Dose escalation schedule: difference between revisions
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| 10 | Step intervals for weekly agents are conventionally four weeks, which is approximately the time to steady state for a peptide with a half-life of several days. Escalating faster raises the dose before the previous step is fully expressed, so both exposure and adverse effects accumulate.{{r|knudsen2019}} | 10 | Step intervals for weekly agents are conventionally four weeks, which is approximately the time to steady state for a peptide with a half-life of several days. Escalating faster raises the dose before the previous step is fully expressed, so both exposure and adverse effects accumulate.{{r|knudsen2019}} |
| 11 | 11 | ||
| + | 12 | Compressing an escalation predictably increases gastrointestinal adverse events and discontinuation. This is one of the better-characterised relationships in the field, since the escalation schedules used in trials were themselves selected on tolerability grounds.{{r|wilding2021}} | |
| + | 13 | ||
| 12 | == Why escalation works == | 14 | == Why escalation works == |
| 13 | Nausea and vomiting from incretin agonism attenuate with continued exposure at a constant dose, an adaptation associated with the attenuation of the delay in [[Gastric emptying|gastric emptying]] over the same period. Escalation exploits that adaptation by holding each dose long enough for it to occur before increasing.{{r|drucker2018}} | 15 | Nausea and vomiting from incretin agonism attenuate with continued exposure at a constant dose, an adaptation associated with the attenuation of the delay in [[Gastric emptying|gastric emptying]] over the same period. Escalation exploits that adaptation by holding each dose long enough for it to occur before increasing.{{r|drucker2018}} |
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| 21 | <ref name="drucker2018">Drucker DJ. "Mechanisms of action and therapeutic application of glucagon-like peptide-1." ''Cell Metabolism'' 27(4):740–756 (2018). PMID 29617641.</ref> | 23 | <ref name="drucker2018">Drucker DJ. "Mechanisms of action and therapeutic application of glucagon-like peptide-1." ''Cell Metabolism'' 27(4):740–756 (2018). PMID 29617641.</ref> |
| 22 | <ref name="knudsen2019">Knudsen LB, Lau J. "The discovery and development of liraglutide and semaglutide." ''Frontiers in Endocrinology'' 10:155 (2019). PMID 31031702.</ref> | 24 | <ref name="knudsen2019">Knudsen LB, Lau J. "The discovery and development of liraglutide and semaglutide." ''Frontiers in Endocrinology'' 10:155 (2019). PMID 31031702.</ref> |
| + | 25 | <ref name="wilding2021">Wilding JPH, Batterham RL, Calanna S, et al. "Once-weekly semaglutide in adults with overweight or obesity." ''New England Journal of Medicine'' 384(11):989–1002 (2021). PMID 33567185.</ref> | |
| 23 | 26 | ||
| 24 | {{DEFAULTSORT:Dose escalation schedule}} | 27 | {{DEFAULTSORT:Dose escalation schedule}} |