Quantitative and Mechanistic Understanding of AZD1775 Penetration across Human Blood–Brain Barrier in Glioblastoma Patients Using an IVIVE–PBPK Modeling Approach

Abstract

Purpose AZD1775, a first-in-class, small-molecule inhibitor of the Wee1 tyrosine kinase, is under evaluation as a potential chemo- and radiosensitizer for treating glioblastoma. This study was to prospectively, quantitatively, and mechanistically investigate the penetration of AZD1775 across the human blood–brain barrier (BBB). Experimental Design AZD1775 plasma and tumor pharmacokinetics were evaluated in 20 patients with glioblastoma. The drug metabolism, transcellular passive permeability, and interactions with efflux and uptake transporters were determined using human derived in vitro systems. A whole-body physiologically based pharmacokinetic (PBPK) model integrated with a four-compartment permeability-limited brain model was developed for predicting the kinetics of AZD1775 BBB penetration and assessing the factors modulating this process. Results AZD1775 exhibited good tumor penetration in patients with glioblastoma, with the unbound tumor-to-plasma concentration ratio ranging from 1.3 to 24.4 (median, 3.2). It was a substrate for ABCB1, ABCG2, and OATP1A2, but not for OATP2B1 or OAT3. AZD1775 transcellular passive permeability and active efflux clearance across MDCKII–ABCB1 or MDCKII–ABCG2 cell monolayers were dependent on the basolateral pH. The PBPK model well predicted observed drug plasma and tumor concentrations in patients. The extent and rate of drug BBB penetration were influenced by BBB integrity, efflux and uptake active transporter activity, and drug binding to brain tissue. Conclusions In the relatively acidic tumor microenvironment where ABCB1/ABCG2 transporter-mediated efflux clearance is reduced, OATP1A2-mediated active uptake becomes dominant, driving AZD1775 penetration into brain tumor. Variations in the brain tumor regional pH, transporter expression/activity, and BBB integrity collectively contribute to the heterogeneity of AZD1775 penetration into brain tumors.

Jumping the Barrier: Modeling Drug Penetration across the Blood–Brain Barrier

“…The model depicts reversible drug movement from (1) blood to heterogeneous (healthy and tumor) brain, (2) blood to cranial CSF, (3) brain to cranial CSF, (4) cranial CSF to spinal CSF, and then both CSF compartments back to blood. Abbreviations: PBPK, physiologically-based pharmacokinetics; BBB, blood-brain barrier; BTB, blood-tumor barrier; CSF, cerebrospinal fluid; CL, clearance; Q, flow rate.…”

“…The use of PBPK modeling provides gravitas to simulation results based on inclusion of a plethora of additional data, such as relevant drug metabolizing enzymes and transporters for that drug, as well as relevant pharmacogenetics differences. In this study by Li et al (1), their whole-body PBPK model with mechanistic 4 compartment brain disposition was able to successfully capture the measured observed clinical data. The fact that such high concentrations of AZD1775 were measured clinically from the resected brain tumor samples supports evidence that the BTB is altered, likely due to pH where active ABCB1 and ABCG2 efflux clearance is reduced, and with passive transcellular transport and OATP1A2-mediated active uptake unaffected, an overall net influx allows more drug to penetrate into the brain tumor.…”

“…In this issue of Clinical Cancer Research , Li and colleagues (1) report on the use of an integrated quantitative, clinical pharmacology approach incorporating clinical trial data and in vitro-in vivo extrapolation (IVIVE) coupled with physiologically-based pharmacokinetic (PBPK) modeling to assess the penetration of AZD1775 across human blood-brain barrier (BBB) in glioblastoma patients.…”

“…In an effort to improve the predictive abilities of identifying anticancer agents that will sufficiently penetrate into brain upon systemic administration, specifically brain tumor tissue, Li et al (1) developed a whole-body PBPK model that utilized not only observed clinical plasma and brain tissue PK data, but also the drug’s physicochemical properties (lipophilicity, pKa, etc), protein and tissue binding, and metabolism and transport data obtained in vitro . This model can also account for a healthy brain tissue microenvironment pH range of 7.0 – 7.8, compared with the more acidic brain tumor microenvironment (pH range 5.8 – 7.2) (3–5).…”

“…Using this clinical data, along with in vitro metabolism and transporter data, a whole-body PBPK model was developed. AZD1775 was rapidly absorbed (no lag time), widely distributed (Vd ss =19.2 L/kg), and shown to be cleared through numerous means, including renal (6 L/hr), hepatic (total human liver microsome activity 197 pmol/min/mg; Km=4.94uM), and an intestinal intrinsic clearance of 17 uL/min (1). …”