Stepwise shortening of agalsidase beta infusion duration in Fabry disease: Clinical experience with infusion rate escalation protocol

191 Background: Ramucirumab is a human recombinant immunoglobin G1 monoclonal antibody (mAb) antagonist of vascular endothelial growth factor receptor-2. Ramucirumab dosed at 8 mg/kg every 2 weeks or 10 mg/kg every 3 weeks, either as monotherapy or in combination with chemotherapy, was initially studied with as an intravenous infusion over 60 minutes following premedication with a histamine-1 receptor antagonist. Lengthy intravenous infusions are inconvenient for patients and increase the workloads of nursing and administrative staff. Shortening the infusion duration of ramucirumab could therefore benefit both patients and healthcare professionals. The current analysis determined the impact such a change could have on the pharmacokinetic (PK) profile of ramucirumab. Additionally, the relationship between infusion rate and incidence of immediate infusion-related reactions (IRRs; occurring on the day of administration), common adverse events associated with mAb infusions, was assessed. Methods: A population pharmacokinetic model was established using concentration–time data collected from 2522 patients who received one of five different ramucirumab regimens involving an intravenous infusion over ~60 minutes in 17 clinical studies. The final PK model was used to simulate concentration–time profiles and exposure parameters following ramucirumab infusion durations of 30 vs 60 min. Phase II/III clinical study data from patients receiving ramucirumab were pooled to assess the association between ramucirumab infusion rate and incidence of immediate IRRs using multivariate logistic regression analysis. Results: Ramucirumab infusions of 30- and 60-min durations resulted in equivalent concentration–time profiles and, hence, equivalent systemic exposure to ramucirumab. Among 3216 patients receiving ramucirumab in phase II/III studies, 254 (7.9%) had at least one immediate any-grade IRR; 17 (0.5%) experienced grade ≥3 immediate IRRs. The incidence of immediate IRRs (any grade or grade ≥3) was similar across infusion rate quartiles. Under multivariate logistic analysis, infusion rate was not significantly associated with an increased risk of an immediate IRR (odds ratio per 1 mg/min increase 1.014, 95% confidence interval 0.999, 1.030; p=0.071). Conclusions: Administering ramucirumab using different infusion durations (30 vs 60 min) did not affect ramucirumab exposure. Analysis of clinical study data showed a faster infusion rate was not associated with an increased risk of immediate IRRs. It is considered unlikely that shortening the infusion duration of ramucirumab will impact its clinical efficacy or overall safety profile, and is now an option for administration in the U.S.

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Effect of oral versus gastric delivery on gastric emptying of corn oil emulsions

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1997.273.4.r1263 ◽

1997 ◽

Vol 273 (4) ◽

pp. R1263-R1270 ◽

Cited By ~ 9

Author(s):

Joel M. Kaplan ◽

William Siemers ◽

Harvey J. Grill

Keyword(s):

Gastric Emptying ◽

Energy Density ◽

Infusion Rate ◽

Corn Oil ◽

Stimulus Parameters ◽

Oil Concentration ◽

Delivery Route ◽

Oil Emulsions ◽

Infusion Duration

Several studies have shown that fluids delivered to the stomach tend to empty more rapidly than when ingested by mouth. To better characterize the “delivery route effect” for corn oil, rats received intragastric or intraoral infusions matched for concentration and for the rate and duration of stimulus delivery. We showed, first, that more than twice as much oil emptied by the end of 12-min intragastric versus intraoral infusions but that the emptying curves remained roughly parallel for 1 h after infusion offset. Remaining experiments therefore focused on stimulus parameters of relevance to emptying control during stomach fill. Emptying during intragastric infusions approximately doubled with doublings of oil concentration (25–50%), infusion duration (6–12 and 12–24 min), and infusion rate (0.5–1.0 ml/min). Emptying during intraoral infusions, by contrast, was entirely unaffected by these manipulations. Unlike oil emptying, glucose emptying did not vary as a function of delivery route. The nutrient specificity of the delivery route effect cannot be explained in terms of energy density, as the effect was obtained for oil but not for glucose when their energy densities were equated (50% glucose, 25% corn oil). In discussion, we suggest that the oral influence on corn oil emptying during stomach fill is a gating factor that enables the expression of inhibition derived from postgastric nutrient stimulation.

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Treatment switch in Fabry disease- a matter of dose?

Journal of Medical Genetics ◽

10.1136/jmedgenet-2020-106874 ◽

2020 ◽

pp. jmedgenet-2020-106874

Author(s):

Malte Lenders ◽

Peter Nordbeck ◽

Sima Canaan-Kühl ◽

Lukas Kreul ◽

Thomas Duning ◽

...

Keyword(s):

Fabry Disease ◽

Dose Group ◽

Clinical Symptoms ◽

Organ Damage ◽

Agalsidase Beta ◽

Disease Epidemiology ◽

Reduced Dose ◽

Clinical Events ◽

Agalsidase Alfa ◽

Switch Group

BackgroundPatients with Fabry disease (FD) on reduced dose of agalsidase-beta or after switch to agalsidase-alfa show a decline in chronic kidney disease epidemiology collaboration-based estimated glomerular filtration rate (eGFR) and a worsened plasma lyso-Gb3 decrease. Hence, the most effective dose is still a matter of debate.MethodsIn this prospective observational study, we assessed end-organ damage and clinical symptoms in 78 patients who had received agalsidase-beta (1.0 mg/kg) for >1 year, which were assigned to continue this treatment (agalsidase-beta, regular-dose group, n=17); received a reduced dose of agalsidase-beta and subsequent switch to agalsidase-alfa (0.2 mg/kg) or a direct switch to 0.2 mg/kg agalsidase-alfa (switch group, n=22); or were re-switched to agalsidase-beta after receiving agalsidase-alfa for 12 months (re-switch group, n=39) with a follow-up of 88±25 months.ResultsNo differences for clinical events were observed for all groups. Patients within the re-switch group started with the worst eGFR values at baseline (p=0.0217). Overall, eGFR values remained stable in the regular-dose group (p=0.1052) and decreased significantly in the re-switch and switch groups (p<0.0001 and p=0.0052, respectively). However, in all groups males presented with an annual loss of eGFR by –2.9, –2.5 and −3.9 mL/min/1.73 m² (regular-dose, re-switch, switch groups, all p<0.05). In females, eGFR decreased significantly only in the re-switch group by −2.9 mL/min/1.73 m² per year (p<0.01). Lyso-Gb3 decreased in the re-switch group after a change back to agalsidase-beta (p<0.05).ConclusionsOur data suggest that a re-switch to high dosage of agalsidase results in a better biochemical response, but not in a significant renal amelioration especially in classical males.

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