FDA rende impervio il percorso dei farmaci

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FDA rende impervio il percorso dei farmaci

• "Dietro le crescenti difficoltà che i nuovi
  farmaci incontrano, negli Stati Uniti, prima di
  riuscire ad arrivare sul mercato, c'è la scienza
  e non la politica o il sistema dei prezzi"
  afferma Janet Woodcock, direttore del Centro di
  valutazione sui medicinali e ricerca della Food
  and Drug Administration.
• E rigetta le accuse mosse negli ultimi tempi allo
  stesso organismo secondo alcune associazioni di
  pazienti e aziende farmaceutiche, l"FDA non vuole
  correre alcun rischio e quindi ostacola il lancio
  di prodotti innovativi, dopo aver approvato, nel
  passato, medicinali che si sono rivelati
  pericolosi e a volte letali.
• Secondo le dichiarazioni dellesperta, comparse
  sul Financial Times, la percentuale di successo
  nel lancio di nuovi farmaci sul mercato
  ultimamente è andata diminuendo, ponendo sempre
  più sotto pressione le compagnie produttrici e
  deprimendo gli investitori, soprattutto dal
  momento che molti medicinali blockbuster stanno
  per perdere la loro protezione brevettuale.
• Ma quando l"FDA non concede il via libera a nuovi
  prodotti - tiene a precisare Woodcock - lo fa
  basandosi sui dati di efficacia e sicurezza e non
  su logiche politiche, di conservatorismo o di
  risparmio economico.
• Pur ammettendo che la lunghezza e l'ampiezza
  medie dei trial clinici sono aumentate, l'esperta
  spiega che questo è il risultato della migliorata
  capacità degli enti regolatori di identificare i
  possibili rischi per la salute dei pazienti.
• Woodcock rivela che, per il prossimo autunno, la
  FDA emanerà alcune proposte per ridurre i costi
  di sviluppo dei farmaci standardizzando il
  formato e il contenuto dei trial clinici.

27 marzo 2008
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Come ci si tiene aggiornati

• Convegno su "Come accelerare il processo di Drug
  Discovery"Click e Flow Chemistry, Microonde e
  dintorni.16 e 23 Maggio 2008PAVIAhttp//www.lab
  medchem.pv.it/labmedchem/drug_discorvery.html
•  

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Sintesi asimmetrica

• Organocatalytic Asymmetric Synthesis Using
  Proline and Related Molecules. Part 2.
• Hiyoshizo Kotsuki, Hideaki Ikishima, and Atsushi
  Okuyama. Heterocycles (2008)

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Da lead a farmacoProfarmaci e farmaci
latenziati
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Profarmaci e farmaci latenziati(Prodrugs)
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Prodrug concept

• Only seldom an active agent with optimal
  structural configuration for eliciting the
  desired therapeutic response at the target site
  possesses the best molecular form and properties
  for its delivery to the site of ultimate action.
• There are several approaches that potentially can
  be taken in when dealing with poor drug delivery
  characteristics
• New drug analogues of the original drug
• Dosage form

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Farmaci latenziati

• Sono composti che contengono già il principio
  attivo che viene però trasformato in un derivato
  da cui verrà rilasciato in vivo.
• (Succinilsulfatiazolo sulfatiazolo)

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Farmaco latenziato succinilsulfatiazolo
Sulfatiazolo
Succinilsulfatiazolo Sulfamidico intestinale
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Profarmaci

• I profarmaci sono sostanze biologicamente
  inattive che nellorganismo vengono trasformate
  in sostanze attive, con migliorate qualità
  farmacocinetiche e farmacodinamiche.
• (proguanile
  cicloguanile
• antimalarico)

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Profarmaco proguanile
Ossidazione
Cicloguanile
Proguanile
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Pro-farmaci e farmaci latenziati

• Hanno lo scopo di risolvere problemi legati a
• Passaggio di membrana
• Facile eliminazione
• Caratteristiche indesiderate (sapore, odore)

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Illustrazione schematica di Pro-Drug

• Drug vs prodrug

B A R R I E R
Drug
Drug
Pro-moiety

Trasformazione enzimatica o non-enzimatica
Pro-Drug
Pro-drug
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Advantages of a prodrug

• The prodrug is able to overcome one or more of
  the barriers to drug delivery more efficiently
  than the parent drug.
• These barriers include
• physicochemical properties
• pharmacokinetic properties

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Physicochemical properties

• Poor aqueous solubility
• Prevents the drug from being administered in form
  of injectables
• Gives rise to dissolution rate-limited (and
  variable) oral bioavailability
• Low lipophilicity
• Limits the design of lipid-based formulations
• Chemical instability
• Prevents the drug from being incorporated into
  adequate dosage forms

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Poor water solubility N-Mannich bases

• Transformation of an amide into an N-Mannich
  bases introduces a readily ionisable amino
  function which may allow the preparation of
  derivatives with greatly enhanced water
  solubility.

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Base di Mannich tetracicline
Tetraciclina
Rolitetraciclina
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Pharmacokinetic properties

• Incomplete absorption across biological membranes
  (gastrointestinal mucosa and blood-brain barrier)
• Unfavourable metabolism
• Low and variable bioavailability (extensive
  first-pass metabolism)

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Tossicità legata al metabolismo cloramfenicolo
Metabolismo
R NO2 NO NHOH NH2
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Caratteristica essenziale di un profarmaco
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Characteristics of a prodrug

• The changes in physicochemical properties and the
  pharmacological profile of the drug are
  transient, since the well-characterized parent
  drug molecule is regenerated in vivo.
• Introduction of a number of chemical transient
  changes in the drug molecule is possible, thus
  allowing prodrug derivatives with a broad
  spectrum of physicochemical properties to be
  considered.
• Prodrug formation can be considered as a means to
  mask temporarily undesirable physicochemical
  properties of the parent molecule.

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Reconversion in vivo

• The most prominent requirement of a prodrug is
  its reconversion to the parent drug in vivo.
• The conversion may take place at different times,
  depending on the specific goal for which the
  prodrug is designed
• Before absorption
• After entrance into the systemic circulation
• At specific site of drug action

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From the prodrug to the drug

• The most prominent requirement of a prodrug is
  its reconversion to the parent drug in vivo.
• Conversion or activation of a prodrug to the
  parent drug molecule in the body is the result of
  enzyme-mediated cleavage or pH-dependent
  hydrolysis.
• Within a homologous series of derivatives, the
  chemical nature of the promoiety may give rise to
  both electronic and steric effects, influencing
  the lability of the prodrug bond.

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Prediction of reactivity of the prodrug

• The most serious drawback of prodrugs which do
  not require an enzymatic release of the the
  active agent is their inherent lability, which
  raises stability issues at least in case of
  liquid dosage forms.
• Prediction of chemical reactivity through
  substituent effects is often possible from
  empirical linear free energy relationships
  (LFERs).
• In particular, neutral or alkaline hydrolysis of
  ester functions are facilitated by low electron
  density at the carbonyl carbon atom.
• This situation can be realized by introducing an
  electronegative substituent in a proper position
  of an aromatic ring or in an aliphatic chain.

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Bio-Regeneration of the drug most common
reactions

• Though there are examples of drugs generated from
  their prodrugs by biochemical reductive or
  oxidative processes, the most common prodrugs
  require a hydrolytic cleavage, mediated by
  hydrolases such as esterases and lipases.
• The rates of these reactions can be described to
  some degree as a function of some combination of
  electronic, steric, and hydrophobic parameters.
  However, application of LFERs to enzyme-catalyzed
  reactions is less straightforward than with
  chemical reactions.
• In particular significant interspecies variation
  should be taken into account. (e.g esters are
  hydrolyzed markedly faster in rat plasma than in
  human plasma. Dog plasma often is less efficient
  than human plasma).

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Attivazione per riduzione
Acido 5-aminosalicilico
Sulfasalazina
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Applications of the prodrug approach

• Oral absorption
• Dermal absorption
• Ocular absorption
• Prevention of first-pass metabolism
• Site-specific drug delivery (may be achieved by
  site-directed drug delivery or site-specific
  bioactivation)
• Improvement of drug formulation

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Oral absorption

• For orally administered drugs one major challenge
  of reaching their sites of action is that they
  have to cross intestinal epithelial cells to
  enter the systemic circulation.
• Poor transport properties may lead to low
  bioavailability, which may also result from low
  water solubility, low stability in the
  gastrointestinal juices or extensive first-pass
  metabolism.

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Oral absorption beta-lattami

• Well-known examples are the ampicillin
  derivatives.
• Being zwitterionic in the pH range of the
  gastrointestinal tract, ampicillin possesses a
  low lipophilicity and the absorption fraction
  after oral administration is about 30.
• Altering its polarity by esterification to form
  the prodrugs pivampicillin and bacampicillin
  resulted in essentially complete absorption.
• During or after entering into the systemic
  circulation, these prodrugs are cleaved by
  enzymes to give the active antibiotic.

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Assorbimento orale beta-lattami
R H Ampicillina
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Oral absorption beta-lattami

• The poor gastrointestinal absorption of
  carbenicillin is due to acid-catalyzed
  degradation of the drug in the stomach as well as
  to its strongly polar character.
• By bioreversible esterification of the side-chain
  carboxyl group, the more acid-stable and
  lipophilic derivatives carindacillin and
  carfecillin are obtained.
• Following absorption, carbenicillin is released
  in the blood by enzymatic hydrolysis of these
  clinically useful prodrugs.

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Assorbimento orale beta-lattami
R H Carbenicillina
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Dermal absorption

• The potential of various prodrug types to enhance
  the delivery of drugs through the skin
  (transdermal delivery) or into the skin (dermal
  delivery) have been investigated.
• Most drug diffuse poorly through the skin, in
  particular through stratum corneum, because of
  unfavourable physicochemical properties.
• In order to diffuse readily through the skin, a
  drug should possess adequate water as well as
  lipid solubility.
• The dermal delivery of several drug molecules
  such as steroids, antiviral, and antipsoriasis
  agents has been improved by the use of prodrugs.

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Dermal absorption

• Levonorgestrel is a very potent, lipophilic
  contraceptive drug, which is very poorly soluble
  in water (1 mg/ml at 25 C) and does not permeate
  through the skin at a sufficient rate.
• Two carbonate ester prodrugs containing hydroxyl
  functional groups in the alkyl portion of the
  pro-moiety were synthesized.
• The solubility of these prodrugs was better than
  the parent compound both in aqueous ethanol and
  in octanol.
• They enhanced the transdermal delivery of
  levonorgestrel by 30 and 15 times, respectively.

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Farmaci latenziati ormoni
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Site-directed drug delivery

• The design of prodrugs directed selectively to
  their site of action, should take into account
  the following basal criteria
• The prodrug should be able to reach its site of
  action
• The prodrug should be converted efficiently to
  the drug at the site of action
• The parent active should to some extent be
  retained at the target site for a sufficient
  period of time to exert its effect.

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Site-specific drug delivery

• Site specific drug delivery through site-specific
  prodrug activation may be accomplished exploiting
  that a target tissue contains specific enzymes or
  higher concentration of particular enzymes
  relative to non-target tissues. (Sulfamidici
  intestinali)

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Sulfamidici intestinali
Sulfatiazolo
Succinilsulfatiazolo Sulfamidico intestinale
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Ocular absorption

• Pilocarpine is used as a typical miotic agent for
  controlling the elevated intraocular pressure
  associated with glaucoma.
• Its ocular bioavailability is low and its
  duration of action is short.
• This requires frequent dosing (3-6 times a day)
  and leads to transient peaks and valleys in
  pilocarpine concentration in the eye.
• In turn, this results in dose-related ocular
  side-effects, e.g. myopia and miosis.
• Eventually, this leads to a high incidence of
  patient non-compliance, which in turn can
  generate inadequate pressure control and
  deterioration of vision.

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Ocular absorption pilocarpine prodrug

• A useful prodrug of pilocarpine should
• Exhibit a higher lipophilicity than pilocarpine
  in order to enable an efficient corneal membrane
  transport
• Possess adequate solubility and stability for
  formulation as eyedrops
• Be converted to the active within the cornea or
  once the membrane has been passed
• Lead to a controlled release and hence prolonged
  duration of action of pilocarpine.

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Ocular absorption

• Pilocarpic acid esters may be promising prodrug
  candidates with the above mentioned requirements.
• In aqueous solution the esters undergo
  quantitative and apparent specific base-catalyzed
  lactonization to pilocarpine.
• The various esters differ greatly in their rates
  of cyclization. The variation is strongly
  dependent on the polar effects exerted by the
  alcohol portion of the esters.

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Ocular absorption
Pilocarpina
Acidi pilocarpici
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Prodrug di diversi gruppi funzionali

• COOH Esteri, amidi

OH
Esteri carbossilici Esteri carbonati Esteri
fosforici Eteri
Tioesteri Tioeteri
SH
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Macromolecular transport vectors
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Macromolecular transport vectors

• The chemotherapeutic utility of macromolecular
  prodrugs, in which a drug is attached to a
  macromolecule through a bioreversable linkage, to
  provide drug targeting, has been the focus of
  intense research for decades.
• The rational behind this approach is that the
  transport properties of the macromolecular
  prodrug should be dictated predominantly by the
  macromolecular transport vector.
• In the field of cancer, chemotherapy design of
  such compounds have received considerable
  interest, since anticancer agents tend to be
  highly toxic and their effectiveness limited by a
  very small therapeutic ratio.
• Macromolecules endowed with intrinsic target
  receptor affinities (e.g. monoclonal antibodies
  and hormones) have been evaluated.

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Macromolecular transport vectors

• The search for parenteral site-specific soluble
  macromolecular drug carrier systems faces several
  difficulties
• The multitude of physiological barriers the
  macromolecular prodrug encounters on its way from
  the administration site to the ultimate target of
  the drug entity.
• The task of accomplishing the correct timing,
  e.g. selective regeneration and suitable
  maintenance of the active agent at the target
  site.
• Potential immunogenicity and loss of the
  intrinsic receptor affinity upon covalent linkage
  of the cytotoxic agent.

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Commento sui prodrugs
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Prodrug design in an industrial setting

• Traditionally, lead selection has been based
  almost exclusively on target activities with
  little attention to the physicochemical and
  pharmacokinetic behaviour of the potential leads.
• In recent years, preliminary data related to the
  latter two areas have been included in the
  selection criteria.

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Prodrug approach

• Prodrug design comprises an area of drug research
  devoted to optimization of drug delivery.

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Application of the prodrug approach

• Attempts to identify suitable derivatives to
  improve drug therapy, when the physicochemical
  characteristics of a very interesting lead
  constitute an impediment to its further
  development.
• Improved competitiveness of the drug in the
  marketplace, accomplished by the optimization of
  parameters like bioavailabilty or pharmacokinetic
  profile.
• Development of two or more dosage forms of the
  drug candidate.
• Strategies in the area of patent life.

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Regulatory authorities

• The regulatory authorities consider a prodrug of
  a lead as a new chemical entity (NCE).
• Thus, already performed studies on the parent
  compounds have to be done also on the prodrug.
• Prodrug design should therefore constitute an
  integral part of the drug design process.

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In conclusione
Drug
Prodrug moiety
Modification of physico-chemical properties