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).