Anatomy of a TK Profile: AUC, Cmax, Tmax & Half-Life Explained — Transcript

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1. 0:00Good morning everyone. Today we are talking about the anatomy of a TK
2. 0:04profile. So, what is a TK profile?
3. 0:08What are the elements within a TK profile?
4. 0:10And how does that translate to toxicology? Like, why is this important?
5. 0:14So you can see here on this little graph this is essentially a TK
6. 0:18curve. So you have this curve right here,
7. 0:22and this correlates to, you can see on the x-axis,
8. 0:25you have hours post dose, and the y-axis issue of concentration.
9. 0:29And so each of these little points, imagine they're a little data points here
10. 0:33at each of where these lines hit the curve.
11. 0:36And this is basically saying at two hours post dosage,
12. 0:40for example, the concentration in the plasma or the serum,
13. 0:43basically in systemic circulation in the blood,
14. 0:46is this. And so you can see at,
15. 0:50eight hours, it correlates to a 100 nanograms per mil concentration
16. 0:55within the blood. We'll say plasma because that's a typically standard a way to
17. 0:59measure to measure this. So, this would be the curve that you would
18. 1:04have. You'd plot all these points out.
19. 1:06If this was an IV dose, you would have the maximum,
20. 1:10your Cmax concentration at zero because IV dosing
21. 1:15is 100% absorption instantly. And so that starts up
22. 1:20here and goes down. This is more of what hypothetically an oral
23. 1:24dose would look like where it's, negligible and then the dose starts to get
24. 1:28absorbed into the body. It hits a maximum point and then it starts to
25. 1:32clear and it goes back down. and so these are the different parameters that
26. 1:35we look for when we talk about a TK profile.
27. 1:37The most important by far is AUC.
28. 1:40So this is the area under the curve and it is literally the area
29. 1:45under the curve. So this is usually in hours times nanogram per mil.
30. 1:49or it can be in different units. And so this is your exposure.
31. 1:53So you might hear exposure a lot. I know I talk about it a
32. 1:56lot, that is your AUC and that is what we use to correlate findings
33. 2:00within each other, within dose groups, within studies,
34. 2:03across species. We correlate findings and experiments.
35. 2:06Exposure to the human, we translate that to the clinic,
36. 2:09that's how we understand our NOALs and how those impact our entire
37. 2:14program as a whole, and exposure is basically how much of
38. 2:19the drug, this test system, be it an animal or a human,
39. 2:22how much of that test system is being exposed to the drug and the
40. 2:26resulting consequences of that, whether it is toxicity,
41. 2:29if it's an efficacy study, you would have exposure within a pharmacology study,
42. 2:33so at what exposure do you see an efficacious effect or an effective dose
43. 2:39You'll see 0 to 72 is this graphed only because we're out to 72
44. 2:44hours post-dose. A lot of times you'll see 0 to 24,
45. 2:47that's very common because you want to see it over a day,
46. 2:50but you might have 0 to infinity, or a different 0 to 168,
47. 2:53which is, you know, a week, and to be able to understand the exposure
48. 2:58over a certain time period. And then over here you can see that we
49. 3:01have Cmax, so Cmax is the maximum concentration that that drug reaches in
50. 3:06the systemic circulation. And you can see that on the graph where this graph
51. 3:10peaks right here at 100 nanograms per mil and so that peaks at 8
52. 3:14hours. And so our Cmax is the actual concentration and
53. 3:18then our Tmax is the time that we measure the actual concentration.
54. 3:23Some drugs can be Cmax driven,
55. 3:25and the toxicity can be Cmax driven where you don't see toxicity unless you
56. 3:29reach a certain Cmax. And this is similar to exposure where you need to
57. 3:33potentially reach a certain exposure to see toxicity,
58. 3:36but Cmax is common, particularly with biologics and large molecules,
59. 3:41And Cmin is also important because you want to sometimes understand what's at the
60. 3:45minimum level that you're going to see that biological effect or toxicity and how
61. 3:49that translates to the program overall. And then you have your last perimeter here
62. 3:54at the bottom. You can see T1 half and this is your half-life.
63. 3:57This is how long it takes for 50% of the drug to be reduced
64. 4:00within the system. So you can see here that our Cmax is at 100
65. 4:02nanograms per mil at
66. 4:068 hours, and then it gets reduced to 50 nanograms per mil at 24
67. 4:09hours. And so the difference between 8
68. 4:14and 24 would be 16 hours, so 16 would be your half-life. And so
69. 4:17half-life is important because it's how we understand dosing regimen If your
70. 4:22drug needs to be at a certain Cmax or exposure to work and your
71. 4:26half-life is 8 hours,
72. 4:30then you're going to need to dose more than once per day most likely
73. 4:33to be able to continue to hit that Cmax or that AUC to show
74. 4:37that you have assessed toxicity within the realm of the efficacious exposure
75. 4:42or Cmax on the flip side we might have really long
76. 4:47half-lifes so biologics they have half-lifes that can be weeks on end
77. 4:51and so this is important to understand if you need to do weekly dosing
78. 4:54or bi-weekly dosing or even monthly dosing or even quarterly dosing in some
79. 4:59cases it depends on how long that drug can stay in the system above
80. 5:03a certain level whether that's within your therapeutic window whether it's above the Cmax
81. 5:08you need to hit or whether it's you know above the exposure that you
82. 5:11need to hit and how long you're gonna have until you need to dose
83. 5:15the next dose. And so sometimes you might see some waves on
84. 5:20a graph that shows where that minimum level is that you that drug needs
85. 5:23to stay above so that we can accurately assess what toxicity looks like while
86. 5:27the drug is at that level for an extended period of time.
87. 5:30And so half-life is really important. when we are doing studies in rats and
88. 5:34dogs or monkeys, for example, the half-life is and TK profiles
89. 5:39within different species can differ so much that you might have to dose
90. 5:44twice a day in the dog and once a day in the rat because
91. 5:47the clearance and the elimination creates a really fast half-life and so you have
92. 5:52to keep dosing to keep up with the exposure the Cmax needed to be
93. 5:55able to to accurately assess that toxicity.
94. 5:58So all of these work pretty much in cohesion with each other but this
95. 6:01is an overview, very quick overview, of a TK profile.
96. 6:04this is what we look at in any tox study to be able to
97. 6:07understand the kinetics of the drug and
98. 6:12how that relates, and how that coincides with
99. 6:16the drug. the toxicity that we see as well and then how we can
100. 6:20translate that into the human. If you want to know more about
101. 6:25this we do a deep dive in this in my course,
102. 6:27the complete guide to non-clinical development.
103. 6:29We go over this in module seven and we go through
104. 6:34all of this PK, we go through TK,
105. 6:37pharmacokinetics, toxicokinetics, and we go through how this integrates
106. 6:41into tox studies and non-clinical programs and how that translates to the clinic as
107. 6:45well as a little bit of pharmacology work as well. So check it out,
108. 6:48it'll be linked in the description of this video. It's on Nonclinical Academy and
109. 6:52I'll see you in the next video.