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Samenvatting non-cilnical drug development
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Dit is een korte samenvatting over het deel non-cilnical drug development
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Non-clinical DD (Annaert)ADME testing (vroege ontwikkeling)
• Na discovery
• Exploratief
• PK-profiel en algemene veiligheid onderzoeken
• PK = concentratie ifv tijd
➔ PKPD = effect ifv tijd
• PD = effect ifv concentratie
𝐹∗𝑉𝑑 𝑏𝑖𝑜𝑙𝑜𝑔𝑖𝑠𝑐ℎ𝑒 𝑏𝑒𝑠𝑐ℎ𝑖𝑘𝑏𝑎𝑎𝑟ℎ𝑒𝑖𝑑 (𝐵𝐵)∗𝑑𝑖𝑠𝑡𝑟𝑖𝑏𝑢𝑡𝑖𝑒𝑣𝑜𝑙𝑢𝑚𝑒
• 𝐴𝑈𝐶 = 𝐶𝑙
= 𝑘𝑙𝑎𝑟𝑖𝑛𝑔
o F verschilt tussen mensen
o 𝐹 = 𝐹𝑎 ∗ 𝐹𝐺𝐼 ∗ 𝐹ℎ𝑒𝑝
▪ 𝐹𝑎 = geabsorbeerde fractie in portale ader
▪ 𝐹𝐺𝐼 = fractie die metabolisatie vermijdt in darmwand
▪ 𝐹ℎ𝑒𝑝 = fractie die metabolisatie vermijdt in lever (first-pass)
• Dier → mens extrapolatie
o Allometric scaling
o y = a*BWb
▪ y = PK parameter
▪ A = allometrische schalingsparameter
▪ BW = fysiologiche schalingsparameter bv. orgaanbevloeiing of gewicht
▪ b = allometrische exponent
o Houdt geen rekening met ander metabolisme in dier en mens → mechanismen begrijpen
• PBPK-model = physoliology based PK model → in vitro input nodig
• Absorptie
o Caco 2 (cancer colon cellen)
▪ Indicatie voor absorptie door darmwand
▪ Vormen hechte monolaag met transporters en enzymen op semipermeabel
membraan→ Papp meten → voorspelling fa → voorspelling F
▪ Oppervlakte, concentratie en snelheid gekend → Papp → flux
▪ 𝐽 = 𝑃𝑎𝑝𝑝 ∗ 𝐶0
• J = flux = snelheid van GM-diffusie (apicaal (AP) → basolateraal (BL))
• 𝑃𝑎𝑝𝑝 = schijnbare permeabiliteit coëfficiënt
• 𝐶0 = initiële concentratie (afhankelijk van oplosbaarheid en LogP)
• Laag → efflux transporter substraat → lagere F
▪ Voordelen
• High throughput
• Humane cellen
• Eenvoudig
• Gecontroleerde omstandigheden
• Brengen ook transporters (bv. Pgp) tot expressie → beter dan enkel log
P → ook polariteit van transport bekijken (invloed efflux-transporters)
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