APPARATUS AND METHODS FOR ADMINISTRATION OF A NAUSEOGENIC COMPOUND FROM A DRUG DELIVERY DEVICE
Provided is a method for treating a subject, comprising contacting the subject with a drug delivery device comprising a nauseogenic compound, wherein the drug delivery device administers the nauseogenic compound to the subject, and the contacting occurs after an administration of the drug delivery device comprising the nauseogenic compound to a human patient population during a first clinical trial; and wherein less than 10% of the human patient population, to whom the drug delivery device comprising the nauseogenic compound was administered, reported having nausea and/or vomiting during the first clinical trial.
1 . A method for treating a subject, comprising
contacting the subject with a drug delivery device comprising a nauseogenic compound, wherein the drug delivery device administers the nauseogenic compound to the subject, and the contacting occurs after an administration of the drug delivery device comprising the nauseogenic compound to a human patient population during a first clinical trial;
wherein
less than 10% of the human patient population, to whom the drug delivery device comprising the nauseogenic compound was administered, reported having nausea and/or vomiting during the first clinical trial.
2 . The method of claim 1 , wherein less than 5% of the human patient population reported having nausea and/or vomiting during the first clinical trial.
3 . A method for treating a subject, comprising
contacting the subject with a drug delivery device comprising a nauseogenic compound and the drug delivery device administers the nauseogenic compound to the subject,
wherein
incidence of nausea and/or vomiting is 10% or less during a first clinical trial regarding administration of the drug delivery device comprising a continuous dose of the nauseogenic compound to a first human patient population; and
incidence of nausea and/or vomiting is 15% or greater during a second clinical trial regarding administration of an injectable or oral dose of the nauseogenic compound to a second human patient population.
4 . A method for treating a subject, comprising
contacting the subject with a drug delivery device comprising a nauseogenic compound and the drug delivery device administers the nauseogenic compound to the subject,
wherein
incidence of nausea and/or vomiting, reported as a percentage of a first human patient population, during a first clinical trial regarding administration of the drug delivery device comprising a continuous dose of the nauseogenic compound to the first human patient population, is reduced by at least 20% relative to incidence of nausea and/or vomiting, reported as a percentage of a second human patient population, during a second clinical trial regarding an administration of an injectable or an oral dose of the nauseogenic compound to the second human patient population.
5 . The method of any one of the preceding claims, for treating type-2 diabetes in a subject.
6 . The method of any one of the preceding claims, wherein the nauseogenic compound is a nauseogenic peptide.
7 . The method of any one of the preceding claims, wherein the nauseogenic compound is a long-acting nauseogenic peptide.
8 . The method of any one of the preceding claims, for treating a subject for type-2 diabetes, comprising contacting the subject with an implantable osmotic drug delivery device comprising a long-acting nauseogenic peptide.
9 . The method of any one of claims 1 - 4 , wherein the long-acting nauseogenic peptide is selected from GLP-1 receptor agonist, PYY analog, amylin agonist, CGRP analog, or neurotensin analog.
10 . The method of any one of the preceding claims, wherein the nauseogenic compound is a GLP-1 receptor agonist.
11 . The method of claim 10 , wherein the long-acting GLP-1 receptor agonist is exenatide dispersed in a biocompatible polymer (Bydureon®), semaglutide (Ozempic®), liraglutide (Victoza®), albiglutide (Tanzeum®), or dulaglutide (Trulicity®).
12 . The method of claim 11 , wherein the long-acting GLP-1 receptor agonist is semaglutide.
13 . The method of claim 11 , wherein the long-acting GLP-1 receptor agonist is liraglutide.
14 . The method of claim 11 , wherein the long-acting GLP-1 receptor agonist is albiglutide.
15 . The method of claim 11 , wherein the long-acting GLP-1 receptor agonist is dulaglutide.
16 . The method of claim 11 , wherein the long-acting GLP-1 receptor agonist is exenatide dispersed in a biocompatible polymer.
17 . The method of any preceding claim, wherein the drug delivery device administers the nauseogenic compound to the subject,
during the first 24 hours following initiation of administration, less than or equal to 90% of mean steady state concentration (C ss ) of the nauseogenic compound is attained in the plasma of the subject; and
once C ss is attained, C ss of the nauseogenic compound is maintained in the plasma of the subject for at least two weeks.
18 . A method for treating a subject, comprising contacting the subject with a drug delivery device comprising a dose of a nauseogenic compound,
wherein
the drug delivery device administers the nauseogenic compound to the subject,
during the first 24 hours following initiation of administration, less than or equal to 90% of mean steady state concentration (C ss ) of the nauseogenic compound is attained in the plasma of the subject; and
once C ss is attained, C ss of the nauseogenic compound is maintained in the plasma of the subject for at least two weeks.
19 . The method of claim 17 or 18 , wherein incidence of nausea is reduced in the subject during treatment.
20 . The method of any one of claims 17 - 19 , wherein incidence of nausea is less than 10% of subjects treated.
21 . The method of any one of claims 17 - 20 , wherein incidence of nausea is less than 5% of subjects treated.
22 . The method of any one of claims 17 - 21 , wherein during the first 2 days following initiation of administration, less than or equal to 90% of mean steady state concentration (C ss ) of the nauseogenic compound is attained in the plasma of the subject.
23 . The method of any one of claims 17 - 22 , wherein during the first 7 days following initiation of administration, less than or equal to 90% of mean steady state concentration (C ss ) of the nauseogenic compound is attained in the plasma of the subject.
24 . The method of any one of claims 17 - 23 , wherein during the first 14 days following initiation of administration, less than or equal to 90% of mean steady state concentration (C ss ) of the nauseogenic compound is attained in the plasma of the subject.
25 . The method of any one of claims 17 - 24 , wherein initial concentration (C I ) in plasma of the nauseogenic compound, during the first 12 hours following initiation of administration, is less than or equal to 25% of mean steady state concentration (C ss ) in plasma of the nauseogenic compound that will be attained in the subject.
26 . The method of any one of claims 17 - 25 , wherein d[nauseogenic compound]/dt is less than 4% of the mean steady state concentration (C ss ) of the nauseogenic compound per hour.
27 . The method of any one of claims 17 - 26 , wherein d[nauseogenic compound]/dt is less than 2% of the mean steady state concentration (C ss ) of the nauseogenic compound per hour.
28 . The method of any one of claims 17 - 27 , wherein d[nauseogenic compound]/dt is less than 1% of the mean steady state concentration (C ss ) of the nauseogenic compound per hour.
29 . The method of any one of claims 17 - 28 , wherein d[nauseogenic compound]/dt is less than 0.5% of the mean steady state concentration (C ss ) of the nauseogenic compound per hour.
30 . The method of any one of claims 17 - 29 , wherein d[nauseogenic compound]/dt is less than 0.25% of the mean steady state concentration (C ss ) of the nauseogenic compound per hour.
31 . The method of any one of claims 17 - 30 , wherein
d[nauseogenic compound]/dt is less than 4% of the mean steady state concentration (C ss ) of the nauseogenic compound per hour; and
less than or equal to 90% of mean steady state concentration (C ss ) of the nauseogenic compound is attained in the plasma of the subject during the first 7 days following administration.
32 . The method of any one of claims 17 - 31 , without incurring substantial peak-trough fluctuations in plasma concentration of the nauseogenic compound.
33 . The method of any one of claims 17 - 32 , wherein a maximum steady state concentration C max of nauseogenic compound does not substantially exceed the mean steady state concentration (C ss ) of the nauseogenic compound.
34 . The method of any one of claims 17 - 33 , wherein the mean steady state concentration (C ss ) of the nauseogenic compound, once reached in the subject, is substantially maintained for at least one month.
35 . The method of any one of claims 1 - 34 , wherein the nauseogenic compound has an elimination half-life (t 1/2 ) in humans of 1 day to 14 days.
36 . The method of any one of claims 1 - 35 , wherein the nauseogenic compound has an elimination half-life (t 1/2 ) in humans of 6 days to 10 days.
37 . The method of any one of claims 1 - 36 , wherein the device is an implantable drug delivery device.
38 . The method of any one of claims 1 - 37 , wherein the device is an implantable osmotic drug delivery device.
39 . The method of claim 38 , wherein contacting comprises subdermal placement of the implantable osmotic drug delivery device.
40 . The method of claim 38 , wherein the implantable osmotic drug delivery device administers a continuous dose of the nauseogenic compound.
41 . The method of any one of claims 1 - 40 , wherein the nauseogenic compound is a long-acting nauseogenic peptide.
42 . The method of any one of claims 1 - 36 , wherein the device is a non-implantable delivery device.
43 . The method of claim 42 , wherein contacting comprises affixing the non-implantable delivery device to an outer surface of the patient's skin.
44 . The method of any one of claims 1 - 43 , for treating diabetes in a subject.
45 . The method of any one of claims 1 - 44 , for treating type-2 diabetes in a subject.
46 . The method of any one of claims 1 - 45 , wherein the drug delivery device comprises a solid suspension of the nauseogenic compound.
47 . The method of any one of claims 1 - 46 , wherein the drug delivery device comprises an anhydrous formulation of the nauseogenic compound.
48 . The method of any one of claims 1 - 47 , wherein the nauseogenic compound is a long-acting nauseogenic peptide having a binding affinity to its intended receptor that is decreased 20-50 fold in the presence of 4% human serum albumin when comparing the binding affinity in the presence of very low concentration 0.1% of human serum albumin.
49 . The method of any one of claims 1 - 48 , wherein the nauseogenic compound is a long-acting nauseogenic peptide having an apparent K D for association with albumin not greater than 1 micromole/liter.
50 . The method of any one of claims 1 - 49 , wherein the nauseogenic compound is a long-acting nauseogenic peptide having an off rate for dissociation of nauseogenic compound from albumin not greater than 0.002/sec.
51 . The method of any one of claims 1 - 50 , wherein the nauseogenic compound is an acylated long-acting GLP-1 receptor agonist that binds human serum albumin (HSA) and exhibits an albumin-mediated potency decrease of 10-25 fold in the presence of 4% human serum albumin relative its potency in the presence of very low concentration 0.1% of human serum albumin.
52 . The method of any one of claims 1 - 51 , wherein the nauseogenic compound is an acylated long-acting GLP-1 receptor agonist that binds human serum albumin (HSA) and exhibits an albumin-mediated potency shift 20-50 fold relative to potency shift for human GLP-1 [7-36]NH 2 .
53 . The method of any one of claims 1 - 52 , wherein the nauseogenic compound is a nauseogenic peptide.
54 . The method of any one of claims 1 - 53 , wherein the nauseogenic compound is a long-acting nauseogenic peptide.
55 . A method for treating a subject for type-2 diabetes, comprising contacting the subject with an implantable osmotic drug delivery device comprising a long-acting nauseogenic peptide.
56 . The method of any one of claims 1 - 54 , wherein the nauseogenic compound or long-acting nauseogenic peptide comprises a lipophilic group, optionally bound to the peptide via a spacer.
57 . The method of any one of claims 1 - 56 , wherein the nauseogenic compound or long-acting nauseogenic peptide has a t 1/2 of at least about 24 hours in humans following subcutaneous administration.
58 . The method of any one of claims 17 - 57 , wherein the long-acting nauseogenic peptide is selected from GLP-1 receptor agonist, PYY analog, amylin agonist, CGRP analog, or neurotensin analog.
59 . The method of any one of claims 17 - 58 , wherein the long-acting nauseogenic peptide is selected from GLP-1 receptor agonist, PYY analog, amylin agonist, CGRP analog, or neurotensin analog, each of which comprises a lipophilic group, optionally bound to the peptide via a spacer.
60 . The method of any one of claims 17 - 59 , wherein the long-acting nauseogenic peptide is a GLP-1 receptor agonist.
61 . The method of claim 60 , wherein the long-acting GLP-1 receptor agonist is selected from any of the compounds of Formula I, Formula II, Formula III, Formula IV, and Formula V.
62 . The method of claim 60 , wherein the long-acting GLP-1 receptor agonist is selected from any of the compounds of SEQ ID NO. 1, SEQ ID NO. 2, SEQ ID NO. 3, SEQ ID NO. 4, SEQ ID NO. 5, SEQ ID NO. 6, SEQ ID NO. 7, SEQ ID NO. 8, SEQ ID NO. 9, and SEQ ID NO. 10.
63 . The method of claim 60 , wherein the long-acting GLP-1 receptor agonist is exenatide dispersed in a biocompatible polymer (Bydureon®), semaglutide (Ozempic®), liraglutide (Victoza®), albiglutide (Tanzeum®), or dulaglutide (Trulicity®).
64 . The method of claim 63 , wherein the long-acting GLP-1 receptor agonist is semaglutide.
65 . The method of claim 63 , wherein the long-acting GLP-1 receptor agonist is liraglutide.
66 . The method of claim 63 , wherein the long-acting GLP-1 receptor agonist is albiglutide.
67 . The method of claim 63 , wherein the long-acting GLP-1 receptor agonist is dulaglutide.
68 . The method of claim 63 , wherein the long-acting GLP-1 receptor agonist is exenatide dispersed in a biocompatible polymer.
69 . An apparatus comprising a drug delivery device and a nauseogenic compound that, upon being contacted with a subject, provides administration of a dose of the nauseogenic compound to the subject;
wherein
during the first 24 hours following initiation of administration, less than or equal to 90% of mean steady state concentration (C ss ) of the nauseogenic compound is attained in the plasma of the subject; and
once C ss is attained, C ss of the nauseogenic compound is maintained in the plasma of the subject for at least two weeks.