Responding to change with the same - flu "magic drug" oseltamivir

Influenza, the full name of influenza
.
It is an acute respiratory disease caused by influenza A, B and
C.
Influenza virus is an RNA virus, named HxNy according to its surface antigen (where x=1~15, y=1~9), where H stands for Hemagglutinin and N stands for Neuraminidase (Hemagglutinin)
.
Oseltamivir is a specific inhibitor of neuraminidase, which inhibits the separation of mature influenza virus from host cells, thereby inhibiting the spread of influenza virus in the human body to play a role in the treatment of influenza
.
Oseltamivir is a successful case of structure-based rational drug design
.
In the research and development process of oseltamivir, computer-aided drug design methods were widely used, and neuraminidase inhibitors with high efficiency, low toxicity and strong specificity were designed according to the three-dimensional structure of the target enzyme
.
On the basis of zanamivir, oseltamivir is obtained by rational drug design according to the molecular structure of the natural substrate of neuraminidase and the spatial structure of the catalytic center of neuraminidase
.
Oseltamivir was first synthesized in 1996 and obtained a US patent on February 26, 1998.
It was first launched in Sweden in October 1999, and subsequently entered the Canadian, EU and US markets, and was approved for launch in China in 2002
.
As an RNA virus, influenza virus is prone to mutation, but in order to perform its specific function, there must be some fragments that are less prone to mutation, that is, highly conserved sequences
.
The action site of oseltamivir is a highly conserved amino acid sequence in neuraminidase.
As an analog of sialic acid, the substrate of neuraminidase, it binds to it and prevents it from hydrolyzing mature viruses and host cells.
Inter-thrombin-sialic acid linkage, thereby preventing viral replication
.
In order to obtain an effective inhibitor of neuraminidase, the ionic configuration of the intermediate sialic acid transition state was simulated at the initial stage of design, but the constructed compound had the ability to inhibit neuraminidase activity in vitro but was inactive in animal models and had no choice for influenza virus.
This is because the intervention of some groups makes absorption difficult, and not only influenza virus, but other viruses, bacteria and even human liver microsomes contain neuraminidase, so further optimization is required
.
The researchers converted the transition state intermediate into a class of carbocyclic compounds through the principle of isosteric, which is easy to modify the structure and reduce the electron cloud density on the carbocyclic double bond.
Secondly, the hydroxyl group on the 4th position was replaced with an amino group to enhance the coordination.
The affinity of the body with neuraminidase
.
In order to further optimize and facilitate the design of oral drugs, the side chain of glycerol was replaced with 2-ethylpropyl which can undergo extensive hydrophobic interaction, which further enhanced the inhibitory activity of the drug
.
Finally, the method of esterification of the original drug was adopted to esterify the carboxyl group at position 2 to facilitate oral absorption, and the well-known oseltamivir was obtained
.
Oseltamivir phosphate is the first orally effective inhibitor of influenza virus neuraminidase, which is mainly used clinically to relieve the symptoms of influenza
.
At present, oseltamivir is mainly synthesized from shikimic acid and quinic acid as raw materials
.
Quinic acid is extracted from the bark of Cinchona tree.
Cinchona tree is suitable for growing in a warm, frost-free climate environment all year round.
The annual average temperature is required to be 21 °C, and the average minimum temperature is 13.
5 °C.
When the temperature is as low as 1 to 2 When the temperature is lower than 0℃, the aboveground part will freeze to death
.
Due to the strict requirements on the climatic environment, the distribution range of cinchona trees is narrow and the number is limited, which leads to the unstable supply of quinic acid raw materials
.
Toxic azides are also involved in the synthesis of oseltamivir from quinic acid
.
Therefore, shikimic acid derived from the spice star anise is theoretically a better choice
.
The following figure shows the synthetic route from shikimate to oseltamivir phosphate: The pharmacokinetic profile of the active metabolite of oseltamivir is linearly related to dose
.
In the study, oseltamivir and its active metabolites were determined in plasma and urine samples using sensitive liquid chromatography or tandem mass spectrometry
.
1 Absorption After oral administration, oseltamivir phosphate is rapidly absorbed in the gastrointestinal tract, and is rapidly converted into the active metabolite oseltamivir carboxylate (otherwise known as Ro 64-0802) by liver and intestinal wall esterases
.
The absolute bioavailability of the active metabolite produced by oral oseltamivir is 80%
.
After 30 minutes of oral administration, the active metabolite can be detected in the plasma and its concentration reaches the maximum concentration after 3 to 4 hours
.
Relative to the active metabolite, less than 5% of the drug exists as a prodrug
.
The active metabolite of oseltamivir remains in plasma longer after oral administration compared with intravenous administration
.
Except for the difference in half-life, there was no significant difference in the pharmacokinetics between intravenous and oral administration
.
Neither feeding nor administration under conditions that alter gastric pH will affect the bioavailability of oseltamivir
.
Plasma concentrations of the active metabolite were proportional to the dose of oseltamivir and showed only a small degree of inter-individual variability
.
2 Distribution Distribution Studies on ferrets, rats and rabbits have shown that the active metabolites of the drug can reach all sites of influenza virus infection
.
Studies have shown that after oral administration of oseltamivir phosphate, its active metabolites can reach effective antiviral concentrations in the lungs, bronchi, bronchoalveolar lavage fluid, nasal mucosa, middle ear and trachea
.
3 Metabolism Metabolism For most people, the active metabolites will decline with a half-life of 6 to 10h after accumulating to peak plasma concentrations
.
Apart from extensive conversion to Ro 64-0802 by hepatic or intestinal esterases, no other metabolites of oseltamivir have been found in humans
.
In vitro studies have shown that neither oseltamivir phosphate nor its active metabolites are substrates or inhibitors of cytochrome P450 isoenzymes; neither oseltamivir nor its active metabolites are mixed with human cytochrome P450 oxidase or cytochrome P450.
glucuronyltransferase interaction
.
4 Elimination Elimination Oseltamivir is mainly eliminated (>90%) by conversion to the active metabolite and excretion by the kidneys
.
Approximately 60-70% of the oral dose is present in urine as the active metabolite, and less than 5% is present as oseltamivir
.
The renal clearance of oseltamivir and its active metabolites both exceeded the glomerular filtration rate, indicating that in addition to glomerular filtration, oseltamivir also relies on the anion transport pathway secreted by the renal tubules for clearance
.
After oral administration of oseltamivir, the residual drug in the stool was found to be less than 20% of the initial dose, of which 50% was oseltamivir and 50% was its active metabolite
.
5 Adverse reactions The most common: gastrointestinal adverse reactions, such as nausea, vomiting, indigestion, abdominal pain, etc.
, the incidence rate is 6%-15%, most of the symptoms are mild, and disappear after drug withdrawal
.
According to the pharmacokinetic characteristics of oseltamivir, food has no effect on the absorption of the drug, but taking oseltamivir with food may reduce gastrointestinal discomfort and improve tolerance, so it is recommended to take it with food
.
Rarely: Allergic reactions may occur, manifesting as a rash
.
Individual cases: dizziness, headache, hallucinations, abnormal behavior, lethargy, anxiety and other symptoms may occur, and severe cases may develop into depression or even suicide
.
6 Supplementary half-life (half-life, T1/2) refers to the time required for the absorption, distribution and elimination of half of the drug (or blood concentration) in the body, called absorption half-life (T1/2ka), distribution half-life (T1/2α, two compartments).
model) and elimination half-life (T1/2ke, one-compartment model), (T1/2β, two-compartment model) or (T1/2λ, non-compartment model)
.
The half-life here refers to the elimination half-life T1/2β
.
Cytochrome P-450 mixed-function oxidase can form "active oxygen" complexes with molecular oxygen to oxidize exogenous chemicals that enter the liver and lung
.
The main enzymes that metabolize drugs in the human body are the cytochrome P450 superfamily (Cytochrome P450 proteins, CYP).
Metabolism of xenobiotics, including most clinical drugs, can produce metabolites that may be toxic
.
P450 enzymes can transfer electrons through the iron ions in heme in its structure, oxidize heterologous substances, enhance the water solubility of heterologous substances, and make them easier to excrete from the body
.
Oseltamivir was first developed by Gilead Sciences
.
In 1995, the relevant in vitro experiments have determined that the drug is effective and safe, and it can be applied for human clinical trials
.
But a clinical trial costing hundreds of millions of dollars was an astronomical sum for Gilead at the time, and it was time to find a partner
.
In January 1996, Gilead began to negotiate with a number of large pharmaceutical companies on the transfer of usage rights, and Roche became the best choice
.
On September 30 of the same year, Gilead and Roche reached an agreement to transfer the production and sales rights of GS4104 to Roche.
Roche paid Gilead US$10 million to continue the trial.
If the clinical trial went well, Roche would pay another US$40 million.
After the listing, Roche will also share a portion of the sales profits to Gilead
.
The patent for the oseltamivir compound was submitted by Gilead to the US Patent and Trademark Office on December 27, 1996 and approved for patent rights on June 9, 1998, and was subsequently transferred to Roche Pharmaceuticals
.
By the second half of 2005, bird flu had a tendency to spread globally
.
The WHO also issued a warning, and Roche donated 3 million boxes of Tamiflu to the WHO drug reserve, but due to the surge in global sales, there are still many organizations and individuals accusing Roche of monopolizing patents
.
In this case, although the patent has not yet expired, Roche finally decided to grant some countries and regions the right to produce their own products.

.
On November 15, 2010, the Indian generic drug company Natco (that is, the prototype of glenin produced in the movie I'm not the God of Medicine) submitted the first PIV challenge
.
After a complicated patent dispute, the original drug company and the generic drug company reached a settlement
.
On August 3, 2016, the FDA approved the first generic version of oseltamivir phosphate from Natco, which also received a 180-day market exclusivity period
.
Oseltamivir Phosphate's first imitation status is enviable, but the road to imitation is not smooth: from Natco's earliest challenge to Tamiflu's patent to the final approval of generic products, the relationship between generic drug companies and original research drug companies The patent dispute lasted a full 6 years
.
You must know that it took only 7 years for oseltamivir phosphate from compound screening to product launch, while it took a generic drug company 6 years to obtain a first imitation variety.
From this point of view, successfully imitating an excellent product also It's not a simple matter
.
By 2019, the FDA had approved 11 generic manufacturers of oseltamivir phosphate, and China's Shanghai Pharmaceuticals and Sunshine had also obtained production authorizations
.
Since then, the two pharmaceutical companies have marketed them under the trade names of Orfi and Kewei respectively, realizing the localization of oseltamivir
.
Strictly speaking, GlaxoSmithKline's zanamivir is the First-in-Class of neuraminidase inhibitors, but in terms of market performance, oseltamivir phosphate is far stronger than zanamivir
.
From a time point of view, the two drugs were launched at almost the same time in 1999, but the market performance was very different
.
The biggest reason for this is the difference in the way of administration
.
And this is fundamentally derived from the different thinking of new drug design by scientists
.
The physicochemical properties of zanamivir determine that the drug is not suitable for oral administration.
To solve this problem, GSK scientists plan to develop the drug into a powder inhaler
.
They believe that: on the one hand, inhalation can improve the bioavailability of drugs and directly solve the problem of low bioavailability of oral administration; on the other hand, influenza itself is a respiratory infectious disease, and inhalation can directly act on the respiratory system.
system
.
For oseltamivir phosphate, the same problem was faced at the beginning, but the thinking of the Gilead scientists was very different from that of GlaxoSmithKline: First, in terms of the way of administration, they believed that flu patients often had difficulty breathing.
Symptoms, in the face of inhalation and oral administration, patients may prefer the latter
.
Therefore, in order to solve the problem of oral bioavailability, Gilead adopted the prodrug technology to esterify the original compound to obtain oseltamivir phosphate
.
It later turned out that oral administration was more acceptable to patients
.
Look at the domestic market
.
Judging from the current brand market structure of oseltamivir, Roche's market share has plummeted in recent years, and Shanghai Pharmaceutical's sales have always accounted for less than 10%.
Occupy the vast majority of the market share of this species
.
It can be seen that the market operation of HEC "Kewei" is very successful, and the market advantage mainly depends on the following points: 1.
Expanding the population of the drug Oseltamivir was originally only 75mg capsules.
Launched "Kewei" granules, targeting the children's drug market
.
Following the liberalization of the "two-child policy" and the shortage of special medicines for children in recent years, "Kewei" granules seized market opportunities and expanded rapidly
.
With the improvement of parents' willingness to pay for children, the market prospect of "Kewei" children is promising
.
2 The market-enhancing alternative oseltamivir was originally mainly aimed at large-scale outbreaks of influenza and severe influenza.
Now, due to the safety, efficacy and economy of oseltamivir, it has been recommended in various guidelines for influenza.
First-line medication, at the same time, strengthen the education of doctors and patients, gradually transform oseltamivir from an emergency medication for major influenza outbreaks to influenza prevention and treatment drugs, and gradually replace traditional amantadine and rimantadine
.
With the expansion of the scope of clinical drugs, the increase in the number of drug users, and the exertion of the market substitution effect, the influenza antiviral drug market has reached more than 80%
.
3 Self-built sales team Compared with Dongyang Sunshine, Roche and Shanghai Pharma did not pay enough attention to this variety of drugs
.
Since anti-influenza virus drugs are not part of Roche's main strategic development direction, Roche has not invested too much resources in the promotion of Tamiflu in China; and Shanghai has a wide variety of pharmaceutical products and complex product lines, so Orfi's sales have always been Relatively sluggish, and has slowly begun to withdraw from the market
.
Based on this, HEC has invested heavily in the clinical promotion of "Kewei".
In the past, Kewei's sales were mainly based on investment promotion agents.
After 2012, HEC started to build its own academic team to strengthen the education of doctors and patients on medication
.
With its own sales team, "Kewei" has become the company's main product
.
4 Significant price advantage It can be seen from the bid-winning data of oseltamivir that the bid price of “Kewei” is only 60% of that of “Duffy”, which is close to that of “Orfi”.
"Gradually abandoning the market, "Kewei" has a significant price competitive advantage with "Duffy" by virtue of its price advantage
.
To sum up, the competitive advantage of Dongyang Sunshine Kewei is obvious
.
Oseltamivir took just seven years from the establishment of a research and development team by Gilead in 1992 to its successful approval for marketing in 1999, which is very rare in the history of new drug research and development in modern times, and has become a classic case of rational drug design
.
This has also brought us a lot of inspiration: First, in the selection of research drug projects, after a breakthrough is found, research should be carried out decisively, and scientific research funds should be used efficiently and reasonably, especially in the case of relatively insufficient investment in innovative drug research in China.

.
Secondly, the example of oseltamivir tells us that me-too and me-better drugs are also one of the effective ways to develop new drugs
.
Then, with the rapid development of science and technology today, drug developers should learn to use various resources, especially structural biology and computer-aided drug design technology, which can not only save the cost of scientific research, but also improve the efficiency of research and development
.
Finally, in the process of drug design, not only the activity of the compound should be considered, but also the compliance of the drug.
Considering the problem from the perspective of the patient, this will determine the market competitiveness of the drug
.
Thanks to Wu Xingxin and Xu Yizhu for their help and guidance in writing this tweet
.
About the author Drug-seeking truth group They are students of the new drug research and development strategy course of Nanjing University.
This article is jointly completed by Li Yuting, Yang Hanyu, Zeng Yan, Zhang Diya and Liu Qiang, members of the 5 groups of new drugs in the course
.
They are full of vigor, their fighting spirit is high, they are down-to-earth to learn the knowledge of new drug research and development, and they firmly believe that I love my teacher and I love the truth more
.
They are the successors of the new generation of pharmaceutical industry, and they are the future light in the field of new drug research and development! *This article is only for academic content exchange and does not constitute any medication advice! References [1] He G, Massarella J, Ward P.
Clinical pharmacokinetics of the prodrug oseltamivir and its active metabolite Ro 64-0802.
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Clinical pharmacokinetics, 1999, 37(6).
[2] Yuan Bing, Li Runfeng , Yang Chunguang, Zhang Sheng, Zhang Yunhui, Jiao Jianlin, Zhang Rongping, Xia Xueshan, Yang Zifeng.
Pharmacokinetic and pharmacodynamic application of oseltamivir in tree shrews[J].
Chinese Journal of Comparative Medicine,2019,29( 02):7-13.
[3] Davies BE.
Pharmacokinetics of oseltamivir: an oral antiviral for the treatment and prophylaxis of influenza in diverse populations.
J Antimicrob Chemother.
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