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Applicaton of biopharmaceutics in new drug development

Presented by:Vrushali V. Sonawadekar.

1st year M-PHARMDept. of pharmaceutics

Kle college of pharmacy Belagavi..

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contents• Introduction• Importance of bio pharmaceutics in development

process • Discovery• Pre-clinical testing • Clinical trials• Post clinical surveillance• Advanced clinical development• conclusion

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Introduction • The task of discovering & developing safe & effective

drug is gaining lots of importance these days.• It is becoming an increasingly challenging undertaking.• Facts of drug discovery & development :1. Time :10-15 years2. Cost :800 millions-1 billions3. Drug tested :5000-10000 molecules4. Subject tested :1000-5000 5. Drug approved :1

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• Modern discovery is the product of cooperation• Both public & private organization play an unique

roles in translating basic research into medicine• Major biopharmaceutical companies are the primary

source of R & D funding of new medicines.• Smaller companies conduct basic research , drug

discovery , preclinical experiments & in some cases clinical trials.

• The national institute of health (INH) provides leadership & funding stimulate basic research & early stage development of technologies.

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Importance of Biopharmaceutics in the Overall Development Process

• Biopharmaceutics is an integral component of the overall development cycle of a drug

• Evaluation begins during the drug discovery process, proceeds through compound selection, preclinical efficacy and safety testing, formulation development, clinical efficacy studies, and post approval stages.

• At each stage, biopharmaceutical scientists interface with in multiple disciplines including discovery chemistry and biology, drug safety assessment, clinical development, pharmaceutical development, regulatory affairs, marketing, and manufacturing

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• The ensuing section will discuss the general activities and impact at each stage of development and provide an overall view of the role of biopharmaceutics at various stages of drug development.

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Discovery and Preclinical Development:

• The preclinical development stage encompasses aspects of both drug discovery and drug development.

• Depending on the desired therapeutic action, the target blood concentration–time profile must be considered with respect to Cmax, tmax, AUC, clearance, accumulation, and dose proportionality.

• Species effects are also an important consideration since ADME

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• The physical–chemical properties of the drug candidate, such as solubility, sta- bility, and lipophilicity, influence the in vivo performance and must be considered for any drug candidate .

• Preclinical ADME studies in vivo using various animal models are also necessary to assess blood concentration–timeprofiles, AUC, Cmax, tmax, dose proportionality, accumulation upon multiple dosing or enzyme induction.

• Stability of compounds is another factor that must be evalu- ated as it affects the integrity of the material being dosed, could potentially lead to generation of degradants with distinct pharmacologic action or toxicity, and also impacts the handling and shelf-life of a pharmaceutical product.

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• Discovery involves followings :

1. Pre-discovery : Understanding the disease2. Target identification :choose molecules to target

with a drug.3. Target validation : Test the target & confirm its roles in

disease4. Drug discovery : find a promising lead compound that could

becomes a drug.5. Early safety tests : perform initial tests on lead .6. Lead optimization : alter the structure of lead compound to

improve properties .• 5000-10000 molecules are selected & tested.

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• Scientists test Absorption , Distribution , Metabolisms , Excretion & Toxicological (ADME/Tox) properties or pharmacokinetics.

• Successful drug must be :1. Absorption into the bloodstream 2. Distribution to the proper site of action in the body.3. Metabolized efficiently & effectively 4. Successfully excreted from the body 5. Demonstrated to be not toxic.

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Pre-clinical testing• With more optimised compounds in hand

researchers turns their attention to testing them extensively to determine if they should move on to testing in humans.

• Scientists carry out in vitro & in vivo tests• They try to understand a drug’s kinetics toxicity &

carcinogenicity.• The U.S Food & Drug Administration (FDA) requires

extremely thorough testing before the candidate drug can be studied in humans.

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• Around 250 drugs are tested in pre clinical phase of which at least 5 molecules are selected as “candidate drug”

• After selection of candidate drugs sponsors file a IND (Investigational New Drug) Application to FDA.

• The Application includes :1. The results of the pre clinical work2. The candidate drug‘s chemical structure &3. How it is thought to work in the body 4. A listing of any side effects &5. Manufacturing information

• The IND also provides a detailed clinical trials plan that outlines how where & by whom the studies will be performed.

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• In addition to the IND application , all clinical trial must be reviewed & approved by the “institutional review board” (IRB) at the institutions where the trials will takes place.

• This source includes the developments of appropriate informed consent which will be required of all clinical trial at any time if problems arise.

• The company sponsoring the research must provide comprehensive regular reports to the FDA & the IRB on the progress of clinical trials.

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Clinical trials• This phase is the longest one in drug development from 2-10 years

• A suitable clinical design is developed . These includes 1. Placebo controlled trials2. Randomized trials3. Double blinded studies

• Clinical trials comprise of three phases1. Phase 12. Phase 23. Phase 34. Phase 4 i.e pre-marketing surveillance

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Phase 1 trials• The candidate drug is tested in people for the first time .• These studies are usually conducted with 20 to 100 healthy

volunteers.

• Usually last 6 months to 1 year (30% of drug fail phase 1 testing)

• A clinical candidate must be tested in formal animal safety studies in multiple species in order to establish a safety profile and provide guidance on the choice of clinical doses.

• Solutions are highly desir- able for dosing because they are homogeneous systems that are easy to administer to animals (particularly rodents), offer dose flexibility, and have the potential for maximizing in vivo exposure by avoiding issues with dissolution.

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However , poorly soluble compounds may lack sufficient solubility to prepare highly concentrated solutions, and pharmaceutically acceptable non-aqueous vehicles or suspensions must be used if a liquid vehicle is necessary.

• used to determine 1. Pharmacokinetics data2. Pharmacodynamics data3. Max. tolerated dose4. Adverse reactions profile

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Phase 2 trials • In phase 2 trials researchers evaluate the candidate drug’s effectiveness

in about 100 to 500 patients with the disease or condition under study.

• Usually 2 years (37% of drugs fails phase 2 testing)

• Used to know1. Preliminary evidence of efficacy2. Pharmacodynamic effects in patients3. Optimal dosage ranges & dosing schedule

• Phase 2 trials are followed by a meeting with FDA to obtained agreement on phase 3 adequate & well controlled study design & analysis plan.

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Phase 3 trials • In phase 3 trials researchers study the drug candidate in a larger

number (about1000-5000)of patients .• Usually last 3 years ( 6%fail phase 3 testing)• Used for1. Confirmation of efficacy2. Establishment of complete safety profile3. Base of regulatory information (labeling)4. Assessment of risk / benefit• Phase 3 trials are both the costliest & longest trials.• Hundreds of sites around the world participate in the study to get a

large & diverse group of patients.• Coordinating all the sites & the data coming from them .

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• In addition to these trials additional special trials should be performed to evaluate drug in :

1. Special populations 2. Interactions3. Special conditions 4. Special toxicities5. Addition potential

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Post-marketing Surveillance• Research on new medicines continues even after approval .• These studies are generally termed as phase 4 trials.• As a much larger no. of patients begin to use the drug ,

companies must continue to monitor it carefully & submit periodic reports , including cases of adverse events ,to the FDA.

• These trials can be set up to evaluate long term safety or how the new medicines affects a specific sub group of patients.

• Yearly safety reports must be filed with the applicable regulatory agencies as long as a drug remains on the market.

• If safety concerns aries the FDA may demands withdrawal of a from the market anytime.

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Advanced clinical development

• As a compound moves from Phase I into Phase II and eventually into Phase III, the objectives of the clinical development program evolve from primarily safety and PK to safety and efficacy.

• PK studies conducted in Phase I and II are used to establish a body of knowledge surrounding the intrinsic properties of the medicinal agent (e.g., clear ance) as well as the dependency of the performance on the actual product used.

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Conclusions

• The discovery & development of new medicines is a long completed process.

• Research based pharmaceutical companies are committed to advancing science & bringing new medicines to patients.

• Increased support from govt & organisation may helps in development safer & cost effective medicines.

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Application of biopharmaceutics in designing of novel drug delivery

system.

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Introduction• The term drug delivery covers a broad range of techniques

used to get therapeutic agents into the human body.• The frequency of administration or the dosing interval of

any drug depends upon its half life or mean residence time (MRT) & its therapeutic index .

• When drug is delivered as a conventional dosage form such as a tablets , the dosing interval is much shorter than the half life of the drug resulting in a no. of limitations associated with such a conventional dosage forms

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1. Poor patients compliance – increased chances of missing the dose of a drug with short half life for which frequent administration is necessary

2. The unavoidable fluctuations in the drug concentration may lead to under medication or over medication as the Css values fall or rise beyond the therapeutic range.

3. The fluctuating drug levels may lead to precipitations of adverse effects especially of a drug with small therapeutic index whenever over –medication occurs.

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• There are two ways to overcomes such a situations

1. Development of new , better & safer drug with long half –lives & large therapeutic indices

2. Effective & safer use of existing drugs through concepts & techniques of novel drug delivery system.

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Factors in the design of novel drug delivery systems

• The basic rationale of a novel drug delivery system is to optimize the biopharmaceutics , pharmacokinetics & pharmacodynamics properties of a drug in such a way that its utility is maximised through reduction in side effects & cure or control of disease condition in shortest possible time by using smallest quantity of drug , administered by the most suitable drug.

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A. Biopharmaceutics characteristics of a drug in the design of novel drug delivery system -

• The performance of a drug presented as a novel delivery system depends upon its-

1. Release from formulations2. Movement within the body during its

passage to the site of action.

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• The desired boiphamaceutics properties of a drug to be used in novel drug delivery system are discussed below

1. Molecular wt of the drug : lower the mol wt , faster & more complete the absorption . The mol size is 150 daltons for spherical compounds & 400 daltons for linear compounds. Eg : proteins & peptides

2. Aqueous solubility of the drug – a drug with good aq. Solubility , especially pH dependent , serves as good candidate for novel drug delivery system eg: pentoxifylline. lower limit of solubility of drug is more than 0.1 mg/ml

3. Apparent partition coefficients / lipophilicity of the drug .- greater the partition coefficients of a drug , greater its lipophilicity & thus , greater its rate & extent of absorption.

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4.Drug permeability : three major drug characteristics that determine the permeability od drug for passive transport across intestinal epithelium are –a. lipophilicity , expressed as Log P .b. Polarity of drug which is majored by the no. of H bond

acceptors & no. of H bonds donors on the drug molecules.c. Molecular size

5. Drug stability : drugs are stable at both gastric & intestinal pH.

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B. Pharmacokinetics characteristics :1. Absorption rate: high.2. Elimination half life: the drug with half life in the range 2- 4

hrs. make good candidate for such a system. Eg. Propranolol.3. Rate of metabolism: a drug which is extensively metabolised

is suitable for novel drug delivery system as long as the rate of metabolism is not too rapid.

4. Dosage form index: it is defined as the ratio of Css MAX. to Css,min. since the goal of novel formulation is to improve therapy by reducing the dosage form index while maintaining the plasma drug level within the therapeutic window, ideally , its value should be as close to one as possible.

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C. Pharmacodynamic properties:1. Drug dose: dose strength of 1g is considered

max.2. Therapeutic range: wide.3. Therapeutic index: wide.4. Plasma concentration – response relationship:

drugs such as reserpine whose pharmacological activity is independent of its concentration are poor candidates for novel drug delivery system.

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Pharmacokinetic principles in a design of novel drug delivery system

• CT is the target concentration to be maintained for T hour.

• Rate of elimination = K.CT.Vd or CT.Vd

• Where K is the elimination rate constant of the drug.• V is the apparent volume of distribution.

• Rate of absorption, Ka Xa should be equal to the rate of elimination to maintain constant concentration. So ,

Ka Xa = K. CT Vd

• Then rate of release should be equal to the rate of absorption and rate of elimination. So,

Rate of release, Kr = K. CT Vd

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So, Maintainence dose = rate of release x duration to be maintained = K. CT Vd T tmax = Log Ka

K Where Ka is absorption rate constant Loading dose = CT Vd e-Ktmax

F • Where F is bioavailability (fraction)• Above is on the basis that drug confers one compartment distribution

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• Equation to express plasma concentration of controlled release

product administered C = K0 (e-KT -1) e-Kt

K Vd

• Where K0 is zero order release rate• ‘T’ is time of total release• ‘t’ is anytime at which concentration is measured• ‘t’ can be less than or equal or more than ‘T’

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Applications of pharmacokinetics in NDDS

• To understand the process of absorption, distribution, elimination of drug, which affects onset and intensity of biological response.

• To access plasma drug concentration response to given dose which is considered as more appropriate parameter than intrinsic pharmacological activity.

• In design and utilization of In-vitro model that can evaluate dissolution characteristics of new compound formulated as new drug formulations and establish meaningful IVIVC.

• In design and development of new drug and their appropriate dosage regimen.

• In safe and effective management of patients by improving drug therapy.

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• To understand the concept of bioavailability which has been used to evaluate and monitor in vivo performance of new dosage forms and generic formulations.

• To carry out the bioavailability and bioequivalence tests.

• We can use the pharmacokinetic principles in the development of the various NDDS.

Eg: The drug with short half life about 2-6 hrs can be formulated as controlled release drugs by using polymers.

The lower bioavailability of the drugs can be increased by using several components like ß-cyclodextrin.

• List of drug carriers in NDDS: Nanosomes, Liposomes, Niosomes, Proniosomes, Vesicular drug delivery

system, Cubisomes, Aquasomes, Pharmacosomes, Miscelles, Nanoparticles, Nanosphere, Microsphere, Microparticle, Dendrimer, Microemulsion, Transferosomes, Nanosuspension, Dendrosomes etc.

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Thank you…