TAKE HOME MESSAGES FORM THE ITC WHITE PAPERS part 7
One area of much debate is the likelihood of transporter mediated DDIs at the human BBB (Blood-brain barrier). Kalvass et al. summarize the ITC’s position on this matter, which can be simply summarized as: it’s unlikely, at least with currently marketed drugs. Despite preclinical examples of drastically enhanced BBB penetration of drugs in the presence of efflux transporter inhibitors or gene knockout animals, the central argument for the authors’ conclusion comes from calculations based on the fraction excreted (fe). Using fe the authors demonstrate that only in cases of near complete inhibition (I/Ki = ∞) of the transporters involved in efflux at the BBB is the fold increase in CNS exposure for a drug significant.
In order to achieve marked increases in BBB penetration (> 4-fold) systemic concentrations of the unbound perpetrator drug would need to be substantially greater than its Ki for P-gp and/or BCRP. The authors go on to mention that other side effects generally preclude the ability to dose current inhibitors at high enough concentrations in humans to achieve significant inhibition. Since the exposure of marketed drugs at the BBB is well below this threshold, the authors postulate the maximum inhibition that is likely to be achieved under clinical conditions to be around 50%, which would result in only a 2-fold increase in brain exposure. Although this is generally well within the safety margins of most marketed drugs, it could be significant for drugs with a very low therapeutic index and thus cannot be completely ignored.
The authors also review a number of in vitro and in vivo methods to assess transporter interactions at the BBB and address advantages and limitations of the various approaches, in vitro models, in vivo analysis, knockout animals, PET imaging. The authors also point out that while CSF concentrations are generally representative of brain interstitial drug concentrations for highly passive compounds, the use of CSF concentrations as a surrogate of unbound brain exposure is not recommended for typical transporter substrates or compounds with poor passive permeability.
Kalvass, J.C., et al., Why Clinical Modulation of Efflux Transport at the Human Blood-Brain Barrier Is Unlikely: The ITC Evidence-Based Position. Clin Pharmacol Ther, 2013. 94(1): p. 80-94.