Human Starting Dose Calculator (MRSD/SSD) — Free Tool Walkthrough — Transcript

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1. 0:00So you've run your tox study,
2. 0:02now you have to figure out how to get that tox study into the
3. 0:04clinic. The biggest thing about non-clinical studies are that the NOAELs and the AUCs
4. 0:08and all the data that
5. 0:13you get from that, the overall summary and what the study director establishes as
6. 0:16those last data points, those last dose levels,
7. 0:19that is what's used to go into the clinic. But how is that calculated,
8. 0:23right? How do we go into the clinic and how do we use our
9. 0:25tox studies to come up with a safe starting dose,
10. 0:28or the maximum recommended starting dose,
11. 0:31or even something for a biologic, for example.
12. 0:34Well this tool, while it's not going to exactly explain it,
13. 0:37that's in another video, this tool is a great tool that I'll have linked
14. 0:41in the description that you can go to and use your doses from your
15. 0:44tox studies, multiple species,
16. 0:46multiple dose levels, multiple body weights,
17. 0:49including a human body weight, and use that to calculate your human dose.
18. 0:54And you can go do multiple species at a time and come up with
19. 0:58your MRSD based on which species is the most
20. 1:02sensitive. So let's take a look at this tool.
21. 1:05as we go down on the left panel here are going to be all
22. 1:08your options. So you have a calculation mode,
23. 1:10you can include your animal study data. You can then export it to Excel
24. 1:15or save as a PDF. But once you put all your parameters in and
25. 1:18you put all your inputs in, you're going to be able to spit out
26. 1:21your starting dose on the right. So let's look at the different options that
27. 1:24we have, right? So we have the MRSD,
28. 1:26which is your non-oncology starting dose that uses your NOAEL,
29. 1:30pretty straightforward. forward. You have your SSD,
30. 1:33which is your safe starting dose. This is used in oncology.
31. 1:36For rodents, we use the STD-10,
32. 1:40or the safe starting severely toxic dose in 10% of the animals.
33. 1:43And we use the HNSTD for non-rodents,
34. 1:46which is the highest non-severely toxic dose.
35. 1:50The other one is an HED only,
36. 1:52or your human equivalent dose. This has NOAEL safety factor application,
37. 1:57just a quick conversion to see what your animal dose would be as a
38. 2:00human. So this is where you pick which one.
39. 2:03If you're running an oncology program, you'd pick SSD.
40. 2:06If you're running a non-oncology program, you'd pick MRSD.
41. 2:09So let's stick with MRSD for now. And then right below that you can
42. 2:13see your human reference weight. So a lot of times this fluctuates depending on
43. 2:17what you're using to justify your starting dose.
44. 2:19Most people use 70. You can change this to 60.
45. 2:2360 is another valid option as well. Then you can choose whichever one you
46. 2:27think is best. Anything below 60 or over 70 is usually not recommended.
47. 2:34And then right below that, you can see the FDA guidance that talks about
48. 2:37all of this stuff, so you can get a little bit more in-depth understanding
49. 2:40of it. So if we continue to go down, we'll stick to 60 for
50. 2:43now. If you continue to go down,
51. 2:46you can see you have your animal study data. And so this data is
52. 2:50essentially your tox studies, whatever tox studies you ran,
53. 2:53your GLP tox. You can do this for your non-GLP,
54. 2:56for your DRFs, as this is something you want to kind of see after
55. 2:59your DRFs what your effects or exposure margins might be,
56. 3:02what your safe starting dose is looking like before you run your GLP.
57. 3:05Great for being able to translate non-clinical data to different teams,
58. 3:09investors, your board, what have you.
59. 3:12But ultimately, if we are picking this for a clinical trial for an FIH,
60. 3:16you would pick which species you ran your GLP tox in,
61. 3:19and then you'd fill in the parameters. So let's say that we ran a
62. 3:22typical rat and dog study for an oncology compound.
63. 3:25We could pick the rat, and we could pick the dog.
64. 3:27And then within each of these are different parameters, so you can see your
65. 3:30KMs which are your conversion factors And we'll talk about where those come from
66. 3:34but this is essentially using your NOAEL You can pick each one that you
67. 3:38want like we said above your MRSD is based on your NOAEL not your
68. 3:42oncology ones. So we're gonna stick with a NOAEL here We're gonna add the
69. 3:46dose of your NOAEL so in your rats Let's say your NOAEL is 150
70. 3:51and then we're gonna add the weight for the rat.
71. 3:53These come pre-populated But based on an average rat weight for your study you
72. 3:57can update these So for example,
73. 4:00if you happen to have a study that you had obese rats Which sometimes
74. 4:04happens you can change the average kigs for your rat Or if you potentially
75. 4:09use sexually mature dogs, those weights are going to be a little bit heavier.
76. 4:12You can pick that. So you can update these if you want.
77. 4:15Otherwise, keep them the way they are and you'll be able to get your
78. 4:18numbers calculated out like that. And that's for the dog.
79. 4:21Same thing. You have your conversion factor NOAEL .
80. 4:24We'll say for the dog our NOAEL was 20 and then we'll stick at
81. 4:2710 kigs about for the dog. This is usually between anywhere from 8 to
82. 4:3110 kigs. We'll say we had some chunky dogs.
83. 4:35And so once you input these numbers in here,
84. 4:38you can see over here on the right that your MRSD is calculated
85. 4:43out. And this uses both the species that you had used in your GLP
86. 4:46tox and it tells you which one is this most sensitive species or you're
87. 4:50driving species. And so your MRSD for a 60 kg human
88. 4:54is going to be 65 mg. That's based on the dog's NOAEL of 20
89. 4:58mg per kg with the NOAEL in the safety factor.
90. 5:01And then that would also tell you your human equivalent dose before the safety
91. 5:05factor in case you need that. And then it breaks it down into exactly
92. 5:09what you did, what numbers were used and how that calculation happened.
93. 5:14So just some warning notes here at the bottom.
94. 5:18A tox judgment note about the FDA's guidance in picking the most appropriate species
95. 5:23and then the BSA scaling. Sometimes it's not the most appropriate route for particular
96. 5:28administration, so topical, nasal,
97. 5:31subcutaneous, or things like that. You can adjust for
98. 5:35that. And then if you're using biologics or large molecules,
99. 5:39typically this is a combination of your NOAEL,
100. 5:41your MABEL, and modeling approaches and computational monitoring,
101. 5:45computational modeling. and that usually has clinical pharmacology,
102. 5:50coming into the picture at that point and doing some complex things that are
103. 5:53not within my wheelhouse. And then down at the bottom,
104. 5:55you can see the different guidances. You can pick them,
105. 5:58you can click on them and, learn a little bit more about them.
106. 6:01And then if you want to know the conversion factors,
107. 6:03the Km factors, this table brings it all down.
108. 6:06So you can double, you can click on that, it opens up,
109. 6:09and it gives you all the conversion factors and what you're actually doing.
110. 6:12So you can get an understanding of the foundation of where these numbers came
111. 6:15from, and then it gives you a couple of quick examples.
112. 6:18So let's go back up and real quick, I'm just going to show you
113. 6:21what it looks like if you were going to do an oncology compound.
114. 6:23So let's do, a safe starting dose.
115. 6:26So an SSD, we're going to go,
116. 6:28let's go to 70 kgs for the human. And we're going to say,
117. 6:31let's say we did the rat and dog. We'll stick with that.
118. 6:34We're going to go, it automatically clicks it down for you.
119. 6:36So the rat is STD 10 and the dog is the HNSTD.
120. 6:40We're going to stay at 150. We're going to stay at 20,
121. 6:42so everything's the same, just the difference is that we're doing an SSD.
122. 6:46And so if we go back up, you're gonna see now the dog is
123. 6:49still the driving species, but that dose,
124. 6:51the human dose, is now 120 mgs versus the 65 mgs we had
125. 6:56before. And actually, let me change this back to 60.
126. 7:00You can see that it's still almost double. It's still a little bit more.
127. 7:02And this is mostly because the safety factor is driving the
128. 7:07greater human dose because there's more wiggle room in oncology.
129. 7:10So typically your safety factor would be 10 in the dog.
130. 7:13It's six. So you're dividing it by a little bit less of a safety
131. 7:17factor, which gives you a higher dose. If the rat was the most sensitive,
132. 7:21You'd see the rat there, too, And so this is what that looks like
133. 7:25and you can play around with it You can actually model any sort of
134. 7:28starting dose that you want, oncology, non-oncology,
135. 7:31and you can add these. You can add whatever different animals you want.
136. 7:34Say you want to see the difference between a mouse and a monkey,
137. 7:37you can add these in as well and choose your starting doses and your
138. 7:41NOAEL whales. You can change this back.
139. 7:44Or if you just want to see what your human equivalent dose is,
140. 7:47you can change that to HED, add a bunch of different species into it,
141. 7:51and then you can see what that's going to look like on the other
142. 7:53side. You can see the difference between what a human equivalent dose is and
143. 7:57then what it is after the fact of a safety factor being applied.
144. 8:00So this is a pretty good tool.
145. 8:02Bookmark it, send it along,
146. 8:04And if you want more content like this, check out my course,
147. 8:07The Complete Guide to Non-Clinical Development. There's 12 plus modules,
148. 8:10plus two bonus modules, three tiers for your experience.
149. 8:13The link is in the comments.