WEBVTT 00:00:00.000 --> 00:00:02.680 Here's a statistic that honestly stops you in 00:00:02.680 --> 00:00:07.259 your tracks. Cardiovascular diseases. They cause 00:00:07.259 --> 00:00:10.599 almost half, think about that, nearly 45 % of 00:00:10.599 --> 00:00:14.380 all deaths from non -communicable diseases globally. 00:00:14.460 --> 00:00:16.539 That's a huge number and it comes straight from 00:00:16.539 --> 00:00:18.679 the World Heart Federation. It really sets the 00:00:18.679 --> 00:00:20.559 stage for why we're talking about a torvastatin 00:00:20.559 --> 00:00:22.800 today. Exactly. You probably know it better as 00:00:22.800 --> 00:00:25.039 Lipitor. That's the brand name Pfizer launched 00:00:25.039 --> 00:00:28.500 way back in 1997. It's one of those drugs that 00:00:28.500 --> 00:00:30.559 truly changed the game in managing heart disease 00:00:30.559 --> 00:00:32.960 risk. It really did. And think about the scale 00:00:32.960 --> 00:00:36.579 CDC data suggests. Almost 38 % of adults right 00:00:36.579 --> 00:00:39.280 here in the US have high cholesterol. So this 00:00:39.280 --> 00:00:42.179 isn't some niche topic. Not at all. It's incredibly 00:00:42.179 --> 00:00:44.799 relevant for, well, potentially millions listening 00:00:44.799 --> 00:00:47.219 right now. Yeah. And our goal today is simple. 00:00:47.520 --> 00:00:50.420 Give you a solid, thorough understanding of atorvastatin. 00:00:50.679 --> 00:00:53.000 But without making your head spin with, you know, 00:00:53.240 --> 00:00:56.159 overly dense science speak. Right. We want this 00:00:56.159 --> 00:00:58.399 to be your quick comprehensive guide. We're going 00:00:58.399 --> 00:00:59.939 to look at where it came from, how it actually 00:00:59.939 --> 00:01:02.299 works inside your body, its impact health -wise, 00:01:02.399 --> 00:01:05.439 economically, and some of the really interesting 00:01:05.439 --> 00:01:07.680 stories behind it all. It's a great lens, actually. 00:01:07.799 --> 00:01:10.540 Looking at one drug like atorvastatin tells you 00:01:10.540 --> 00:01:13.519 so much about how medicines are developed, used, 00:01:14.040 --> 00:01:17.060 regulated the whole life cycle. OK, so let's 00:01:17.060 --> 00:01:19.840 start at the very beginning. Before atorvastatin, 00:01:19.939 --> 00:01:22.700 before statins even, there was cholesterol itself. 00:01:23.140 --> 00:01:25.500 And figuring that out took a while. Oh, definitely. 00:01:25.780 --> 00:01:29.359 This story goes way, way back. 1784, believe 00:01:29.359 --> 00:01:32.599 it or not. A French chemist and physician, Francois 00:01:32.599 --> 00:01:35.640 Poulakier, he was the first to isolate it. And 00:01:35.640 --> 00:01:37.439 he found it in Goldstone's right. Kind of an 00:01:37.439 --> 00:01:39.340 unusual place to discover something so vital. 00:01:39.500 --> 00:01:42.379 It is, isn't it? Then another Frenchman, Michel 00:01:42.379 --> 00:01:44.519 Chevreul, gave it the name cholesterol a bit 00:01:44.519 --> 00:01:47.379 later, comes from the Greek for bile and solid. 00:01:47.540 --> 00:01:49.659 Makes sense, given where Puthier found it. But 00:01:49.659 --> 00:01:51.819 just finding it and naming it isn't the same 00:01:51.819 --> 00:01:53.900 as understanding it. Not at all. That took more 00:01:53.900 --> 00:01:56.939 time. It wasn't until 1888 that Friedrich Ramonitzer, 00:01:57.140 --> 00:01:59.879 an Austrian botanist, figured out its actual 00:01:59.879 --> 00:02:02.900 molecular formula and then cracking its structure, 00:02:03.000 --> 00:02:05.579 that distinctive four ring structure. That was 00:02:05.579 --> 00:02:08.259 a huge focus in the early 20th century. So huge 00:02:08.259 --> 00:02:11.659 it led to Nobel prizes. Two of them for chemistry. 00:02:12.360 --> 00:02:15.379 Heinrich Wieland in 1927 and Adolf Windhouse 00:02:15.379 --> 00:02:18.659 in 1928. That really tells you how scientifically 00:02:18.659 --> 00:02:21.259 important cholesterol was even back then. It 00:02:21.259 --> 00:02:23.639 wasn't just some random discovery. Scientists 00:02:23.639 --> 00:02:26.080 were deeply fascinated by this molecule for a 00:02:26.080 --> 00:02:28.460 long time. Precisely. And all that fundamental 00:02:28.460 --> 00:02:30.699 research, that deep understanding, it laid the 00:02:30.699 --> 00:02:32.960 groundwork. It's why scientists eventually started 00:02:32.960 --> 00:02:35.180 looking for ways to manage cholesterol levels 00:02:35.180 --> 00:02:37.780 therapeutically. Which brings us, finally, to 00:02:37.780 --> 00:02:40.759 the statins. How did we get from understanding 00:02:40.759 --> 00:02:42.979 cholesterol to actually having drugs to lower 00:02:42.979 --> 00:02:46.139 it? The big leap was in the 1970s. Researchers 00:02:46.139 --> 00:02:49.300 at a Japanese company, Sankyo, discovered a compound 00:02:49.300 --> 00:02:51.900 they called compactin. And this was the first 00:02:51.900 --> 00:02:54.599 real glimmer of a cholesterol -lowering drug. 00:02:54.879 --> 00:02:57.340 It was. They saw its potential. Interestingly, 00:02:57.599 --> 00:02:59.960 around the same time, Beecham Pharmaceuticals 00:02:59.960 --> 00:03:02.520 over in the UK, they're part of GSK, now also 00:03:02.520 --> 00:03:05.520 found compactin. A parallel discovery. That happens 00:03:05.520 --> 00:03:08.240 sometimes in science. It does, but Beecham was 00:03:08.240 --> 00:03:10.719 initially looking at it as an antifungal, and 00:03:10.719 --> 00:03:12.639 they ran into a bit of a snag. What was that? 00:03:12.819 --> 00:03:14.919 They couldn't reliably show it lowered cholesterol 00:03:14.919 --> 00:03:17.280 in rats, which was a standard animal model they 00:03:17.280 --> 00:03:20.139 were using. Sankyo, using different models, did 00:03:20.139 --> 00:03:22.099 see the cholesterol -lowering effect more clearly. 00:03:22.639 --> 00:03:25.060 It shows how crucial those early research choices 00:03:25.060 --> 00:03:27.599 can be. So Beecham kind of missed the boat on 00:03:27.599 --> 00:03:29.919 the cholesterol angle initially. But the story 00:03:29.919 --> 00:03:31.439 gets even more interesting, doesn't it? There 00:03:31.439 --> 00:03:34.900 was some early human testing. Yes, and it was 00:03:34.900 --> 00:03:38.719 technically unsanctioned. In 1978, a researcher 00:03:38.719 --> 00:03:41.780 teamed up with a doctor at Osaka University Hospital. 00:03:42.259 --> 00:03:44.620 They gave compactin to an 18 -year -old woman 00:03:44.620 --> 00:03:47.560 who had a severe genetic condition, familial 00:03:47.560 --> 00:03:50.560 hypercholesterolemia. Her levels were incredibly 00:03:50.560 --> 00:03:54.210 high, like 1 ,000 milligDL. Wow. And did it work? 00:03:54.449 --> 00:03:56.930 It did bring her levels down significantly, to 00:03:56.930 --> 00:04:00.650 around 700mgdL, which is still high, but a big 00:04:00.650 --> 00:04:03.250 drop. But there were problems? There were. After 00:04:03.250 --> 00:04:05.650 a few weeks, she developed elevated liver enzymes, 00:04:06.110 --> 00:04:08.770 some muscle issues, symptoms consistent with 00:04:08.770 --> 00:04:10.590 muscular dystrophy, actually. Whoa, that sounds 00:04:10.590 --> 00:04:12.830 serious. It was, but thankfully, the effects 00:04:12.830 --> 00:04:16.230 reversed when they stopped the drug. Later, lower 00:04:16.230 --> 00:04:18.889 doses did show some benefit in reducing cholesterol 00:04:18.889 --> 00:04:21.610 deposits over the long term, even if the initial 00:04:21.610 --> 00:04:24.329 big drop wasn't sustained quite as hoped. So 00:04:24.329 --> 00:04:27.149 a bumpy start, but the potential was clearly 00:04:27.149 --> 00:04:29.649 there. Enough potential to get other companies 00:04:29.649 --> 00:04:32.569 interested. Absolutely. Merck, the big American 00:04:32.569 --> 00:04:34.589 pharmaceutical company, was definitely paying 00:04:34.589 --> 00:04:37.569 attention. The results with Compactin, especially 00:04:37.569 --> 00:04:39.569 in the animal studies, were promising enough 00:04:39.569 --> 00:04:41.610 for them to jump in. How did they get involved? 00:04:41.889 --> 00:04:44.029 They set up a confidentiality agreement with 00:04:44.029 --> 00:04:48.110 Sankyo in 1976, got samples of Compactin, access 00:04:48.110 --> 00:04:50.610 to Sankyo's data. A bit of collaboration mixed 00:04:50.610 --> 00:04:53.139 with competition then? You could say that. Merck 00:04:53.139 --> 00:04:55.259 confirmed Sankyo's results were apparently quite 00:04:55.259 --> 00:04:57.399 impressed, and then started their own hunt for 00:04:57.399 --> 00:04:59.660 similar compounds. And they found one. They did. 00:05:00.120 --> 00:05:03.920 In 1979, a team led by Alfred Albert Isolated 00:05:03.920 --> 00:05:07.019 Lovastatin, also called Mevinilin from a fungus 00:05:07.019 --> 00:05:09.660 Aspergillus terraeus. And the key thing was? 00:05:09.920 --> 00:05:12.560 It was structurally very similar to Compactin. 00:05:12.660 --> 00:05:14.600 Basically, they'd independently found another 00:05:14.600 --> 00:05:17.279 compound that worked in the same way, that really 00:05:17.279 --> 00:05:19.220 solidified the idea that this class of drugs 00:05:19.220 --> 00:05:21.819 had huge therapeutic potential. Okay, so we have 00:05:21.819 --> 00:05:24.480 compactin, then lovastatin, and then comes the 00:05:24.480 --> 00:05:27.800 star of our show today, atorvastatin. Right, 00:05:27.980 --> 00:05:30.420 atorvastatin was the next big step, launched 00:05:30.420 --> 00:05:34.300 by Pfizer in 1997. It built on everything learned 00:05:34.300 --> 00:05:36.279 from those earlier statins. Its chemical name 00:05:36.279 --> 00:05:41.420 is a mouthful, isn't it? Oh yeah, RRR2 -4 -fluorofenyl, 00:05:41.639 --> 00:05:46.360 dihydroxy -5 -1 -methylethyl, 3 -phenyl -4 -phenylamino, 00:05:46.860 --> 00:05:49.600 carbonyl -1 -H -pyrol -1 -heptanoic acid calcium 00:05:49.600 --> 00:05:52.069 salt. 2 .1, you don't need to remember that. 00:05:52.269 --> 00:05:54.389 Definitely not. But Pfizer didn't just discover 00:05:54.389 --> 00:05:56.129 the molecule, they also figured out how to make 00:05:56.129 --> 00:05:58.069 it efficiently, right? That was crucial. Large 00:05:58.069 --> 00:06:00.550 -scale manufacturing is key for any blockbuster 00:06:00.550 --> 00:06:03.170 drug. They developed an improved synthesis method. 00:06:03.209 --> 00:06:05.750 How much better was it? Significantly. The older 00:06:05.750 --> 00:06:09.470 methods had yields around, say, 52%. Pfizer's 00:06:09.470 --> 00:06:12.149 process bumped that up to about 67%. That kind 00:06:12.149 --> 00:06:13.790 of improvement makes a massive difference in 00:06:13.790 --> 00:06:16.069 terms of cost and being able to supply the drug 00:06:16.069 --> 00:06:18.819 globally. Makes total sense. Okay, we've got 00:06:18.819 --> 00:06:20.959 the history down. Now let's dig into the how. 00:06:21.459 --> 00:06:24.220 How does atorvastatin actually lower cholesterol 00:06:24.220 --> 00:06:26.860 in the body? Okay, so this is the mechanism of 00:06:26.860 --> 00:06:29.639 action. Atorvastatin is what we call a selective 00:06:29.639 --> 00:06:32.160 competitive inhibitor. Inhibitor of what? Of 00:06:32.160 --> 00:06:36.379 an enzyme called HMG -CoA reductase. Now this 00:06:36.379 --> 00:06:38.800 enzyme is really important because it controls 00:06:38.800 --> 00:06:41.480 a key step, the rate -limiting step, actually 00:06:41.480 --> 00:06:43.800 in the pathway your body uses to make its own 00:06:43.800 --> 00:06:47.339 cholesterol, primarily in the liver. So a Torvistan 00:06:47.339 --> 00:06:50.319 basically puts the brakes on the body's internal 00:06:50.319 --> 00:06:52.360 cholesterol production line. That's a great way 00:06:52.360 --> 00:06:54.879 to put it. It blocks that enzyme. Now, when the 00:06:54.879 --> 00:06:57.399 liver senses it's making less cholesterol internally, 00:06:57.660 --> 00:07:00.000 it does something clever. What's that? It increases 00:07:00.000 --> 00:07:03.360 the number of LDL receptors on its surface. LDL 00:07:03.360 --> 00:07:05.620 cholesterol is often called the bad cholesterol. 00:07:05.899 --> 00:07:08.839 Ah, so the liver gets better at grabbing the 00:07:08.839 --> 00:07:10.480 LDL cholesterol that's already floating around 00:07:10.480 --> 00:07:13.639 in the blood. Exactly. More receptors mean more 00:07:13.639 --> 00:07:15.800 LDL gets pulled out of circulation, taken up 00:07:15.800 --> 00:07:18.879 by the liver. And the net result is lower levels 00:07:18.879 --> 00:07:21.060 of LDL cholesterol in your plasma. That's the 00:07:21.060 --> 00:07:24.579 main goal. Clever mechanism. Very targeted. So 00:07:24.579 --> 00:07:27.740 who typically gets prescribed a torvastatin? 00:07:28.079 --> 00:07:29.980 What are the main reasons? It's approved for 00:07:29.980 --> 00:07:32.459 several things. First, Primary hyperlipidemia, 00:07:32.699 --> 00:07:34.500 that's just the general term for high cholesterol. 00:07:35.060 --> 00:07:37.759 Then there's familial hypercholesterolemia, both 00:07:37.759 --> 00:07:40.720 the homozygous and heterozygous types. These 00:07:40.720 --> 00:07:43.120 are the genetic forms where people have very 00:07:43.120 --> 00:07:45.660 high cholesterol from a young age. Atorvastatin 00:07:45.660 --> 00:07:48.860 is used in adults and kids down to age 10 for 00:07:48.860 --> 00:07:51.459 this. So common high cholesterol and specific 00:07:51.459 --> 00:07:54.500 genetic types. Right. And then, critically, it's 00:07:54.500 --> 00:07:57.100 used as an addition to diet changes to reduce 00:07:57.100 --> 00:07:59.980 the risk of cardiovascular events, heart attacks, 00:08:00.199 --> 00:08:02.160 strokes. In which groups of people? Several key 00:08:02.160 --> 00:08:04.730 groups. Adults who don't have heart disease yet 00:08:04.730 --> 00:08:06.990 but have multiple risk factors like high blood 00:08:06.990 --> 00:08:09.730 pressure, smoking, family history. Also people 00:08:09.730 --> 00:08:12.310 with type 2 diabetes who have risk factors and 00:08:12.310 --> 00:08:15.310 very importantly people who already have established 00:08:15.310 --> 00:08:17.569 coronary heart disease. And do medical guidelines 00:08:17.569 --> 00:08:19.810 offer specific advice on using it like from the 00:08:19.810 --> 00:08:23.079 cardiology groups? They do. The 218 American 00:08:23.079 --> 00:08:25.259 College of Cardiology guidelines, for example, 00:08:25.459 --> 00:08:28.079 have strong recommendations. For adults aged 00:08:28.079 --> 00:08:32.299 20 to 75 with really high LDL, 190 mil GDL or 00:08:32.299 --> 00:08:35.320 more, they recommend using the maximally tolerated 00:08:35.320 --> 00:08:37.840 dose of a statin. The highest dose someone can 00:08:37.840 --> 00:08:40.460 handle without significant side effects. Exactly. 00:08:40.980 --> 00:08:43.799 Because that LDL level signifies a very high 00:08:43.799 --> 00:08:46.240 risk. What if the statin alone isn't enough for 00:08:46.240 --> 00:08:49.220 those high risk people? Good question. The guidelines 00:08:49.220 --> 00:08:51.559 suggest that if you don't get at least a 50 % 00:08:51.559 --> 00:08:54.720 drop in LDL on the max statin dose, or if your 00:08:54.720 --> 00:08:57.600 LDL stays above 100mgdL, then adding another 00:08:57.600 --> 00:09:00.480 drug, azetimi, should be considered. It's often 00:09:00.480 --> 00:09:02.879 about combination therapy for the toughest cases. 00:09:03.179 --> 00:09:05.120 You mentioned different forms earlier. There's 00:09:05.120 --> 00:09:07.720 an oral suspension. Adder Valley Q. Yes, Adder 00:09:07.720 --> 00:09:09.860 Valley. It's a liquid form. And the interesting 00:09:09.860 --> 00:09:11.740 thing with that one is the specific instruction 00:09:11.740 --> 00:09:13.860 to take it on an empty stomach. Why is that? 00:09:14.120 --> 00:09:16.620 Because food, especially meals high in fat, can 00:09:16.620 --> 00:09:18.860 really decrease how much of the drug gets absorbed 00:09:18.860 --> 00:09:20.860 from the suspension form. So they recommend taking 00:09:20.860 --> 00:09:23.059 it either an hour before you eat or two hours 00:09:23.059 --> 00:09:25.379 after. That's a practical detail patients need 00:09:25.379 --> 00:09:29.000 to know. OK, let's get a bit more technical pharmacokinetics 00:09:29.000 --> 00:09:31.879 and pharmacodynamics. How the body handles the 00:09:31.879 --> 00:09:34.659 drug. What's the usual dose range? Typically, 00:09:34.679 --> 00:09:37.879 it's taken once daily. anywhere from 10 milligrams 00:09:37.879 --> 00:09:40.639 up to 80 milligrams, but the general advice is 00:09:40.639 --> 00:09:42.899 always to use the lowest effective dose. And 00:09:42.899 --> 00:09:45.259 you need more caution with higher doses. Yes, 00:09:45.580 --> 00:09:48.240 doses above 20 milligrams generally warrant a 00:09:48.240 --> 00:09:50.820 bit more care and monitoring. Now, several things 00:09:50.820 --> 00:09:53.620 can affect how your body processes a torvastatin. 00:09:53.960 --> 00:09:56.679 Like what? Kidney function. Kidney function is 00:09:56.679 --> 00:09:59.399 interesting. Having impaired kidneys is a risk 00:09:59.399 --> 00:10:02.940 factor for muscle side effects, myopathy. But, 00:10:03.059 --> 00:10:04.980 surprisingly, it doesn't really change the levels 00:10:04.980 --> 00:10:08.039 of atorvastatin in the blood much. So usually 00:10:08.039 --> 00:10:10.460 no dose adjustment is needed just for kidney 00:10:10.460 --> 00:10:13.200 function, but you definitely need closer monitoring 00:10:13.200 --> 00:10:15.720 for muscle symptoms. Okay. What about the liver? 00:10:16.080 --> 00:10:18.419 since that's where it primarily works. Ah, the 00:10:18.419 --> 00:10:20.399 liver is a different story. Liver impairment 00:10:20.399 --> 00:10:22.860 can dramatically increase adervis fat in levels. 00:10:22.879 --> 00:10:25.080 How dramatic. In people with chronic alcoholic 00:10:25.080 --> 00:10:27.779 liver disease, for instance, levels can be four 00:10:27.779 --> 00:10:30.559 times higher with mild disease and potentially 00:10:30.559 --> 00:10:33.340 11 to even 16 times higher with more severe, 00:10:33.639 --> 00:10:36.519 like child's pubic cirrhosis. Wow, that's huge. 00:10:36.600 --> 00:10:39.340 It is, which is why atorvastatin is actually 00:10:39.340 --> 00:10:41.960 contraindicated, meaning you absolutely shouldn't 00:10:41.960 --> 00:10:44.600 use it in patients with active, severe liver 00:10:44.600 --> 00:10:47.269 failure or decompensation. serosis, and you have 00:10:47.269 --> 00:10:49.850 to use it very cautiously in anyone who drinks 00:10:49.850 --> 00:10:52.309 a lot of alcohol or has a history of liver disease. 00:10:52.450 --> 00:10:54.549 Critical safety point. Any other patient factors? 00:10:55.210 --> 00:10:59.450 Age, gender. Yep. Older people tend to have somewhat 00:10:59.450 --> 00:11:02.350 higher plasma concentrations. There are also 00:11:02.350 --> 00:11:04.190 slight differences between men and women. Women 00:11:04.190 --> 00:11:06.629 might have slightly higher peak levels and overall 00:11:06.629 --> 00:11:08.909 exposure, but it generally doesn't seem to make 00:11:08.909 --> 00:11:10.789 a clinically meaningful difference in how much 00:11:10.789 --> 00:11:13.769 their LDL cholesterol is lowered. And food. Right. 00:11:13.769 --> 00:11:15.779 You mentioned it for H or Vella Q. Right. For 00:11:15.779 --> 00:11:18.039 the suspension, high -fat meals significantly 00:11:18.039 --> 00:11:20.759 cut down absorption. For the tablets, food can 00:11:20.759 --> 00:11:23.000 decrease the rate of absorption slightly, but 00:11:23.000 --> 00:11:24.980 maybe not the overall extent as much. Still, 00:11:25.159 --> 00:11:26.940 that empty stomach rule for atrial velocue is 00:11:26.940 --> 00:11:30.039 important. Got it. How does the body actually 00:11:30.039 --> 00:11:33.279 break down a torvastatin? It's extensively metabolized, 00:11:33.299 --> 00:11:35.600 mostly in the liver, by a specific enzyme system 00:11:35.600 --> 00:11:40.419 called cytochrome P4503A4, or CYT3A4 for short. 00:11:40.860 --> 00:11:43.220 And that metabolism process is important. Very. 00:11:43.279 --> 00:11:46.100 It actually creates active metabolites by -products 00:11:46.100 --> 00:11:47.980 that also have cholesterol -lowering activity. 00:11:48.360 --> 00:11:50.139 In fact, these metabolites are thought to account 00:11:50.139 --> 00:11:53.139 for about 70 % of the drug's total inhibitory 00:11:53.139 --> 00:11:56.299 effect on that HMG -CoA reductase enzyme. And 00:11:56.299 --> 00:11:58.840 whenever you hear about enzymes like CYP3A4, 00:11:58.940 --> 00:12:01.080 you immediately think about it. Drug interactions. 00:12:01.440 --> 00:12:03.779 Exactly. Because so many other drugs are also 00:12:03.779 --> 00:12:07.679 metabolized by, or affect, CYP3A4. So what are 00:12:07.679 --> 00:12:10.080 the key interactions to watch out for with Atorvastatin? 00:12:10.360 --> 00:12:13.179 Well, drugs that strongly inhibit CYP3A4 can 00:12:13.179 --> 00:12:15.779 significantly increase adorvastatin levels, raising 00:12:15.779 --> 00:12:18.299 the risk of muscle problems, myopathy, or even 00:12:18.299 --> 00:12:20.620 rhabdomyolysis. Like which drugs? Things like 00:12:20.620 --> 00:12:23.500 the antibiotic clarithromycin, certain anti -fungal 00:12:23.500 --> 00:12:27.240 drugs like juconazole, some HIV protease inhibitors. 00:12:27.740 --> 00:12:30.279 Using these with adorvastatin requires caution, 00:12:30.519 --> 00:12:32.919 maybe lower doses, or sometimes avoiding the 00:12:32.919 --> 00:12:36.279 combination altogether. Also, drugs like sequosporine 00:12:36.279 --> 00:12:38.320 or gemfibrozole increase the risk through other 00:12:38.320 --> 00:12:40.549 mechanisms, too, and combining them with atorvastatin 00:12:40.549 --> 00:12:43.250 is generally not recommended. What about drugs 00:12:43.250 --> 00:12:47.789 that induce CYP3A4 make it work faster? Right. 00:12:47.909 --> 00:12:49.970 Inducers can do the opposite. They can decrease 00:12:49.970 --> 00:12:52.190 atorvastatin levels, potentially making it less 00:12:52.190 --> 00:12:55.230 effective. Refampin, an antibiotic used for TB, 00:12:55.330 --> 00:12:57.570 is a key example. The interaction is complex, 00:12:57.590 --> 00:12:59.750 so sometimes taking them at the exact same time 00:12:59.750 --> 00:13:02.279 is recommended to manage it. OK. Any others, 00:13:02.779 --> 00:13:05.220 specific antivirals? Yes. With certain hepatitis 00:13:05.220 --> 00:13:07.940 C drugs, like Albus -Fergratza -Previer, the 00:13:07.940 --> 00:13:10.139 adervostatin dose needs to be limited, usually 00:13:10.139 --> 00:13:12.899 to no more than 20 milligrams daily. And even 00:13:12.899 --> 00:13:15.500 common things, food interactions. Grapefruit 00:13:15.500 --> 00:13:19.820 juice. It's a classic CYP3A4 inhibitor, primarily 00:13:19.820 --> 00:13:22.490 in the gut wall. Drinking large amounts can increase 00:13:22.490 --> 00:13:25.210 atervistatin levels. And even some over -the 00:13:25.210 --> 00:13:28.129 -counter things like antacids, specifically those 00:13:28.129 --> 00:13:30.570 containing magnesium and aluminum hydroxides 00:13:30.570 --> 00:13:34.269 like Malox TC, can slightly decrease atervistatin 00:13:34.269 --> 00:13:37.169 absorption. It's a minefield. Really shows why 00:13:37.169 --> 00:13:39.110 telling your doctor and pharmacist everything 00:13:39.110 --> 00:13:41.590 you take, including supplements and juices, is 00:13:41.590 --> 00:13:44.370 so important. Absolutely crucial. Okay, let's 00:13:44.370 --> 00:13:48.230 shift focus to making the drug. Manufacturing. 00:13:48.490 --> 00:13:50.169 You mentioned Pfizer improved the synthesis. 00:13:50.409 --> 00:13:53.509 Is it a simple process? Oh, far from it. The 00:13:53.509 --> 00:13:55.570 chemical synthesis of atorvastatin calcium is 00:13:55.570 --> 00:13:58.169 actually quite complex. Over the years, many 00:13:58.169 --> 00:13:59.750 different synthetic routes have been published, 00:13:59.870 --> 00:14:02.110 reflecting ongoing efforts to make it more efficient 00:14:02.110 --> 00:14:04.450 and cost effective. Given how much of it is used 00:14:04.450 --> 00:14:07.470 worldwide, efficiency must be paramount. Exactly. 00:14:07.789 --> 00:14:09.950 And the field is still evolving. There's research 00:14:09.950 --> 00:14:12.730 into using continuous manufacturing processes. 00:14:12.789 --> 00:14:14.850 What's that? Instead of making the drug in separate 00:14:14.850 --> 00:14:17.610 batches, it's a more modern approach, where the 00:14:17.610 --> 00:14:20.149 different chemical steps flow continuously one 00:14:20.149 --> 00:14:22.990 after the other. It can potentially improve efficiency, 00:14:23.470 --> 00:14:25.789 quality control, and maybe even reduce costs 00:14:25.789 --> 00:14:28.429 further down the line. Sounds like a smart direction 00:14:28.429 --> 00:14:30.950 for high -volume drugs. And quality control must 00:14:30.950 --> 00:14:33.909 be incredibly strict throughout. Absolutely non 00:14:33.909 --> 00:14:36.350 -negotiable. Pharmaceutical manufacturing is 00:14:36.350 --> 00:14:39.570 tightly regulated. process validation, quality 00:14:39.570 --> 00:14:42.490 checks on raw materials, in -process monitoring, 00:14:42.830 --> 00:14:45.330 testing the final product. Everything has to 00:14:45.330 --> 00:14:47.769 meet stringent standards set by agencies like 00:14:47.769 --> 00:14:51.370 the FDA to ensure safety, purity, and effectiveness 00:14:51.370 --> 00:14:54.629 in every single pill or dose. Right. Which leads 00:14:54.629 --> 00:14:57.629 us neatly into the regulatory side. Getting a 00:14:57.629 --> 00:15:00.230 drug like Lipitor approved and navigating the 00:15:00.230 --> 00:15:02.470 world of generics. What's the basic process? 00:15:02.649 --> 00:15:04.629 For a new brand -name drug, like Lipitor was, 00:15:04.789 --> 00:15:06.990 the company submits a new drug application, an 00:15:06.990 --> 00:15:09.889 NDA, to the FDA. It's a massive dossier with 00:15:09.889 --> 00:15:12.029 all the preclinical and clinical trial data showing 00:15:12.029 --> 00:15:14.690 it's safe and effective. And for generics? They 00:15:14.690 --> 00:15:17.669 file an abbreviated new drug application, or 00:15:17.669 --> 00:15:20.250 NNDA. They typically don't need to repeat all 00:15:20.250 --> 00:15:22.490 the big clinical trials. They primarily need 00:15:22.490 --> 00:15:25.289 to show their version is bioequivalent, meaning 00:15:25.289 --> 00:15:28.129 it gets absorbed into the body, similarly to 00:15:28.129 --> 00:15:31.039 the brand -name drug. But a key part of the NDA 00:15:31.039 --> 00:15:33.340 is dealing with patents. Ah yes, the patents. 00:15:33.950 --> 00:15:36.070 That's where things often get complicated and 00:15:36.070 --> 00:15:38.970 litigious. Very often. A generic company wanting 00:15:38.970 --> 00:15:42.009 to launch before the brand patents expire usually 00:15:42.009 --> 00:15:44.629 files what's called a Paragraph V certification 00:15:44.629 --> 00:15:47.450 with their NDA. What does that mean? It's basically 00:15:47.450 --> 00:15:50.049 the generic company saying they believe the patent 00:15:50.049 --> 00:15:52.789 on the brand drug is either invalid or that their 00:15:52.789 --> 00:15:55.470 generic version won't infringe it. This almost 00:15:55.470 --> 00:15:57.669 always triggers a lawsuit from the brand company. 00:15:57.809 --> 00:16:00.190 And the Torvastatin definitely had its share 00:16:00.190 --> 00:16:04.350 of patent battle. Oh, big time. later acquired 00:16:04.350 --> 00:16:07.029 initially had the main patent on the atorvastatin 00:16:07.029 --> 00:16:10.009 molecule itself, the 893 patent, but the real 00:16:10.009 --> 00:16:11.809 fireworks started with a later patent. Which 00:16:11.809 --> 00:16:14.169 one was that? The 995 patent. This one covered 00:16:14.169 --> 00:16:17.629 a specific crystalline form of atorvastatin calcium 00:16:17.629 --> 00:16:20.570 and it became hugely controversial. Why? What 00:16:20.570 --> 00:16:22.809 was the issue? There were allegations, which 00:16:22.809 --> 00:16:25.190 became central to legal challenges, about the 00:16:25.190 --> 00:16:27.990 biological activity data submitted to get that 00:16:27.990 --> 00:16:30.850 patent. The claim submitted suggested the pure 00:16:30.850 --> 00:16:33.149 active form was ten times more active than a 00:16:33.149 --> 00:16:35.690 mixture of forms, but later analysis indicated 00:16:35.690 --> 00:16:38.070 the difference was much smaller, maybe closer 00:16:38.070 --> 00:16:40.220 to two -fold. That's a pretty big difference 00:16:40.220 --> 00:16:42.059 in reported activity. How did that play out? 00:16:42.220 --> 00:16:44.919 It became a major point of contention in lawsuits 00:16:44.919 --> 00:16:48.720 challenging the 995 patents validity. Eventually, 00:16:49.039 --> 00:16:51.360 Pfizer itself, during a reexamination of the 00:16:51.360 --> 00:16:54.259 patent, actually had to disavow the reliability 00:16:54.259 --> 00:16:57.299 of that specific piece of biological data to 00:16:57.299 --> 00:17:00.120 the U .S. Patent Office. Wow. So that must have 00:17:00.120 --> 00:17:02.820 weakened their position on that patent. It certainly 00:17:02.820 --> 00:17:05.539 complicated things, but Pfizer didn't stop there. 00:17:05.710 --> 00:17:09.150 As the original 893 patent expiry loomed, they 00:17:09.150 --> 00:17:11.710 also tried using process patents. Patents on 00:17:11.710 --> 00:17:14.309 how the drug was made. Exactly. Patents like 00:17:14.309 --> 00:17:17.170 the 740 and 511 covered specific methods for 00:17:17.170 --> 00:17:19.509 converting crystalline and orvastatin back into 00:17:19.509 --> 00:17:22.349 an amorphous non -crystalline form. They tried 00:17:22.349 --> 00:17:24.589 to argue in court that generic companies, like 00:17:24.589 --> 00:17:27.430 Ranbaxy, would inevitably infringe these process 00:17:27.430 --> 00:17:29.170 patents when making their versions. Did that 00:17:29.170 --> 00:17:32.589 work? Ultimately, no. The courts ruled against 00:17:32.589 --> 00:17:35.130 Pfizer on those process patent claims in the 00:17:35.130 --> 00:17:37.930 Rambaxi litigation. They didn't provide the extended 00:17:37.930 --> 00:17:40.390 market lockup Pfizer was seeking. Speaking of 00:17:40.390 --> 00:17:43.509 Rambaxi, that legal fight was a really big deal 00:17:43.509 --> 00:17:45.730 for generic atorvastatin, wasn't it? It was pivotal. 00:17:45.869 --> 00:17:48.910 Rambaxi was one of the first, if not the first, 00:17:49.150 --> 00:17:52.349 generic company to file an NDA with that paragraph 00:17:52.349 --> 00:17:54.730 three challenge against Pfizer's patents. And 00:17:54.730 --> 00:17:57.250 being first to file matters. Yes. It usually 00:17:57.250 --> 00:18:01.190 grants the generic company a valuable 180 day 00:18:01.190 --> 00:18:04.490 period of market exclusivity for their generic 00:18:04.490 --> 00:18:07.230 version once it's approved. So the stakes were 00:18:07.230 --> 00:18:09.769 incredibly high. There was intense litigation. 00:18:09.930 --> 00:18:12.569 But it ended in a settlement, right? Which delayed 00:18:12.569 --> 00:18:14.910 the generic? That's correct. Pfizer and Rambaxi 00:18:14.910 --> 00:18:17.289 reached settlement agreement. The outcome was 00:18:17.289 --> 00:18:19.609 that Ranbaxy agreed not to launch its generic 00:18:19.609 --> 00:18:22.150 atorvastatin in the U .S. until November 30, 00:18:22.329 --> 00:18:24.910 2011. Without that deal, you can bet Ranbaxy 00:18:24.910 --> 00:18:26.910 would have pushed to get to market much, much 00:18:26.910 --> 00:18:29.710 sooner. It bought Pfizer significant extra time 00:18:29.710 --> 00:18:32.230 for Lipitor's blockbuster sales. There was also 00:18:32.230 --> 00:18:34.450 that slightly unusual citizen petition Pfizer 00:18:34.450 --> 00:18:37.349 filed, right? Yeah. About the form of atorvastatin. 00:18:37.769 --> 00:18:40.539 Yes, that was another tactic. Pfizer filed a 00:18:40.539 --> 00:18:42.839 petition with the FDA raising concerns because 00:18:42.839 --> 00:18:46.220 Ranbaxy's proposed generic used an amorphous 00:18:46.220 --> 00:18:49.660 form of atorvastatin, whereas Lipidor used a 00:18:49.660 --> 00:18:52.099 crystalline form. What was their argument? They 00:18:52.099 --> 00:18:54.259 were essentially questioning if the amorphous 00:18:54.259 --> 00:18:56.920 form would be as stable or behave the same way. 00:18:57.299 --> 00:19:00.000 However, the FDA denied Pfizer's petition. On 00:19:00.000 --> 00:19:03.019 what grounds? The FDA basically reiterated its 00:19:03.019 --> 00:19:06.759 standard position. A generic drug substance doesn't 00:19:06.759 --> 00:19:09.140 have to be the exact same physical form, like 00:19:09.140 --> 00:19:11.460 crystalline versus amorphous, as the brand name, 00:19:11.680 --> 00:19:14.380 as long as the generic company proves bioequivalence 00:19:14.380 --> 00:19:17.079 and stability. So that route didn't block ran 00:19:17.079 --> 00:19:19.960 backs either. So despite a complex and hard fought 00:19:19.960 --> 00:19:23.180 battle, generic Itorvastatin did eventually arrive. 00:19:23.759 --> 00:19:25.759 Okay, let's switch back to the patient experience. 00:19:26.319 --> 00:19:28.619 Safety and tolerability. What are the most common 00:19:28.619 --> 00:19:31.950 things people report? Muscle pain or myalgia 00:19:31.950 --> 00:19:33.990 is definitely the most common side effect people 00:19:33.990 --> 00:19:36.329 associate with statins, including a torvastatin. 00:19:36.789 --> 00:19:39.509 For many it's mild, but for some it can be quite 00:19:39.509 --> 00:19:41.650 bothersome and lead them to stop the medication. 00:19:41.930 --> 00:19:44.750 But there are more serious muscle issues too, 00:19:45.089 --> 00:19:48.430 though rare. Yes. Myopathy, which is more significant 00:19:48.430 --> 00:19:51.369 muscle pain or weakness, often with elevated 00:19:51.369 --> 00:19:54.230 muscle enzyme levels, and the most severe form, 00:19:54.609 --> 00:19:57.009 rhabdomyolysis. That's the one that can affect 00:19:57.009 --> 00:19:59.809 the kidneys. Correct. It involves extensive muscle 00:19:59.809 --> 00:20:01.990 breakdown, releasing substances that can damage 00:20:01.990 --> 00:20:05.430 the kidneys. It's rare, but serious. The risk 00:20:05.430 --> 00:20:07.930 is higher in people with kidney problems already, 00:20:07.930 --> 00:20:11.130 or when atorvastatin is taken with certain interacting 00:20:11.130 --> 00:20:13.210 drugs we discussed earlier. What about other 00:20:13.210 --> 00:20:16.579 organs? The liver. Liver enzyme elevations can 00:20:16.579 --> 00:20:20.160 occur. You might see rises in AST and ALT on 00:20:20.160 --> 00:20:22.900 blood tests. These are relatively common, often 00:20:22.900 --> 00:20:25.440 temporary, and frequently don't signify actual 00:20:25.440 --> 00:20:28.119 liver damage. But routine monitoring used to 00:20:28.119 --> 00:20:30.359 be standard practice, though guidelines have 00:20:30.359 --> 00:20:33.259 evolved. Serious liver failure is extremely rare, 00:20:33.259 --> 00:20:35.019 but has been reported. And there's been talk 00:20:35.019 --> 00:20:37.500 about statins and diabetes risk. Yes, that's 00:20:37.500 --> 00:20:39.799 another area of focus. Studies have shown a slightly 00:20:39.799 --> 00:20:42.099 increased risk of developing new onset type 2 00:20:42.099 --> 00:20:44.869 diabetes, particularly with higher statin doses. 00:20:45.130 --> 00:20:47.410 How do doctors weigh that risk against the benefits? 00:20:47.769 --> 00:20:50.569 It's a risk benefit calculation. For most people 00:20:50.569 --> 00:20:52.970 prescribed statins, especially those at high 00:20:52.970 --> 00:20:55.890 cardiovascular risk, the proven benefits in preventing 00:20:55.890 --> 00:20:58.130 heart attacks and strokes are generally considered 00:20:58.130 --> 00:21:01.170 to far outweigh the small increased risk of diabetes. 00:21:01.910 --> 00:21:03.950 But it's something to be aware of and monitor 00:21:03.950 --> 00:21:06.450 for. Any groups who absolutely shouldn't take 00:21:06.450 --> 00:21:09.880 it. Pregnant women. Atorvastatin is contraindicated 00:21:09.880 --> 00:21:12.720 in pregnancy. Cholesterol is essential for fetal 00:21:12.720 --> 00:21:14.880 development, so blocking its synthesis could 00:21:14.880 --> 00:21:17.480 potentially harm the fetus. It should be stopped 00:21:17.480 --> 00:21:20.920 if pregnancy occurs. Breastfeeding is also generally 00:21:20.920 --> 00:21:23.440 not advised, as the drug might pass into breast 00:21:23.440 --> 00:21:26.990 milk. any other side effects people might encounter, 00:21:27.309 --> 00:21:29.890 things seen in trials. Clinical trials have reported 00:21:29.890 --> 00:21:32.650 various other things, fatigue or malaise, digestive 00:21:32.650 --> 00:21:36.329 upset like nausea or diarrhea, joint pain, arthralgia, 00:21:36.849 --> 00:21:40.009 sometimes headache. Less common things like insomnia, 00:21:40.349 --> 00:21:43.089 dizziness, skin reactions can occur too. So it 00:21:43.089 --> 00:21:45.569 comes back to good communication between doctor 00:21:45.569 --> 00:21:47.750 and patient. Absolutely. Counseling patients 00:21:47.750 --> 00:21:50.470 on what to watch for, especially muscle symptoms, 00:21:50.750 --> 00:21:52.809 explaining the liver monitoring, the pregnancy 00:21:52.809 --> 00:21:55.369 issue, it's all vital. Let's zoom out again. 00:21:55.890 --> 00:21:58.950 The economic side. Lepidur was famously the best 00:21:58.950 --> 00:22:01.049 -selling drug in the world for a long time. The 00:22:01.049 --> 00:22:03.230 market impact must have been huge. Absolutely 00:22:03.230 --> 00:22:06.309 massive. The overall global market for statins 00:22:06.309 --> 00:22:08.730 and cholesterol -lowering drugs in general is 00:22:08.730 --> 00:22:11.380 enormous. And that's driven by the sheer prevalence 00:22:11.380 --> 00:22:14.680 of cardiovascular disease worldwide. The demand 00:22:14.680 --> 00:22:17.480 is consistently high. And generics change that 00:22:17.480 --> 00:22:19.880 market profoundly. Completely. The arrival of 00:22:19.880 --> 00:22:22.460 generic atorvastatin dramatically lowered costs 00:22:22.460 --> 00:22:26.200 and massively increased patient access. It also 00:22:26.200 --> 00:22:28.480 put a spotlight on the importance of manufacturing 00:22:28.480 --> 00:22:31.980 the core ingredient, the atorvastatin API, or 00:22:31.980 --> 00:22:34.319 active pharmaceutical ingredient. API production 00:22:34.319 --> 00:22:36.740 becomes a big business in itself. It does. And 00:22:36.740 --> 00:22:38.920 you see strategic partnerships forming between 00:22:38.920 --> 00:22:40.720 the drug companies selling the finished pills 00:22:40.720 --> 00:22:43.079 and the specialized manufacturers making the 00:22:43.079 --> 00:22:46.039 API, all aimed at securing the supply chain and 00:22:46.039 --> 00:22:49.039 keeping costs manageable. So economically, generics 00:22:49.039 --> 00:22:50.980 have been a huge win for health care systems 00:22:50.980 --> 00:22:53.779 and patients. What about the cultural side? Lipitor 00:22:53.779 --> 00:22:57.079 became a household name. It really did. Statins 00:22:57.079 --> 00:22:59.960 in general, and Lipitor, perhaps most prominently, 00:23:00.400 --> 00:23:02.460 definitely raised public awareness about cholesterol, 00:23:02.779 --> 00:23:05.779 risk factors, and heart disease prevention. But 00:23:05.779 --> 00:23:07.900 it also attracted scrutiny. You're thinking of 00:23:07.900 --> 00:23:10.819 marketing campaigns. Particularly the big Lipitor 00:23:10.819 --> 00:23:13.799 campaign, featuring Dr. Robert Jarvik, the inventor 00:23:13.799 --> 00:23:16.640 of the artificial heart. The tagline was, for 00:23:16.640 --> 00:23:19.380 me, there is no substitute. Right. I remember 00:23:19.380 --> 00:23:21.779 that one. It caused quite a stir, didn't it? 00:23:21.960 --> 00:23:24.650 It did. Questions were raised about whether Dr. 00:23:24.890 --> 00:23:27.289 Jarvik was actually a cardiologist or even took 00:23:27.289 --> 00:23:30.490 Lipitor himself regularly. The authenticity of 00:23:30.490 --> 00:23:33.069 some aspects, like him appearing to row crew 00:23:33.069 --> 00:23:35.089 when he didn't, was questioned. What was the 00:23:35.089 --> 00:23:38.099 concern? It was misleading. The concern, which 00:23:38.099 --> 00:23:40.519 led to things like a congressional inquiry into 00:23:40.519 --> 00:23:42.900 Pfizer's marketing, was that the campaign might 00:23:42.900 --> 00:23:45.920 imply that brand name Libitor was uniquely necessary 00:23:45.920 --> 00:23:48.460 or superior to potentially equivalent and much 00:23:48.460 --> 00:23:51.000 cheaper generics even after they became available. 00:23:51.180 --> 00:23:53.380 So it fueled the debate about direct -to -consumer 00:23:53.380 --> 00:23:56.410 drug advertising. Exactly. And the broader discussion 00:23:56.410 --> 00:23:59.089 about brand loyalty versus cost -effectiveness, 00:23:59.390 --> 00:24:01.690 especially for preventative medications, the 00:24:01.690 --> 00:24:04.210 only -lipitor -is -lipitor message was clearly 00:24:04.210 --> 00:24:07.349 designed to combat the shift to generics. Fascinating. 00:24:07.829 --> 00:24:10.730 So a drug with this incredible scientific backstory, 00:24:11.549 --> 00:24:14.990 complex mechanism, major legal dramas, and a 00:24:14.990 --> 00:24:17.769 huge societal footprint. It really touches on 00:24:17.769 --> 00:24:20.809 so many aspects of medicine in society. OK, well, 00:24:20.890 --> 00:24:22.549 we've covered a lot of ground in this deep dive 00:24:22.549 --> 00:24:25.089 on atorvastatin. Let's try to quickly recap the 00:24:25.089 --> 00:24:27.309 big points. We started with a long history of 00:24:27.309 --> 00:24:29.369 cholesterol science, leading to the first statins, 00:24:29.750 --> 00:24:32.269 compactin and lovastatin. Then visors development 00:24:32.269 --> 00:24:34.710 of atorvastatin, including improving how it was 00:24:34.710 --> 00:24:37.220 made. We talked about how it works inhibiting 00:24:37.220 --> 00:24:40.839 HMG CoA reductase to lower LDL. Right. We covered 00:24:40.839 --> 00:24:43.279 who it's for, high cholesterol, genetic conditions, 00:24:43.480 --> 00:24:45.440 risk reduction, and what the guidelines say. 00:24:45.819 --> 00:24:48.299 We looked at how the body handles it, pharmacokinetics, 00:24:48.539 --> 00:24:51.039 those crucial liver considerations, and the many 00:24:51.039 --> 00:24:53.859 potential drug interactions. Plus the manufacturing 00:24:53.859 --> 00:24:56.500 intricacies, the whole regulatory maze with NDAs, 00:24:56.660 --> 00:24:59.299 NDAs, and those intense patent fights, especially 00:24:59.299 --> 00:25:02.319 with Ranbaxy. Then, safety muscle pain being 00:25:02.319 --> 00:25:05.740 common, the rare but serious rhabdo, liver effects, 00:25:05.900 --> 00:25:08.640 the diabetes link, and why it's a no -go in pregnancy. 00:25:08.900 --> 00:25:11.380 And finally, its enormous economic impact, first 00:25:11.380 --> 00:25:14.039 as a blockbuster, then with generics and its 00:25:14.039 --> 00:25:16.460 cultural influence, including that memorable 00:25:16.460 --> 00:25:19.299 Jarvik ad campaign and the debates it sparked. 00:25:19.480 --> 00:25:21.180 And for you listening, it just highlights this 00:25:21.180 --> 00:25:23.640 whole complex journey a medication takes, right? 00:25:23.640 --> 00:25:26.559 From a lab idea to something millions rely on, 00:25:26.920 --> 00:25:29.660 constantly shaped by science, regulation, economics, 00:25:29.640 --> 00:25:32.420 and even marketing. Definitely. So here's something 00:25:32.420 --> 00:25:34.539 to leave you thinking about. We have this incredibly 00:25:34.539 --> 00:25:37.859 effective drug, atorvastatin, now widely available 00:25:37.859 --> 00:25:40.779 as a low -cost generic. How do we strike the 00:25:40.779 --> 00:25:43.460 right balance? How do we ensure everyone who 00:25:43.460 --> 00:25:46.019 needs it can access it affordably while still 00:25:46.019 --> 00:25:48.099 making sure pharmaceutical companies have the 00:25:48.099 --> 00:25:50.700 incentive to innovate and develop the next generation 00:25:50.700 --> 00:25:53.039 of life -saving drugs? And layered on top of 00:25:53.039 --> 00:25:55.440 that, what's the role of clear, honest, ethical 00:25:55.440 --> 00:25:57.859 communication from doctors, from companies, from 00:25:57.859 --> 00:26:00.579 regulators in making sure we all trust the medications 00:26:00.579 --> 00:26:03.420 we rely on? It's a big question. touching on 00:26:03.420 --> 00:26:06.299 personal health, public policy, and the future 00:26:06.299 --> 00:26:09.220 of medicine. Something to ponder. Thanks for 00:26:09.220 --> 00:26:10.400 joining us for this deep dive.