Use of Aprepitant to Prevent Nausea and Vomiting in Children
Use of Aprepitant to Prevent Nausea and Vomiting in Children
Within two years of its approval, aprepitant was being used in adolescents to prevent CINV. The first clinical trial of aprepitant use in pediatrics was published in 2009. Gore and colleagues conducted a phase 3 randomized, double-blind, placebo-controlled study of the efficacy and tolerability of aprepitant in 46 patients between 11 and 19 years of age. Patients were randomized to receive the adult aprepitant regimen of 125 mg orally on day 1, followed by 80 mg on days 2 and 3, or placebo. All patients received dexamethasone and ondansetron. Complete response was defined as no emesis or need for rescue therapy over the first 5 days following chemotherapy. A significantly greater percentage of patients in the aprepitant group had a complete response (35.7% versus 5.6%). The percentage who did not require rescue antiemetics was also higher, 42.9% versus 22.2%. There were no serious drug-related adverse events and no patients discontinued treatment.
Several observational and retrospective studies have been published since that early report, adding to our experience with aprepitant in younger children and different cancer types. In 2013, Bauters and colleagues analyzed the results of aprepitant use in 20 patients (mean age 14 years, range 8–16 years) receiving a total 104 cycles of moderate or highly emetogenic chemotherapy. All patients received a 5-HT3 antagonist and dexamethasone 30 minutes prior to chemotherapy, as well as aprepitant 125 mg on day 1 followed by 80 mg on days 2 and 3. A complete response was observed in 89 cycles (85.6%). In spite of the multimodal approach, however, 13 patients still required rescue antiemetics.
Bodge and colleagues found a complete response rate of 38.9% in a group of 11 patients enrolled in their prospective observational study. The patients, ranging in age from 12 months to 17 years, all received ondansetron, dexamethasone, and aprepitant, rounded to the nearest 20 mg. Shillingburg and Biondo evaluated the tolerability of aprepitant in 26 children (11 months to 17 years of age) receiving a total of 114 chemotherapy cycles. Patients > 20 kg received the adult regimen, while patients 15–20 kg received 80 mg for 3 days and a single patient < 15 kg received 80 mg on day 1 and 40 mg on days 2 and 3. Twenty-five patients received aprepitant for CINV prevention and one patient for PONV prevention. No adverse effects believed to be related to aprepitant were reported. Although efficacy was not assessed in this report, the authors did report that only 8 patients required rescue antiemetics.
Aprepitant was also found to reduce CINV in a retrospective comparison study of 52 children and young adults (10–21 years of age) with central nervous system tumors.Eighteen of the patients received aprepitant with a regimen of ondansetron every 8 hours. Breakthrough vomiting was treated with the addition of lorazepam with or without diphenhydramine or promethazine. Aprepitant was given at a dose of 125 mg on day 1 followed by 80 mg on days 2 and 3. Patients who did not receive aprepitant had a significantly greater likelihood of developing grade 2 or 3 (severe) emesis during their first course of highly emetogenic chemotherapy (odds ratio 4.15, 95% CI 1.59, 10.82, p = 0.03). On the day after chemotherapy completion, the results remained significant, with 44% of controls having delayed grade 2 or 3 emesis, compared to only 16% of the aprepitant patients.
Two recent prospective studies have provided more detailed information on aprepitant use in children. In the April 2015 issue of Lancet Oncology, Kang and colleagues published the results of a phase 3 study evaluating the safety and efficacy of aprepitant for prevention of CINV in children. Three hundred and seven patients between 6 months and 17 years of age were enrolled in this international randomized, double-blind study which compared aprepitant 3 mg/kg (maximum 125 mg) on day 1 with 2 mg/kg (maximum 80 mg) on days 2 and 3 plus ondansetron on day 1 to placebo for 3 days plus ondansetron on day 1. Younger patients received an investigational oral aprepitant suspension. Patients were grouped by age and the emetogenic potential of their chemotherapy. The primary endpoint was the proportion of patients with a complete response and no need for rescue medication during the delayed phase (25–120 hours after chemotherapy). Secondary endpoints included response during the acute phase (0–24 hours) and overall response.
Fifty-one percent of the patients in the aprepitant group achieved the primary endpoint, compared to only 26% of the controls (p < 0.0001). Sixtysix percent of the aprepitant group experienced no acute CINV, compared to 52% of controls (p = 0.014) and overall efficacy was seen in 47% of the aprepitant group and 21% of the controls (p < 0.0001). Fewer patients in the aprepitant group required dexamethasone (32% versus 48%) and they had a longer time to the first dexamethasone dose (p = 0.0024). There were no differences among age groups. Adverse effects were similar in the aprepitant group and controls.
A subsequent randomized, double-blind, placebo-controlled study focused on response to aprepitant as add-on therapy during the acute phase after chemotherapy administration. Ninety-three children between 5 and 18 years of age were enrolled in this single-center study. All patients received ondansetron (0.15 mg/kg) and dexamethasone (0.15 mg/kg), with the first dose given intravenously and the subsequent doses given orally. Aprepitant was given to patients weighing 15–40 kg as an 80 mg dose on days 1–3 and to patients 41–65 kg as 125 mg on day 1 followed by 80 mg on days 2 and 3. Patients in the control group received a placebo. Doses were given 1 hour before chemotherapy. A complete response was defined as no more than 2 episodes of emesis in the first 24 hours after administration of the first chemotherapy dose until 24 hours after the last dose. A significantly greater proportion of patients in patients in the aprepitant group had a complete response compared to the controls (48% versus 12%, p < 0.001). The incidence of acute moderate to severe vomiting was also less with aprepitant (38% versus 72%, p = 0.001). No major adverse effects were reported.
Merck is currently enrolling patients in two phase IIb clinical trials that will provide additional information on the use of aprepitant and fosaprepitant in children within the next several years. The first study will evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of fosaprepitant for CINV in children. Patients (newborn to 11 years of age) will receive 3 doses of a weight-adjusted fosaprepitant dose or placebo, in combination with ondansetron prior to their first cycle of chemotherapy. Fosaprepitant may then be continued in an open-label phase for cycles 2–6. The results of this study should provide optimal dosing for future efficacy studies. The second clinical trial will evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of aprepitant in the prevention of pediatric PONV. Patients from birth to 17 years of age will be randomized to receive aprepitant in one of 4 doses, ondansetron, or placebo prior to induction of anesthesia. The anticipated completion time for both studies is mid to late-2016.
Use in Children and Adolescents
Within two years of its approval, aprepitant was being used in adolescents to prevent CINV. The first clinical trial of aprepitant use in pediatrics was published in 2009. Gore and colleagues conducted a phase 3 randomized, double-blind, placebo-controlled study of the efficacy and tolerability of aprepitant in 46 patients between 11 and 19 years of age. Patients were randomized to receive the adult aprepitant regimen of 125 mg orally on day 1, followed by 80 mg on days 2 and 3, or placebo. All patients received dexamethasone and ondansetron. Complete response was defined as no emesis or need for rescue therapy over the first 5 days following chemotherapy. A significantly greater percentage of patients in the aprepitant group had a complete response (35.7% versus 5.6%). The percentage who did not require rescue antiemetics was also higher, 42.9% versus 22.2%. There were no serious drug-related adverse events and no patients discontinued treatment.
Several observational and retrospective studies have been published since that early report, adding to our experience with aprepitant in younger children and different cancer types. In 2013, Bauters and colleagues analyzed the results of aprepitant use in 20 patients (mean age 14 years, range 8–16 years) receiving a total 104 cycles of moderate or highly emetogenic chemotherapy. All patients received a 5-HT3 antagonist and dexamethasone 30 minutes prior to chemotherapy, as well as aprepitant 125 mg on day 1 followed by 80 mg on days 2 and 3. A complete response was observed in 89 cycles (85.6%). In spite of the multimodal approach, however, 13 patients still required rescue antiemetics.
Bodge and colleagues found a complete response rate of 38.9% in a group of 11 patients enrolled in their prospective observational study. The patients, ranging in age from 12 months to 17 years, all received ondansetron, dexamethasone, and aprepitant, rounded to the nearest 20 mg. Shillingburg and Biondo evaluated the tolerability of aprepitant in 26 children (11 months to 17 years of age) receiving a total of 114 chemotherapy cycles. Patients > 20 kg received the adult regimen, while patients 15–20 kg received 80 mg for 3 days and a single patient < 15 kg received 80 mg on day 1 and 40 mg on days 2 and 3. Twenty-five patients received aprepitant for CINV prevention and one patient for PONV prevention. No adverse effects believed to be related to aprepitant were reported. Although efficacy was not assessed in this report, the authors did report that only 8 patients required rescue antiemetics.
Aprepitant was also found to reduce CINV in a retrospective comparison study of 52 children and young adults (10–21 years of age) with central nervous system tumors.Eighteen of the patients received aprepitant with a regimen of ondansetron every 8 hours. Breakthrough vomiting was treated with the addition of lorazepam with or without diphenhydramine or promethazine. Aprepitant was given at a dose of 125 mg on day 1 followed by 80 mg on days 2 and 3. Patients who did not receive aprepitant had a significantly greater likelihood of developing grade 2 or 3 (severe) emesis during their first course of highly emetogenic chemotherapy (odds ratio 4.15, 95% CI 1.59, 10.82, p = 0.03). On the day after chemotherapy completion, the results remained significant, with 44% of controls having delayed grade 2 or 3 emesis, compared to only 16% of the aprepitant patients.
Two recent prospective studies have provided more detailed information on aprepitant use in children. In the April 2015 issue of Lancet Oncology, Kang and colleagues published the results of a phase 3 study evaluating the safety and efficacy of aprepitant for prevention of CINV in children. Three hundred and seven patients between 6 months and 17 years of age were enrolled in this international randomized, double-blind study which compared aprepitant 3 mg/kg (maximum 125 mg) on day 1 with 2 mg/kg (maximum 80 mg) on days 2 and 3 plus ondansetron on day 1 to placebo for 3 days plus ondansetron on day 1. Younger patients received an investigational oral aprepitant suspension. Patients were grouped by age and the emetogenic potential of their chemotherapy. The primary endpoint was the proportion of patients with a complete response and no need for rescue medication during the delayed phase (25–120 hours after chemotherapy). Secondary endpoints included response during the acute phase (0–24 hours) and overall response.
Fifty-one percent of the patients in the aprepitant group achieved the primary endpoint, compared to only 26% of the controls (p < 0.0001). Sixtysix percent of the aprepitant group experienced no acute CINV, compared to 52% of controls (p = 0.014) and overall efficacy was seen in 47% of the aprepitant group and 21% of the controls (p < 0.0001). Fewer patients in the aprepitant group required dexamethasone (32% versus 48%) and they had a longer time to the first dexamethasone dose (p = 0.0024). There were no differences among age groups. Adverse effects were similar in the aprepitant group and controls.
A subsequent randomized, double-blind, placebo-controlled study focused on response to aprepitant as add-on therapy during the acute phase after chemotherapy administration. Ninety-three children between 5 and 18 years of age were enrolled in this single-center study. All patients received ondansetron (0.15 mg/kg) and dexamethasone (0.15 mg/kg), with the first dose given intravenously and the subsequent doses given orally. Aprepitant was given to patients weighing 15–40 kg as an 80 mg dose on days 1–3 and to patients 41–65 kg as 125 mg on day 1 followed by 80 mg on days 2 and 3. Patients in the control group received a placebo. Doses were given 1 hour before chemotherapy. A complete response was defined as no more than 2 episodes of emesis in the first 24 hours after administration of the first chemotherapy dose until 24 hours after the last dose. A significantly greater proportion of patients in patients in the aprepitant group had a complete response compared to the controls (48% versus 12%, p < 0.001). The incidence of acute moderate to severe vomiting was also less with aprepitant (38% versus 72%, p = 0.001). No major adverse effects were reported.
Merck is currently enrolling patients in two phase IIb clinical trials that will provide additional information on the use of aprepitant and fosaprepitant in children within the next several years. The first study will evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of fosaprepitant for CINV in children. Patients (newborn to 11 years of age) will receive 3 doses of a weight-adjusted fosaprepitant dose or placebo, in combination with ondansetron prior to their first cycle of chemotherapy. Fosaprepitant may then be continued in an open-label phase for cycles 2–6. The results of this study should provide optimal dosing for future efficacy studies. The second clinical trial will evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of aprepitant in the prevention of pediatric PONV. Patients from birth to 17 years of age will be randomized to receive aprepitant in one of 4 doses, ondansetron, or placebo prior to induction of anesthesia. The anticipated completion time for both studies is mid to late-2016.
Source...