Pancopride (LAS 30451)

Prevention of highly emetogenic chemotherapy-induced vomiting: a double blind, randomized crossover study to compare pancopride (LAS 30451) and pancopride plus dexamethasone

Aims: Pancopride (PNC) is a new 5HT3 receptor antagonist which has demonstrated complete protection from nausea and vomiting in 25-73% of patients treated with highly emetogenic chemotherapy. A double-blind, randomized crossover study was carried out to assess whether the addition of dexamethasone (DXM) to PNC increases the antiemetic efficacy. Methods: PNC (0.2 mg/kg. i.v. 30 min before chemotherapy) plus placebo (PLC) was compared with PNC (same dose and schedule) plus DXM (20 mg. i.v. immediately before PNC). In the second cycle, patients received the alternative antiemetic treatment. Eighty patients were included in the study (PNC + DXM = 39, PNC + PLC = 41), 29 of whom were women and 51 men. Fifty-four percent of the patients in the PNC + DXM group and 59% of those in the PNC + PLC group received chemotherapy containing cisplatin. Seventy-seven patients completed the first cycle and 70 the second. Results: Complete protection was obtained in 19/16 patients (50/46%) with PNC + PLC and in 32/22 (82/63%) with PNC + DXM (P < 0.001). Latency was significantly longer in the PNC + DXM group. The efficacy of both treatments was unaffected by the order of administration. Side effects were mild in both groups. Conclusions: The combination of PNC + DXM is more efficacious than PNC + PLC in protection against highly emetogenic chemotherapy-induced vomiting.

LAS 30451: a novel 5-HT3 antagonist

[The clinical development of an antiemetic in oncology. A meta-analysis]

Background: To perform meta-analysis (MT) on antiemetic efficacy of LAS 30451 (Pancopride) in high and moderately emetogenic chemotherapy (CT).
Methods: The results of 13 phase II and III clinical trials comparing the efficacy of different doses of the drug under study with or without corticoids, or versus standard treatment (methochlopramide and/or corticosteroids and diphenhydramine) were included. The principal variable was complete protection in the acute phase (0 vomiting following 24 h post treatment).
Results: The design was open in 3, simple blind in 4 and double blind in 6, with 11 being parallel and 2 crossed. The trials were carried out in 39 centers of 5 countries with 999 patients who received 1,292 cycles of antiemetic treatment. On comparison of lower or equal doses at 0.2 mg/kg of pancopride vs higher doses global OR was 0.94 (p = 0.72) with a global percentage difference (GPD) of -4.69% (p = 0.23) and GPD equal to -6.90. On treatment without cysplatin global OFR was equal to 1.10 (p = 0.69) with GPD of -8.99% favoring dosage lower than or equal to 0.2 mg/kg. The dexamethasone increased antiemetic efficacy of pancopride in both treatments with cysplatin (50% vs 76%, p = 0.08) and without cysplatin (50% to 89%, p = 0.02). When pancopride was compared with that of standard antiemetic treatment (methochlopramide and/or corticosteroids) global OR was equal to 0.69 (p = 0.07) with GPD of -6.84% favoring the control treatment. In CT containing cysplatin, global OR was equal to 0.73 (p = 0.38) with GPD of -3.28% and with CT without cysplatin the global OR was 0.66. (p = 0.12) with a GPD of -4.92% in both cases favoring the control treatment.
Conclusions: No statistically significant differences were observed with regard to the antiemetic efficacy of pancopride on comparison of different doses of the drug. The antiemetic efficacy of pancopride increases when given together with dexamethasone. The efficacy of pancopride is lower to that of methochlopramide in combination with corticosteroids and/or diphenhydramine although the differences are not statistically significant.

Single dose pharmacokinetics and tolerance of pancopride in healthy volunteers

Pancopride (LAS 30451, CAS 121650-80-4) is a new selective 5-hydroxytryptamine3 receptor antagonist which has demonstrated antiemetic properties in animal models. The tolerance and pharmacokinetics of pancopride and its effect on the 5-hydroxytryptamine flare test were examined in healthy male volunteers, in three single-dose studies. The studies consisted of two rising dose tolerance and kinetic studies with placebo control, each involving 14 volunteers, and an absolute bioavailability study involving 12 volunteers. The doses used in the rising dose studies were 0.5-20 mg intravenous pancopride in the first study, and 5-40 mg pancopride as oral solution in the second study. For the absolute bioavailability study, 20 mg doses as intravenous infusion, oral tablet and oral solution were compared. Pancopride was well tolerated at these doses in these studies. There were no significant effects on pulse rate, blood pressure, or electrocardiograms, or on haematology or serum biochemistry. Few adverse events were recorded, the most significant being gastrointestinal effects (including diarrhoea and soft stools) seen particularly with the 40 mg oral dose. Pharmacokinetic parameters for the 24 h after dosing were derived from plasma and urine pancopride levels, determined using a capillary gas chromatography-mass spectrometry method. Linear kinetics appeared to apply over the intravenous dose range 5-20 mg. Urinary recovery of unchanged pancopride was in the order of 10-17% over the 24 h after dosing.(ABSTRACT TRUNCATED AT 250 WORDS)

Pancopride, a potent and long-acting 5-HT3 receptor antagonist, is orally effective against anticancer drug-evoked emesis

Pancopride ((+-)N-(1-azabicyclo-[2,2,2]-oct-3-yl)-2-cyclopropylmethoxy-4-ami no-5-chlorobenzamide) is a new potent and selective 5-HT3 receptor antagonist, orally and parenterally effective against cytotoxic drug-induced emesis. In vitro, pancopride displayed high affinity (Ki = 0.40 nM) for [3H]GR65630-labelled 5-HT3 recognition sites in membranes from the cortex of rat brains. In vivo, pancopride antagonized 5-HT-induced bradycardia in anaesthetized rats when administered i.v. 5 min (ID50 = 0.56 microgram/kg) or p.o. 60 min (ID50 = 8.7 micrograms/kg) before 5-HT challenge. A single oral dose (10 micrograms/kg) of pancopride produced a significant inhibition of the bradycardic reflex over an 8-h period. Pancopride dose dependently inhibited the number of vomiting episodes and delayed the onset of vomiting induced by cisplatin in dogs (ID50 = 3.6 micrograms/kg i.v. and 7.1 micrograms/kg p.o.). Pancopride was also effective in blocking mechlorethamine- and dacarbazine-induced emesis. Unlike metoclopramide, pancopride was shown to lack any measurable antidopaminergic activity both in vitro and in vivo. These results support clinical data, indicating that pancopride will be a useful drug for treating cytostatic-induced emesis in humans.