayed and overall). Palonosetron, unlike any other 5-HT3 RA, has shown efficacy in the delayed phase [14,28–30] , and is thus a logical choice of 5-HT3 RA to include in a fixed-dose combination with netupitant. Netupitant Netupitant is a new, highly selective NK1 RA that is being developed by Helsinn Healthcare SA. It has been studied mainly as an oral fixeddose combination with palonosetron (netupitant 300 mg plus palonosetron 0.5 mg).
future science group
Oral fixed-dose netupitant & palonosetron for treatment of CINV ●●Chemistry
Netupitant (2-[3,5-bis-trifluoromethyl-phenyl]N-methyl-N-[6-{4-methyl-piperazin-1-yl}-4-otolyl-pyridin-3-yl]-isobutyramide) (Figure 2) is a member of the novel, achiral pyridine class of potent and orally active NK1 RAs formed from 6-chloronicotinic acid through the introduction of the o-tolyl substituent at C4 of the pyridine ring [31,32] . ●●Pharmacodynamics of netupitant
In Chinese hamster ovary cells expressing the human NK1 receptor, netupitant inhibited the stimulatory effects of substance P, showing dose-dependent, selective and insurmountable NK1 receptor antagonism [33] . Netupitant in the 1–10-mg/kg dose range inhibited NK1dependent in vivo effects (including substance P-elicited scratching, biting and licking in mice), NK1 agonist-mediated foot tapping in gerbils [33] and diverse emetic challenge in ferrets [34] . In an acute emesis model in which ferrets were administered cisplatin 10 mg/kg, a single administration of netupitant had superior antiemetic activity compared with thrice-daily ondansetron [34] . When added to NG108-15 cells in the absence of serotonin, both palonosetron and netupitant on their own inhibited the substance P-mediated dose response, an effect that was enhanced when both drugs were present [35] . In an acute and delayed emesis model in which cisplatin 5 mg/kg was used in order to induce emesis in ferrets, the combination of netupitant plus palonosetron administered once before cisplatin provided comparable antiemetic activity to ondansetron plus aprepitant thrice daily, with both regimens also including dexamethasone once daily [34] . In a PET brain imaging study in humans, the NK1 receptor occupancy by netupitant at 100, 300 and 450 mg was 90% or higher with all doses in the majority of tested brain regions [36] . Netupitant & palonosetron ●●Drug interactions, metabolism
& pharmacokinetics of NEPA
The main pharmacokinetic parameters of NEPA are summarized in Table 1 [36–40] . The antiemetic NK1 RA aprepitant, which is currently the only NK1 RA approved for the prevention of CINV, is both an inducer and inhibitor of CYP3A4 [41] , and is also associated with a significant induction of CYP2C9 [42] . Below, we discuss the pharmacokinetic data regarding
future science group
Drug Evaluation
N O N
H
H
.HCl
Figure 1. Palonosetron.
the novel NK1 RA netupitant. In vitro drug– drug interaction studies showed that netupitant has no significant potential to inhibit the P450 isoenzymes CYP1A2, 2C19 and 2D6, with estimated half maximal inhibitory concentration values in excess of 100 μM. Interactions involving CYP2C9-metabolized drugs, such as warfarin, are also unlikely based on the expected plasma concentration of netupitant in the low micromolar range [43] , although it would be of interest to verify this in a trial. However, metabolic drug–drug interactions are possible for drugs metabolized mainly by CYP3A4, based on the high in vitro affinity of netupitant for this isoenzyme [43] . Two pharmacokinetic studies conducted in healthy volunteers showed that netupitant, as a CYP3A4 inhibitor, increased the area under the concentration–time curve (AUC) extrapolated to infinity of midazolam by 144% and of erythromycin by 30% [44] . Moreover, exposure to dexamethasone was increased when coadministered with netupitant 300 mg (as assessed by the AUC), with a mean increase of 72% on day 1 and 138% on day 4. Three other randomized, open-label, crossover studies of healthy volunteers investigated the pharmaco kinetics of the NEPA fixed-dose combination [37] . These studies showed there were no significant pharmacokinetic interactions between netupitant and palonosetron, and that there were no clinically significant interactions between NEPA and oral contraceptives. Furthermore, coadministration of the CYP3A4 inhibitor ketoconazole or the CYP3A4 inducer rifampicin with NEPA resulted in a 140% increase and 83% decrease, respectively, in netupitant exposure, as assessed by the AUC. These findings suggest that netupitant is a moderate inhibitor of CYP3A4 and its coadministration with drugs that are substrates of CYP3A4 may require dose adjustments of those drugs [37,44] . A further Phase I study investigated the effects of netupitant on
www.futuremedicine.com
10.2217/FON.14.260
Drug Evaluation Lorusso, Karthaus & Aapro HC
3
N
CF3 N
N O N CH3
HC
3
CH3
CF3
CH3
Figure 2. Netupitant.
the pharmacokinetics of digoxin at steady state in healthy volunteers, following in vitro findings suggesting that netupitant is a substrate for, and a weak inhibitor of, P-glycoprotein [45] . However, a single oral dose of netupitant 450 mg did not affect digoxin exposure. In a Phase I absorption/distribution/metabolism/excretion study conducted in healthy male volunteers, a single nominal dose of 14 C-netupitant 300 mg was rapidly absorbed and the drug was extensively metabolized via phase I and II hepatic metabolism [36] . Elimination of more than 90% of the drug was predicted at day 29 and occurred principally via the hepatic/ biliary route (>85%), with 85% hepatic/biliary,
Review of oral fixed-dose combination netupitant and palonosetron (NEPA) for the treatment of chemotherapy-induced nausea and vomiting Vito Lorusso*,1, Meinolf Karthaus2 & Matti Aapro3
Abstract Current guidelines recommend the combination of a neurokinin-1 (NK1) receptor antagonist (RA) and a 5-hydroxytryptamine-3 (5-HT3) RA, together with corticosteroids, in order to prevent chemotherapy-induced nausea and vomiting with anthracycline–cyclophosphamide and highly emetogenic chemotherapy, and it is to be considered with moderately emetogenic chemotherapy. Netupitant and palonosetron (NEPA) is a fixed-dose combination of netupitant, a novel, highly selective NK1 RA, and palonosetron, a new-generation 5-HT3 RA, targeting two major emetic pathways in a single oral capsule. In clinical trials, NEPA administered on day 1 together with dexamethasone was highly effective and well tolerated in the prevention of chemotherapy-induced nausea and vomiting in patients with solid tumors undergoing moderately emetogenic chemotherapy or highly emetogenic chemotherapy. NEPA offers maximal convenience, and as a simple guideline-based regimen, has the potential to improve adherence to guidelines. Chemotherapy-induced nausea and vomiting (CINV) is a frequent and debilitating clinical complication in patients undergoing emetogenic chemotherapy. The availability of effective antiemetic treatments is critical since inadequately controlled CINV impairs daily functioning and quality of life, can compromise adherence to treatment and increases the use of healthcare resources [1] . Unfortunately, more than 75% of nurses and physicians underestimate the incidence of CINV in the delayed phase (25–120 h postchemotherapy) after both highly emetogenic chemotherapy (HEC) and moderately emetogenic chemotherapy (MEC) [2] . In fact, patient self-reports of nausea and vomiting are routinely discordant with physician reports, and CINV is often underreported [3,4] . Patients who receive any emetogenic chemotherapy with a prior CINV episode are at increased risk of subsequent CINV [5,6] ; therefore, an optimal antiemetic prophylaxis should be adopted from the first cycle. The mechanisms of CINV are still not completely understood, but are thought to be primarily mediated through neurotransmitters, such as serotonin, dopamine and substance P. Chemotherapeutic agents can cause vomiting by activating neurotransmitter receptors in the chemoreceptor trigger zone, the vomiting center and the GI tract [1] . Whereas serotonin mediates early emesis through the activation of the 5-hydroxytryptamine-3 (5-HT3) receptor, delayed emesis occurring more than 24 h after chemotherapy appears to be mostly mediated by substance P, which acts on the neurokinin-1 (NK1) receptor [7] . The most commonly used antiemetic drug classes are therefore the 5-HT3 receptor antagonists (RAs), corticosteroids and NK1 RAs. Medical Oncology Unit, National Cancer Institute Giovanni Paolo II, 70124 Bari, Italy Hematology & Oncology, Staedt. Klinikum Neuperlach & Harlaching, Munich, Germany 3 Institut Multidisciplinaire d’Oncologie, Genolier, Switzerland *Author for correspondence: Tel.: +39 0805 555 909; [email protected]
Keywords
• antiemetic • chemotherapy-induced nausea and vomiting • NEPA • netupitant • palonosetron
1 2
10.2217/FON.14.260 © 2015 Future Medicine Ltd
Future Oncol. (Epub ahead of print)
part of
ISSN 1479-6694-0794
Drug Evaluation Lorusso, Karthaus & Aapro The Multinational Association of Supportive Care in Cancer (MASCC) [8] , the European Society for Medical Oncology (ESMO) [9] , the American Society of Clinical Oncology (ASCO) [10] and the National Comprehensive Cancer Network (NCCN) [11] , among others, have developed antiemetic prophylaxis recommendations. For patients receiving HEC or anthracycline–cyclophosphamide (AC)-based chemotherapy, the guidelines unanimously suggest that a combination of a 5-HT3 RA, dexamethasone and a NK1 RA be used for acute (day 1) CINV; for MEC, the guidelines endorse a combination of a 5-HT3 RA (palonosetron is preferred) and dexamethasone for acute CINV, although the NCCN and ASCO guidelines state that the addition of aprepitant to the combination may be considered in some patients (reviewed by Jordan et al. [12]). Treatment recommendations in the delayed phase are more variable, although guidelines suggest the combination of dexamethasone and aprepitant for HEC, and following MEC, dexamethasone is the favored agent. Most national guidelines endorse at least one of these evidence-based guideline associations; for example, the Association Francophone pour les Soins Oncologiques de Support (Frenchspeaking Association for Supportive Care in Cancer [AFSOS]) supports the joint MASCC and ESMO recommendations [13] . Most guidelines are conservative in their recommendations and require that any changes are accompanied by high-level evidence. A Phase III trial comparing both intravenous (iv.) palonosetron with granisetron, both with corticosteroids has been influential in this regard, since it showed that palonosetron provides greater protection against CINV compared with granisetron [14] . Indeed, this advantage demonstrated with palonosetron has been noted compared with all first-generation 5-HT3 RAs [15,16] . Consequently, palonosetron is now specifically recommended as a preferred 5-HT3 RA for patients receiving MEC in the MASCC, ESMO, ASCO and NCCN guidelines [8–11,17,18] . Although increased adherence to antiemetic guidelines reduces the incidence of CINV following chemotherapy, these guidelines are frequently not followed [19–21] . The simplification of antiemetic regimens would be beneficial in improving guideline adherence. This article reviews the emerging treatment of CINV with netupitant and palonosetron (NEPA), which targets dual antiemetic pathways with a single administration of an oral fixed-dose
10.2217/FON.14.260
Future Oncol. (Epub ahead of print)
combination of netupitant, a new highly selective NK1 RA, and palonosetron. Palonosetron & other 5-HT3 RAs The first generation of 5-HT3 RAs, comprising dolasetron, granisetron, ondansetron, tropisetron, azasetron and ramosetron, have similar efficacy and toxicities when used at the recommended doses [22] . Their introduction resulted in an improvement in supportive care with regard to the prevention of CINV [16,23] . However, they have not been as effective in the delayed phase (25–120 h) after single-day HEC or MEC as they have been against acute (0–24 h) CINV [24–26] . Palonosetron is a new-generation 5-HT 3 RA with a longer half-life and higher receptor binding affinity, and it appears to be the most effective agent in its class [16] . Palonosetron has demonstrated distinct pharmacologic characteristics compared with the first-generation 5-HT3 RAs, such as triggering receptor internalization and 5-HT3/NK1 receptor cross-talk inhibition [27] . The chemistry of palonosetron hydrochloride – (3aS)-2-(3S)-1-azabicyclo[2.2.2] oct-3-yl]-2,3,3a,4,5,6-hexahydro-1H-benz[de] isoquinolin-1-one (Figure 1) – has been reviewed elsewhere [22] . In a pooled analysis of data from four randomized, double-blind Phase III trials comparing iv. palonosetron 0.25 or 0.75 mg with ondansetron 32 mg, dolasetron 100 mg or granisetron 40 μg/kg, rates of complete response (CR; no emesis and no rescue antiemetics) and complete control (no emesis, no rescue antiemetics and no more than mild nausea) were significantly higher for palonosetron compared with these older 5-HT3 RAs, both in the delayed and overall (0–120 h) phases [28] . In addition, nausea severity was significantly lower for palonosetron in the delayed and overall phases, and emetic episodes were significantly fewer in all three periods (acute, delayed and overall). Palonosetron, unlike any other 5-HT3 RA, has shown efficacy in the delayed phase [14,28–30] , and is thus a logical choice of 5-HT3 RA to include in a fixed-dose combination with netupitant. Netupitant Netupitant is a new, highly selective NK1 RA that is being developed by Helsinn Healthcare SA. It has been studied mainly as an oral fixeddose combination with palonosetron (netupitant 300 mg plus palonosetron 0.5 mg).
future science group
Oral fixed-dose netupitant & palonosetron for treatment of CINV ●●Chemistry
Netupitant (2-[3,5-bis-trifluoromethyl-phenyl]N-methyl-N-[6-{4-methyl-piperazin-1-yl}-4-otolyl-pyridin-3-yl]-isobutyramide) (Figure 2) is a member of the novel, achiral pyridine class of potent and orally active NK1 RAs formed from 6-chloronicotinic acid through the introduction of the o-tolyl substituent at C4 of the pyridine ring [31,32] . ●●Pharmacodynamics of netupitant
In Chinese hamster ovary cells expressing the human NK1 receptor, netupitant inhibited the stimulatory effects of substance P, showing dose-dependent, selective and insurmountable NK1 receptor antagonism [33] . Netupitant in the 1–10-mg/kg dose range inhibited NK1dependent in vivo effects (including substance P-elicited scratching, biting and licking in mice), NK1 agonist-mediated foot tapping in gerbils [33] and diverse emetic challenge in ferrets [34] . In an acute emesis model in which ferrets were administered cisplatin 10 mg/kg, a single administration of netupitant had superior antiemetic activity compared with thrice-daily ondansetron [34] . When added to NG108-15 cells in the absence of serotonin, both palonosetron and netupitant on their own inhibited the substance P-mediated dose response, an effect that was enhanced when both drugs were present [35] . In an acute and delayed emesis model in which cisplatin 5 mg/kg was used in order to induce emesis in ferrets, the combination of netupitant plus palonosetron administered once before cisplatin provided comparable antiemetic activity to ondansetron plus aprepitant thrice daily, with both regimens also including dexamethasone once daily [34] . In a PET brain imaging study in humans, the NK1 receptor occupancy by netupitant at 100, 300 and 450 mg was 90% or higher with all doses in the majority of tested brain regions [36] . Netupitant & palonosetron ●●Drug interactions, metabolism
& pharmacokinetics of NEPA
The main pharmacokinetic parameters of NEPA are summarized in Table 1 [36–40] . The antiemetic NK1 RA aprepitant, which is currently the only NK1 RA approved for the prevention of CINV, is both an inducer and inhibitor of CYP3A4 [41] , and is also associated with a significant induction of CYP2C9 [42] . Below, we discuss the pharmacokinetic data regarding
future science group
Drug Evaluation
N O N
H
H
.HCl
Figure 1. Palonosetron.
the novel NK1 RA netupitant. In vitro drug– drug interaction studies showed that netupitant has no significant potential to inhibit the P450 isoenzymes CYP1A2, 2C19 and 2D6, with estimated half maximal inhibitory concentration values in excess of 100 μM. Interactions involving CYP2C9-metabolized drugs, such as warfarin, are also unlikely based on the expected plasma concentration of netupitant in the low micromolar range [43] , although it would be of interest to verify this in a trial. However, metabolic drug–drug interactions are possible for drugs metabolized mainly by CYP3A4, based on the high in vitro affinity of netupitant for this isoenzyme [43] . Two pharmacokinetic studies conducted in healthy volunteers showed that netupitant, as a CYP3A4 inhibitor, increased the area under the concentration–time curve (AUC) extrapolated to infinity of midazolam by 144% and of erythromycin by 30% [44] . Moreover, exposure to dexamethasone was increased when coadministered with netupitant 300 mg (as assessed by the AUC), with a mean increase of 72% on day 1 and 138% on day 4. Three other randomized, open-label, crossover studies of healthy volunteers investigated the pharmaco kinetics of the NEPA fixed-dose combination [37] . These studies showed there were no significant pharmacokinetic interactions between netupitant and palonosetron, and that there were no clinically significant interactions between NEPA and oral contraceptives. Furthermore, coadministration of the CYP3A4 inhibitor ketoconazole or the CYP3A4 inducer rifampicin with NEPA resulted in a 140% increase and 83% decrease, respectively, in netupitant exposure, as assessed by the AUC. These findings suggest that netupitant is a moderate inhibitor of CYP3A4 and its coadministration with drugs that are substrates of CYP3A4 may require dose adjustments of those drugs [37,44] . A further Phase I study investigated the effects of netupitant on
www.futuremedicine.com
10.2217/FON.14.260
Drug Evaluation Lorusso, Karthaus & Aapro HC
3
N
CF3 N
N O N CH3
HC
3
CH3
CF3
CH3
Figure 2. Netupitant.
the pharmacokinetics of digoxin at steady state in healthy volunteers, following in vitro findings suggesting that netupitant is a substrate for, and a weak inhibitor of, P-glycoprotein [45] . However, a single oral dose of netupitant 450 mg did not affect digoxin exposure. In a Phase I absorption/distribution/metabolism/excretion study conducted in healthy male volunteers, a single nominal dose of 14 C-netupitant 300 mg was rapidly absorbed and the drug was extensively metabolized via phase I and II hepatic metabolism [36] . Elimination of more than 90% of the drug was predicted at day 29 and occurred principally via the hepatic/ biliary route (>85%), with 85% hepatic/biliary,
