GDC-0810 Pharmacokinetics and Transporter-Mediated Drug Interaction Evaluation with an Endogenous Biomarker in the First-in-Human, Dose Escalation Study

Abstract

GDC-0810 (Cheeti et al., 2018) is an orally bioavailable, selective estrogen receptor (ER) degrader developed to treat ER-positive breast cancer. A first-in-human (FIH) dose escalation phase I study (n 5 41) was conducted to characterize the pharmacokinetics (PK) of GDC-0810 and its two major metabolites. GDC-0810 demonstrated linear PK from 100 to 600 mg given once daily. The mean terminal half-life following a single 600 mg dose was approximately 8 hours. Since GDC-0810 is a potent in vitro inhibitor of organic anion transporting polypeptide (OATP) 1B1/3, the kinetic profile of coproporphyrin I (CPI), a promising endogenous biomarker for OATP1B1/3, was analyzed retrospectively in a subset of the plasma samples collected in the same FIH study. CPI exhibited a GDC-0810 dose-dependent increase, suggesting in vivo inhibition of OATP1B transporters. To quantitatively predict the magnitude of OATP1Bmediated drug-drug interactions (DDIs) with pravastatin (a known OATP1B substrate), the in vivo unbound inhibition constant was first estimated using a one-compartment model, and then incorporated to a physiologically based pharmacokinetic model. The model showed some underestimation of the magnitude of the DDI when compared with a clinical DDI study result, while prediction had a relatively large uncertainty due to the small effect size, limited sample size, and variability in CPI kinetics. In conclusion, this study characterized the pharmacokinetic profiles of GDC-0810 in breast cancer patients and demonstrated the utility of CPI in detecting OATP1B-mediated DDIs of a new molecular entity as early as FIH study. SIGNIFICANCE STATEMENTEndogenous biomarkers of transporters have recently been shown to be promising tools in evaluating the risk of clinical transportermediated DDIs. This is the first study to report a pharmacokinetic interaction between an investigational molecule and a transporter biomarker in a first-in-human study. The observed interaction and model-based analysis and the prediction provide important insights on the novel approach to quantitatively predict transporter-mediated DDIs as early as FIH studies in the clinical development.

Substantially Increased Plasma Coproporphyrin‐I Concentrations Associated With OATP1B1*15 Allele in Japanese General Population

“…[19][20][21] Currently, CP-I is assumed to be the most sensitive and specific biomarker for phenotyping of OATP1B activity compared with the other endogenous biomarkers and probe drugs, such as HMG-CoA reductase inhibitors. 22 In fact, CP-I was used for OATP1B activity phenotyping in clinical drug-drug interaction studies 24,[37][38][39] and in model-based analysis of drug-drug interactions. 23,[40][41][42] Three previous studies reported the relationship between plasma CP-I concentrations and OATP1B1 polymorphism, but the numbers of participants in all studies were insufficient to detect significant differences among the genotypes.…”

PBPK Model of Coproporphyrin I: Evaluation of the Impact of SLCO1B1 Genotype, Ethnicity, and Sex on its Inter‐Individual Variability

“…18,35,36 To that end, modeling and simulation studies have provided information on the adequate sample size to identify weak-to-moderate OATP1B inhibitors 18 and used estimated in vivo Ki based on CPI data to simulate the DDI between rifampicin/new inhibitors and statins. 35,36,40 One of the key advantages of CPI as an endogenous biomarker of OATP1B function in vivo is its relatively stable baseline in contrast to other biomarkers (e.g., fatty or bile acids and their conjugates). 15 Recent clinical studies have provided evidence of the effect of OATP1B1 genetic polymorphism 25,28,31 on CPI plasma concentration.…”

G1T48, an oral selective estrogen receptor degrader, and the CDK4/6 inhibitor lerociclib inhibit tumor growth in animal models of endocrine-resistant breast cancer

“…G1T48 binds ER with low nanomolar affinity, inhibits estrogen-mediated target gene expression and breast cancer cell growth, and importantly blocks the tumor promoting effects of ER in both naïve and endocrine therapy-resistant animal models of breast cancer. Similar to AZD9496 and GDC-0810, G1T48 has [56,59,60]. A hallmark feature of fulvestrant differentiating it from compounds like tamoxifen is that fulvestrant is a true antagonist with no agonist activity regardless of tissue context.…”