Appunti di Tecnologia del direzionamento e rilascio controllato dei farmaci - Salmaso

2018/2019 Technology of targeting and controlled release of drugs

Prof Stefano Salmaso e Mauro Ferrari

Technology of targeting and controlled release of drugs

Lunedì 5 novembre 2018

11:34 Laboratorio 14.30 A digiuno - Preparazione particelle polimeriche

Sciencedirect: database incentrato sullo sviluppo e il targeting delle molecole

PubMed: dal punto di vista biomedico

Scopus - Google Scholar: motori di ricerca che cercano pubblicazioni citate nel web e nei vari database.

www.shldirect.com: da informazioni per colloqui di lavoro. Si basa su una serie di test e da informazioni utili per affrontare dei colloqui (tipo hobby, passioni, etc). Siti per lavoro, questi sono americani. Funzionano bene per gli Stati Uniti, meno per l'Europa.

• www.monster.com
• www.careerbuilder.com

Dottorato/Master

Serve per sviluppare competenze pratiche

Dottorati - guarda il sito Euraxess

Topics of the course and Pharmaco-economics

Mercoledì 7 novembre 2018

12:30

• Economic aspects and societal benefit of developing alternative formulation of drugs
• Background of drug delivery system, the relevance of targeted therapeutics, requirements for long circulating systems, design of responsive systems.
• Strategies to control the drug release rate from matrices
• Colloidal (size below 1 nanometer) and dispersed systems; required general features
• Production of polymer based on micro and nano particles for drug delivery and control release of loaded drug. Pharmaceutical use of nanoparticles
• Cyclodextrins: a case of advanced application of a conventional excipient for drug and gene delivery, used at the same place of a virus vector.
• Trans-mucosal and Transdermal route (such as protein through the skin and mucosal, an unconventional route)
• Metal nanoparticles (gold, iron oxide) and nanotubes for site selective delivery of drugs that can be activated with ultrasound and electromagnetic fields, so they can produce ROS against cancer cells.
• Role of international agencies for bio drugs. (se abbiamo tempo facciamo ste robe)
• Notes on Good Laboratory and manufacturing practices

The purpose of the advanced drug delivery science is to ensure the drug achieves the site of action, choosing the pathway that is more convenient, less time and money consuming to avoid the excretion and metabolism. Remember that our macrophages are the worst enemies of nanoparticles. RES (reticulum endothelial system) take up all the nanoparticles, because our system recognizes them as immunogen, because they have the same size as certain bacteria and viruses.

The first idea for nanocarriers is that we encapsulate the drug into the carrier, and this is no longer toxic for the time that remains in the carrier, and it's also not effective. Also with nanocarriers, we can increase plasma half-life of the drugs.

Book in the library

• Controlled drug delivery - Joseph Robinson, Vincent H. Lee

Old but some topics are useful.

One reason of interest in controlled release and delivery systems is for drug repositioning, that happens when there is a very active drug but the patent is expired, so the company can modify the carrier to obtain another patent.

Pharmaco-economics

What would you take into account to calculate the costs? Researched and Developing. It's a very complicated relation because not only the drug competes to generate cost, but also all the things involved with the therapy, such as the nurses, the hospital, the exams, the drugs used in combination with the main drug.

Pharmaco-economics is the science of balancing best outcomes with limited resources in time and money. We have to quantify all the things to obtain all the costs for the therapy.

Goals

• Study the monetary and non-monetary costs (such as if I'll be sick after the therapy and I can't go to work, it's a cost difficult to quantify) and benefits of therapeutic treatments
• The pharmaco-economic value of a new product derives from cost reduction of existing products and/or health benefits (same cost but better treatment is a cost to evaluate)
• FDA approval does not require "pharmaco-economic value", but market does.
• Economic assessments on new therapies are meant to clarify the trade-offs between higher costs and greater benefits.

Aims: The aims of pharmaco-economics studies can be classified into 3 different groups:

• Acceptable clinical outcomes (evidence of remission, eradicate the pathology). Treat a disease that will be chronic for the rest of life once time is a good aim.
• Acceptable humanistic outcomes (evidence of quality of life improvement)
• Acceptable economic outcomes (reduced costs than previous treatment)

At the end, pharmaco-economics analysis compares the costs and consequences (outcomes) of different drug therapies and medical interventions, so it can be useful to set up efficient allocation of limited resources (time and money) among competing alternative medications and services. The company has to decrease R&D costs and increase the sales revenue. So pharmaco-economics analysis can be useful to set up the final price, mediated with the exigence of the Ministry of Health. Costs are not the same as the price of the drug. Cost involves all the resources that are used to produce and deliver a particular drug therapy.

Types of costs

• Direct costs: to generate the drug, involved to deliver services to patients, both medical and non-medical.
• Indirect costs: cost of treatment to patient on society, productivity of patients, lost working days, mortality.
• Intangible costs: something difficult to quantify, such as quality of life, but if we have some benefits from the therapy in terms of life elongation, we have to include them in the pharmaco-economics analysis.

Costs can be described as cost/unit (such as tablet), or the cost of the overall treatment, overall the person per year, cost per disease prevented, and the most important the cost/DALY (disability-adjusted life per year) used to quantify the quality of life.

Both positive and negative outcomes occur to generate the pharmacoeconomic study:

• Positive outcome: drug efficacy
• Negative outcome: ADR (adverse drug reaction): if the treatment can generate adverse reactions that must be solved using other drug therapies.

Summary: Analytical methods

• Cost-Minimization Analysis: assumes equal therapeutic outcomes of various treatments analyzed.
• Cost-Effectiveness Analysis: (the most common) costs in monetary terms/clinical outcomes.
• Cost-Utility Analysis: (when adverse reactions are severe) measure outcomes in QALY (quality-adjusted life).
• Cost-Benefit Analysis: (difficult) measure benefits and costs in $.

Cost minimization analysis

Compare 2 interventions (ex 2 therapies with the same efficiency, equally effective and tolerable). They have the same outcomes (same quality of life), so this analysis determines which therapies cost less. This considers only costs of production or delivery, costs that can be easily calculated. This does not consider costs of treatment failure, severe ADR, drug monitoring, or other healthcare services.

Cost effectiveness analysis

In case the treatments are not equally effective and tolerable, we must consider not only the costs of production but also evaluate the outcome of the therapies. A therapy is a cost-effective strategy when the outcome is worth the cost relative to competing alternatives. We use this analysis when we have to compare 2 different therapies and determine how to use one or the other.

Cost/effectiveness results can be expressed as: cost/treatment, cost/outcome, and cost/life saved. For the cost/outcomes we can consider: Clinical marker can be: mm Hg blood pressure lowering, mg/dL of LDL lowering, or other useful indicators. This numerical data can be compared for 2 different treatments.

The worst scenario is when we have a dominated treatment, the cost is the highest, but the treatment is less effective. The best scenario is when we have a dominating scenario, so the cost is the lowest but the treatment is more effective; however, this is a very rare case. So the most common scenario is the NE quadrant, the more costly (when the treatment is new) and the more effective, and we have to consider if the cost is worth the effectiveness. So in this case, the Cost/effectiveness analysis must be done, also with the SW quadrant.

We do the analysis, and the outcome will tell that Cost-effective is not the least expensive, it may be:

• Less expensive but the same effectiveness
• More expensive and more effective (if the extra benefits are worth the cost in surplus)
• More expensive and less effective (if the extra benefit of competing therapy is not worth the extra cost).

The idea is to understand if the extra benefits gained from the new treatment are worth the increase in cost. Cost-effective is not always cost-saving. With cost-saving we define an intervention that has a lower total cost than an alternative intervention (may not have the same effect). With cost-effectiveness, we define an intervention that is sufficiently effective relative to its total cost when compared with an alternative intervention, considering that they have about the same effect.

So the cost/effectiveness is a global data, it considers also the benefit gained from the patient.

Example

New drug or new drug delivery system in NE or SW quadrant: Drug A is doxorubicin in liposome, and Drug B is just the doxorubicin. Drug A works better than Drug B, but Drug A is more costly than Drug B. How much does it cost us to add one year of perfect health onto the life of our patient? We have to obtain a relevant improvement in the quality of life using drug A instead of drug B.

Pharmaco-economics and controlled release systems

Venerdì 9 novembre 2018

12:31

Cost-utility analysis

In this analysis, we introduce the concept of quality of life, so not only the cost-effective data. It determines the cost of adding one year of perfect health to a patient's life treated with a new drug. The analysis is based on Incremental Cost-effectiveness Ratio (ICER), which is the amount of money spent to add one year of perfect health onto the life of our patient. It’s a ratio of cost to effectiveness per year.

Utility is another parameter, a number that estimates quality of life, associated with a disease state or treatment. It’s a fraction of one unit, in fact perfect health is equal to 1, and dead to 0. These 'parameters' are difficult to quantify, they depend on the health of the patient.

There are 2 types of Quality of Life measures: general and disease-specific, the parameter analyzed for every specific disease is different, for example in the cancer of the lungs we measured ability to breathe. The use of controlled release dosage forms can influence the costs and benefits treatment compared, they have a better outcome after the treatment compared to the standard drugs.

Quality-adjusted life-year (QALY)

In the life expectancy adjusted based on utility. QALY = (time in healthy state) x "utility". For example, 2 years of life based per utility.

Example

Consider one hypothetical chemo drug and its delivery system: One is the standard of care, the other one is the new therapy. Both treatments prolong life, but both have side effects which reduce quality of life.

• Standard of care: 1 year of life prolongation, Utility (level of health) 0.65, QALY 0.65
• New treatment: 1.5 years of life prolongation, Utility 0.5 due to side effects, QALY 0.75

The new treatment is expected to add 0.75 quality-adjusted life-years to our patient's life, so this new drug improved the healthiness of the patient even if it has more side effects.

ICER (incremental cost-effective ratio) is the single most important indicator of an intervention's cost-effectiveness. We can calculate this parameter taking into account the differential cost of the two treatments, dividing the difference between the effectiveness of treatments (QALY'S difference).

So following the previous example, for the standard of care the cost is 12k $, and for the new treatment is 15k $. The resulting ICER is 30.000/QALY. This number expresses the amount of incremental cost per normalized effectiveness per year for the new therapy. It accounts also for the costs related to side effects and level of quality of life treatment.

Is it legit to spend this money to improve the life of 1 patient for 1 year? The choice is up to the health care system of the country (minister) and it depends on how life can be improved, and how easy it is to obtain better life conditions. The new treatment cost to public health 30K $ per patient. Usually, a treatment below 50K/QALY is considered cost-effective, and this cost must be rationalized to the GDP (gross domestic product) of the country, so for example in the USA can be up to 150K/QALY.

Cost-benefit analysis

Instead of parametrizing in clinical data, all the data are expressed with dollars. It's not really used. Costs are compared to monetary benefits of intervention, so outcomes must be converted to dollars. This analysis determines when benefits > costs. Cost-utility analyses are the most complete kind of analysis. In this analysis, all the costs are expressed with dollars, the only things that change are the units used to parametrize the outcomes:

• VARIOUS (but equivalent in comparative groups) in COST MINIMIZATION
• NATURAL UNITS (life years, LDL, blood pressure) in COST EFFECTIVENESS
• QALY in COST UTILITY (the more complete)
• DOLLARS in COST BENEFIT

We have to simplify the data to obtain this analysis, so in many cases, we do oversimplification (every disease is very complex), and in every study there's a kind of standard deviation, due to the different condition of the different patients, in fact some people tolerate less the drugs than others, patients do not remain in one health state, each individual experiences different quality of life, incurs different costs, etc.

Guidelines of pharmaco-economics studies

1. Cost-effectiveness depends on clinical effectiveness, if the drug is not clinically effective the analysis is not necessary.

2. Cost-effectiveness is a relative phenomenon, all the studies are comparative.

3. Economic evaluations can quantify cost savings or incremental benefits received for incremental costs, but not whether these benefits are worth the costs associated.

The best time to do pharmaco-economic studies is during the phase II of clinical studies, to assess the pharmaco-economic value of new drug product, saving time and money. It has much lower cost than a standalone pharmaco-economic study. But some data must be collected when the drug is already in the market, such as the improvements of life duration, so standalone study must be done.

This study is useful to advocate new products before their arrival in the market, even if it is only a preliminary study. Controlled release dosage forms usually have higher costs and higher pharmaco-economic value:

• Increase clinical effectiveness
• Lower total treatment costs
• Provide tailored release profile
• Allow for better compliance usually deriving from lower side effects.

How much chemo drug goes to the tumor when administered parentally? The quantity is under 1%, with drug delivery systems we can obtain 5% of targeting. With very toxic drugs we can reduce the amount of circular drug in the plasma using controlled release systems.

Controlled release systems

"Non sono una panacea per le patologie, devono essere progettati tenendo conto della fisiologia del bersaglio, se il sistema non è disegnato bene dà tossicità agli organi depuratori del corpo."

Classic Administration routes:

Oral (about 70% of drug administration), but the drugs have to resist the low stomach pH and the drug undergoes hepatic clearance and hepatic damage, so the viability of the drug after first passage effect is around 10-20 %, the majority is metabolized. Intravenous/intramuscular: short half-life, biological drugs must use this way of administration. This route avoids first passage effect, so viability is much higher, but first passage effect can't be eliminated. If we have another alternative route, it may have lower first pass effect (and also degradation), so the concentration is higher in the blood.

Alternative administration routes

• Transdermal (through the intact skin), relevant also for macromolecule
• Transmucosal (mucosa of the mouth, intestine, nose, vagina)
• Transocular
• Transalveolar
• Implantable
• Injectable
• Needleless (micro-needle, they arrive to the derma, there's no pain because in the derma there's no nociceptor)

We have to develop polymeric materials with specific features and dedicated technologies, and analyze toxicology of these new systems. We need also new technologies to make these new materials.

Features of the most popular drug delivery forms

Tablet

• Drug forms ingested orally enter the circulation passing through the liver, a large fraction of the drug is metabolized (and can generate liver issues)
• pH effects can influence the extent of delivery,
• Drug with short half-lives, the extent of action is limited to the transit time through the stomach and intestine (6h up to 24h). Controlled release systems can increase the extent of action up to 6 months. Normal drugs stay in the bloodstream up to 24h and not excreted at the first passage in the kidney because the majority of the drug is bound to the protein in the plasma, such as albumin, and only the fraction that is unbound can cross the glomerulus and be excreted in the urine.
• Delivery profile typically has "peaks" and "valleys", so steady state is very hard to obtain with normal drug delivery forms.
• Patient compliance might be a limit, often older ones forget to take the required dose at the correct time.

Intravenous delivery

• This route has no first pass effect by the liver, the bioviability is the highest possible.
• Duration of action is determined by clearance rates, there's no control of the kinetic!
• This is the only route