Model-Based Cellular Kinetic Analysis of Chimeric Antigen Receptor-T Cells in Humans.

Chimeric antigen receptor (CAR)-T cell therapy has achieved considerable success in treating B-cell hematologic malignancies. However, the challenges of extending CAR-T therapy to other tumor types, particularly solid tumors, remain appreciable. There are substantial variabilities in CAR-T cellular kinetics across CAR-designs, CAR-T products, dosing regimens, patient responses, disease types, tumor burdens, and lymphodepletion conditions. As a "living drug," CAR-T cellular kinetics typically exhibit four distinct phases: distribution, expansion, contraction, and persistence. The cellular kinetics of CAR-T may correlate with patient responses, but which factors determine CAR-T cellular kinetics remain poorly defined. Herein, we developed a cellular kinetic model to retrospectively characterize CAR-T kinetics in 217 patients from 7 trials and compared CAR-T kinetics across response status, patient populations, and tumor types. Based on our analysis results, CAR-T cells exhibited a significantly higher cell proliferation rate and capacity but a lower contraction rate in patients who responded to treatment. CAR-T cells proliferate to a higher degree in hematologic malignancies than in solid tumors. Within the assessed dose ranges (107 -109 cells), CAR-T doses were weakly correlated with CAR-T cellular kinetics and patient response status. In conclusion, the developed CAR-T cellular kinetic model adequately characterized the multiphasic CAR-T cellular kinetics and supported systematic evaluations of the potential influencing factors, which can have significant implications for the development of more effective CAR-T therapies.

Modeling Corticosteroid Pharmacokinetics and Pharmacodynamics, Part II: Sex Differences in Methylprednisolone Pharmacokinetics and Corticosterone Suppression.

Methylprednisolone (MPL), a corticosteroid of intermediate potency, remains an important immunomodulatory agent for autoimmune diseases. Although sex differences in corticosteroid pharmacokinetics/pharmacodynamics (PK/PD) have been documented in humans, comprehensive preclinical assessments of such differences have not been conducted. Limited in vitro evidence indicates possible sex differences in corticosteroid PK and PD. Therefore, it is hypothesized that comparative PK/PD assessments of MPL disposition and selected PD actions in both sexes will provide insights into factors controlling sex differences in steroid responses. This report focused on the plasma and tissue pharmacokinetics of MPL and its adrenal suppressive effects. Because time-dependent (estrous) regulation of sex hormones in females can influence drug responses, female rats were studied in the proestrus (high estradiol/progesterone) and estrus (low estradiol/progesterone) phases of the reproductive cycle. Cohorts of male and female rats were given a 50 mg/kg bolus dose of MPL intramuscularly. Plasma and liver concentrations of MPL as well as plasma corticosterone concentrations were assayed using high-performance liquid chromatography. An enhanced minimal physiologically-based PK/PD model was developed to characterize MPL kinetics and corticosterone dynamics. The clearance of MPL was ∼3-fold higher in males compared with females, regardless of estrous phase, likely attributable to sex-specific hepatic metabolism in males. Strong inhibitory effects on adrenal suppression were observed in all animals. These temporal steroid profiles in plasma and tissues will be used to drive receptor/gene-mediated PD effects of MPL in both sexes, as described in a companion article (Part III). SIGNIFICANCE STATEMENT: Sex is a relevant factor influencing the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs. Few preclinical PK/PD studies, however, include sex as a variable. Sex differences in the PK and adrenal suppressive effects of the synthetic corticosteroid, methylprednisolone, were assessed in male and female rats as a function of the 4-day rodent reproductive cycle. Drug exposure was 3-fold higher in females, regardless of estrous stage, compared with males. An extended minimal physiologically-based PK/PD model utilizing in vitro and in vivo measurements was developed and applied. These studies provide a framework to account for sex-dependent variability in drug and endogenous agonist (corticosterone) exposures, serving as a prelude to more intricate assessments of sex-related variability in receptor/gene-mediated PD corticosteroid actions.

Modeling Corticosteroid Pharmacokinetics and Pharmacodynamics, Part III: Estrous Cycle and Estrogen Receptor-Dependent Antagonism of Glucocorticoid-Induced Leucine Zipper (GILZ) Enhancement by Corticosteroids.

Our previous report examined the pharmacokinetics (PK) of methylprednisolone (MPL) and adrenal suppression after a 50 mg/kg IM bolus in male and female rats, and we described in detail the development of a minimal physiologically based pharmacokinetic/pharmacodynamic (mPBPK/PD) model. In continuation of such assessments, we investigated sex differences in genomic MPL responses (PD). Message expression of the glucocorticoid-induced leucine zipper (GILZ) was chosen as a multitissue biomarker of glucocorticoid receptor (GR)-mediated drug response. Potential time-dependent interplay between sex hormone and glucocorticoid signaling in vivo was assessed by comparing the enhancement of GILZ by MPL in the uterus [high estrogen receptor (ER) density] and in liver (lower ER density) from male and female rats dosed within the proestrus (high estradiol/progesterone) and estrus (low estradiol/progesterone) phases of the rodent estrous cycle. An expanded-systems PD model of MPL considering circadian rhythms, multireceptor (ER and GR) control, and estrous variations delineated the determinants controlling receptor/gene-mediated steroid responses. Hepatic GILZ response was ∼3-fold greater in females, regardless of estrous stage, compared with males, driven predominantly by increased MPL exposure in females and a negligible influence of estrogen interaction. In contrast, GILZ response in the uterus during proestrus in females was 60% of that observed in estrus-phased females, despite no PK or receptor differences, providing in vivo support to the hypothesis of estrogen-mediated antagonism of glucocorticoid signaling. The developed model offers a mechanistic platform to assess the determinants of sex and tissue specificity in corticosteroid actions and, in turn, reveals a unique PD drug-hormone interaction occurring in vivo. SIGNIFICANCE STATEMENT: Mechanisms relating to sex-based pharmacodynamic variability in genomic responses to corticosteroids have been unclear. Using combined experimental and systems pharmacology modeling approaches, sex differences in both pharmacokinetic and pharmacodynamic mechanisms controlling the enhancement of a sensitive corticosteroid-regulated biomarker, the glucocorticoid-induced leucine zipper (GILZ), were clarified in vivo. The multiscale minimal physiologically based pharmacokinetics/pharmacodynamic model successfully captured the experimental observations and quantitatively discerned the roles of the rodent estrous cycle (hormonal variation) and tissue specificity in mediating the antagonistic coregulation of GILZ gene synthesis. These findings collectively support the hypothesis that estrogens antagonize pharmacodynamic signaling of genomic corticosteroid actions in vivo in a time- and estrogen receptor-dependent manner.