Free ibuprofen, flurbiprofen, and indomethacin rapidly cross the BBB, with ibuprofen exhibiting a saturable component of transport. Plasma protein binding limits brain NSAID uptake by reducing the free fraction of NSAID in the circulation.
Many studies have reported greater drug uptake into brain than that predicted based upon existing models using the free fraction (f u ) of drug in arterial serum. To explain this difference, circulating plasma proteins have been suggested to interact with capillary membrane in vivo to produce a conformational change that favors net drug dissociation and elevation of f u . Albumin, the principal binding protein in plasma, has two main drug binding sites, Sudlow I and II. We tested this hypothesis using drugs that bind selectively to either site I (warfarin) or site II (ibuprofen), as well as mixed ligands that have affinity for both sites (tolbutamide and valproate). Brain uptake was determined in the presence and absence of albumin using the in situ rat brain perfusion technique. Unidirectional brain uptake transfer constants (K in ) were measured and compared with those predicted using the modified Kety-Crone-Renkin model:Ϫfu ϫ PSu/F ), where F is perfusion flow and PS u is the permeability-surface area product to free drug of brain capillaries. The results demonstrated good agreement between measured and predicted K in over a 100-fold range in perfusion fluid albumin concentration using albumin from three different species (i.e., human, bovine, and rat), as well as whole-rat serum. K in decreased in the presence of albumin in direct proportion to perfusion fluid f u with constant PS u . The results show that brain uptake of selected Sudlow site I and II ligands matches that predicted by the modified Kety-Crone-Renkin model with no evidence for enhanced dissociation.
This publication summarizes the proceedings of day 3 of a 3-day workshop on "Dissolution and Translational Modeling Strategies Enabling Patient-Centric Product Development." Specifically, this publication discusses the current approaches in building clinical relevance into drug product development for solid oral dosage forms, along with challenges that both industry and regulatory agencies are facing in setting clinically relevant drug product specifications (CRDPS) as presented at the workshop. The concept of clinical relevance is a multidisciplinary effort which implies an understanding of the relationship between the critical quality attributes (CQAs) and their impact on predetermined clinical outcomes. Developing this level of understanding, in many cases, requires introducing deliberate but meaningful variations into the critical material attributes (CMAs) and critical process parameters (CPPs) to establish a relationship between the resulting in vitro dissolution/release profiles and in vivo PK performance, a surrogate for clinical outcomes. Alternatively, with the intention of improving the efficiency of the drug product development process by limiting the burden of conducting in vivo studies, this understanding can be either built, or at least enhanced, through in silico efforts, such as IVIVC and physiologically based pharmacokinetic (PBPK) absorption modeling and simulation (M&S). These approaches enable dissolution testing to establish safe boundaries and reject drug product batches falling outside of the established safe range (e.g., due to inadequate in vivo performance) enabling the method to become clinically relevant. Ultimately, these efforts contribute towards patient-centric drug product development and allow regulatory flexibility throughout the lifecycle of the drug product.
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