In vivo imaging in drug development

Investigarea tintelor farmacologice:

Validarea unei tinte farmacologice la om presupune interogarea relatiei de cauzalitate dintre
tabloul clinic al bolii si functia, respectiv activitatea tintei. Una dintre modalitate de a investiga
aceasta relatie este de a marca farmaceuticul cu un radioizotop emitator de pozitroni. Daca, de
exemplu, farmaceuticul marcat demonstreaza afinitate pentru tinta fiziopatologica aleasa dar
tabloul clinic nu se amelioreaza semnificativ, atunci ipoteza clinica este infirmata si resursele pot
fi realocate in alte proiecte. Astfel, imagistica joaca un rol atat economic, cat si de accelerare a
etapelor din procesul de dezvoltare farmaceutica.
Target confidence:
Target validation in man means establishing that target activity is causally related to the
symptoms of the disease under investigation. One approach is to label the drug candidate with a
positron-emitting radioisotope to assess target engagement. If, for example, the drug candidate
can be shown to engage the target but the symptoms of the disease are not changed in a
meaningful way, then the clinical hypothesis has been de-validated and resources can be
deployed in other drug projects. In conclusion, imaging is a useful tool to build target confidence
with the potential to reduce late phase attrition due to lack of efficacy.

Validarea modelelor preclinice si analiza farmacocinetica:

Tehnicile de imagistica anatomica, functionala si moleculara sunt ubicuitare in caracterizarea
modelelor preclinice si analiza modificarilor induse de administrarea farmaceuticelor investigate.
De exemplu, in studiile ADME, distributia (D) farmaceuticului poate fi evaluata prin marcarea
moleculei cu un emitator iar postinjectie se poate urmari comportamentul in timp a
farmaceuticului prin compartimentele organismului model.
Preclinical model validation and pharmacokinetics:
Anatomical, functional and molecular imaging techniques can all play roles in aiding preclinical
model characterization and the changes that ensue following drug administration. Imaging may
also be employed to evaluate drug distribution, with drug molecules labelled with a detectable
probe and distribution monitored throughout time postinjection.
Studii de toxicologie preclinica: Producatorii de farmaceutice au obligatia de a demonstra
eficienta farmacologica si fereastra terapeutica a fiecarui farmaceutic in vederea initiereii
studiilor clinice. Desi imagistica in vivo este pervasiva in studiile de confirmare a eficientei
farmaceuticelor, atat preclinice cat si clinice, in toxicologia preclinica nu este inca pe larg
utilizata. Posibilitatea de a urmari acelasi model animal in evolutie prin achizitii periodice de
imagini poate aduce contributii in studiile de toxicitate cronica, cat si translarea mai facila de la
animal la om prin utilizarea acelorasi markeri surogat.
Preclinical toxicology studies:
Drug developers need to show that drugs are both efficacious and have acceptable toxicity: while
in vivo imaging has been used extensively in both preclinical and clinical efficacy studies, it has
not as yet seen wide-spread use in preclinical toxicology. The ability to image the same animal at
multiple timepoints suggests that imaging is likely to make its greatest contribution in chronic
investigational safety studies. There are also clear advantages such as bridging the gap between
animals and humans by using the same non-invasive endpoints.

Biomarkerii imagistici in studiile clinice: Biomarkerii imagistici sunt pe larg adoptati in

procesul de dezvoltare de noi farmaceutice in multe subdomenii ale patologiei umane, mai ales
in inflamatie, degenerare, ischemie si oncologie. Incorporarea biomarkerilor imagistici in studiile
de faza 1 si 2 la om este conditionata de validarea combinatiei de farmaceutic/biomarkeri
imagistici pe model animal, cu consecinte atat in proiectarea studiilor clinice, cat si in
interpretarea rezultatelor acestora. Exemple in care biomarkeri imagistici au fost translati de la
model animal la om se regasesc in oncologie (FDG-PET, FLT-PET, DCE MRI, ADC MRI),
psihiatrie (IRM functional, farmacoIRM), boala cerebrovasculara si cardiopatie ischemica (ADC
MRI), ateroscleroza (CT, IRM, cuantificari PET a compozitiei, inflamatiei si dimensiunii
placilor de aterom), patologia respiratorie (CT, IRM).
Designing clinical trials with imaging biomarkers:
Imaging biomarkers are used in drug development in many diseases, in particular in
inflammation, degeneration, ischaemia and neoplasia. Use of imaging biomarkers in phase 1 and
phase 2 drug development involves human clinical studies. Before such an imaging biomarker is
used with investigational agents (particularly with first-in-class drugs against targets not
previously addressed in man), animal studies using the same imaging biomarker/drug
combination are often critical, both in the design of the clinical trial, and in interpreting its
outcome. Examples in which imaging biomarkers have been translated between animal and man
include cancer (FDG-PET, FLT-PET, DCE MRI, ADC MRI), psychiatry (functional MRI,
pharmacoMRI), myocardial or cerebrovascular ischaemia (ADC MRI, perfusion), atheroma
(ultrasound, CT, MRI and PET measurements of plaque size, composition and inflammation),
respiratory diseases (CT and MRI).