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Hard sell
Published in Peter C. Gøtzsche, Richard Smith, Drummond Rennie, Deadly Medicines and Organised Crime, 2019
Peter C. Gøtzsche, Richard Smith, Drummond Rennie
I have been a member of the drug committee at our hospital for 20 years and, in 2012, the clinicians wanted to get permission to use some new antinausea drugs as standard. One was palonosetron, which cost 44 times more than ondansetron and 17 times more than granisetron. We were told that in those trials that had been submitted to the drug agency for obtaining marketing approval, palonosetron had a similar effect to the older setrons when heavy chemotherapy was used, but was slightly better when the chemotherapy caused less nausea and vomiting (81% and 69%, respectively, did not develop nausea). I couldn’t participate in the meeting but warned the chairman of the committee against selective publication of the most positive results. I also noted that we needed access to the unpublished trials and their protocols, and that a full Cochrane review was needed if we wanted to know whether the new drugs were any better than the cheap ones.
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Published in Caroline Ashley, Aileen Dunleavy, John Cunningham, The Renal Drug Handbook, 2018
Caroline Ashley, Aileen Dunleavy, John Cunningham
Palonosetron is eliminated by a dual route, about 40% eliminated through the kidney and approximately 50% metabolised by CYP2D6, and to a lesser extent, CYP3A4 and CYP1A2 isoenzymes in the liver to form two primary metabolites, which have less than 1% of the 5HT3 receptor antagonist activity of palonosetron. After a single intravenous dose of [14C]-palonosetron, approximately 80% of the dose was recovered within 144 hours in the urine with unchanged palonosetron representing approximately 40% of the administered dose.
Low-dose dexamethasone with fosaprepitant and palonosetron to prevent cisplatin-induced nausea and vomiting in head and neck cancer patients
Published in Acta Oto-Laryngologica, 2018
Takashi Kono, Tsutomu Ueda, Masaya Takumida, Hiromi Furuie, Takao Hamamoto, Sachio Takeno, Katsuhiro Hirakawa
Procedures: All patients were given 150 mg fosaprepitant and 0.75 mg palonosetron intravenously, once on day 1 in both cycles as baseline antiemetic prophylaxis. Using the minimization method, patients were assigned to either a standard dexamethasone dose group or a low dexamethasone dose group for the first course and then crossed over to the other group for the second course. Patients in the standard group received 9.9 mg of intravenous dexamethasone on day 1 followed by another intravenous dose of 6.6 mg on days 2–4. This dosing of dexamethasone was compliant with the current guidelines [8–10]. On the other hand, patients in the low dexamethasone arm received 3.3 mg of intravenous dexamethasone on days 1–4 (Figure 1). This dose of dexamethasone was calculated based on the finding that 6.6 mg of intravenously delivered dexamethasone and 13.2 mg of it administered with granisetron were almost equally efficacious in the treatment of CDDP-containing chemotherapy for head and neck cancer [14]. Moreover, a pharmacokinetic study showed that aprepitant increased the blood levels of dexamethasone by approximately two-fold via a CYP3A4 interaction on days 1–2 [12].
A patient with oxaliplatin immune-induced syndrome (OIIS) who also developed leucovorin and palonosetron-associated thrombocytopenia
Published in Hematology, 2018
S. A. Curtis, B. R. Curtis, A. I. Lee, J. E. Hendrickson, J. Lacy, N. A. Podoltsev
In most cases of OIIS, the DDPAs formed are exclusive to oxaliplatin. Our case is unique in that no other published cases of OIIS have observed the concomitant development of additional DDPAs to other drugs, and no cases of DDPA to leucovorin or palonosetron have been reported. To our knowledge there is only one case report describing the formation of DDPAs to more than one medication [10]. Oxaliplatin is a third-generation platinum derivative with a variety of cytoxic effects which it causes by forming cross links in DNA which prevent cell replication [11]. Leucovorin is a derivative of tetrahydrofolic acid, a naturally occurring substance, with few known side effects [11]. Palonosetron is a second-generation 5-HT3 antagonist, also with relatively few side effects [12]. These medications do not share similarities in their chemical structure and as leucovorin and palonosetron have never previously been associated with DDPA, we speculate that this rare antibody development may be a part of OIIS and wonder if oxaliplatin-induced immune activation may sometimes be associated with the generation of DDPA to other drugs. The mechanism by which OIIS leads to the formation of additional DDPAs remains unclear.
Pro-netupitant/palonosetron (IV) for the treatment of radio-and-chemotherapy-induced nausea and vomiting
Published in Expert Opinion on Pharmacotherapy, 2018
In humans, the biotransformation of fosnetupitant to netupitant is almost completed (more than 99%) 30 min after the end of infusion [19]. Concentrations of netupitant released from its pro-drug raise progressively in plasma after IV administration of fosnetupitant, reaching Cmax values starting at least 30 min after the end of infusion [19]. Within the IV formulation, the selected dose for the fosnetupitant component is 235 mg (corresponding to a dose of 260 mg of fosnetupitant chloride), which was shown to be equivalent in exposure [i.e. the area under the concentration–time curve (AUC)] to the 300-mg dose of netupitant administered in the oral formulation [19]. The selected dose for the palonosetron component is 0.25 mg, which is the approved IV dose of palonosetron [18]. The pharmacokinetic analysis in healthy subjects showed that the mean Cmax of netupitant after the 30-min IV administration of 235-mg fosnetupitant is higher compared to that after oral administration of 300-mg netupitant (841 vs. 434 ng/mL, respectively; Table 2) [19]. The mean apparent elimination half-life (t1/2) of 235-mg fosnetupitant was shown to be 0.96 h (Table 2).