Full efficacy with no CNS side-effects: unachievable panacea or reality? DMPK considerations in design of drugs with limited brain penetration

Abstract

Optimising drug properties can be an important strategy to limit penetration into the CNS and offers advantages in reducing the risk of undesirable neurological effects When considering the design of these drugs it is important to consider the relative influx and efflux rates at the relevant biological membranes The highest degree of restriction at the brain is probably achievable by utilising active transport to exclude compounds from the brain Affinity for the efflux transporters Pgp and BCRP has been achieved in two in-house chemistry programmes by increasing polar surface area, which resulted in highly orally bioavailable low CNS penetrant compounds in preclinical species.

Insights From an Integrated Physiologically Based Pharmacokinetic Model for Brain Penetration

“…The PBPK model can describe rate and extent of distribution for passively restricted and actively effluxed compounds. As can be seen in Figure 6a, the maximum brain concentration can be blunted by reducing flux (e.g., lowering passive permeability 31 ). Because central toxicity is often driven by the maximum concentration, 4,31 such a strategy may prove useful in peripheral programs attempting to limit central effects.…”

“…As can be seen in Figure 6a, the maximum brain concentration can be blunted by reducing flux (e.g., lowering passive permeability 31 ). Because central toxicity is often driven by the maximum concentration, 4,31 such a strategy may prove useful in peripheral programs attempting to limit central effects. In neuroscience, molecules typically have high brain permeability; the PBPK model, therefore, can be reduced mathematically to capture mechanistic scaling between species.…”

Why Clinical Modulation of Efflux Transport at the Human Blood–Brain Barrier Is Unlikely: The ITC Evidence-Based Position

“…P‐gp is localized to the apical membrane of the BBB, where it functions as both an active barrier to entry and a CNS clearance mechanism by excreting large‐molecular‐weight, lipophilic, uncharged, or cationic compounds 7 . BBB P‐gp can be such an impediment to brain penetration that contemporary CNS drug discovery efforts routinely try to minimize or eliminate P‐gp transport activity in candidate drugs 8 and, for non‐CNS drug targets, may purposefully maximize efflux activity to keep drugs out of the brain 9 . Due to its broad role in preventing access of drugs to the CNS, concerns have emerged that BBB P‐gp inhibition or saturation will increase the brain distribution of drugs, potentially resulting in adverse effects, and that induction could attenuate CNS exposure, leading to a lack of efficacy 3 , 7 .…”

Elucidation of the Impact of P-glycoprotein and Breast Cancer Resistance Protein on the Brain Distribution of Catechol-O-Methyltransferase Inhibitors

“…Hence, greater knowledge of general drug distribution to the brain will contribute to the adoption of drug design strategies that increase or restrict access through the BBB, thereby minimizing the risk of late-stage failures and enhancing preclinical and clinical success. This may be achieved by combining the optimization of the intrinsic permeability of a compound with avoiding or targeting active efflux at the BBB (Cole et al, 2012;Di et al, 2013).…”