Gina Song

Interpatient pharmacokinetic and pharmacodynamic variability of carrier-mediated anticancer agents

Major advances in the field of carrier‐mediated agents (CMAs) have revolutionized drug delivery capabilities over the past decade. While providing numerous advantages over their small‐molecule counterparts (solubility, duration of exposure, and delivery to the site of action are higher), these agents display substantial variability in systemic clearance (CL) and distribution, tumor delivery, and pharmacologic effects. This review provides an overview of factors that affect the pharmacokinetics (PK) and pharmacodynamics (PD) of CMAs in preclinical models and patients.

Factors affecting the pharmacokinetics and pharmacodynamics of liposomal drugs

Various attempts to increase the therapeutic index of the drug while minimizing side effects have been made in drug delivery systems. Among several promising strategies, liposomes represent an advanced technology to target active molecules to the site of action. Rapid clearance of circulating liposomal drugs administered intravenously has been a critical issue because circulation time in the blood affects drug exposure at the target site. The clinical use of liposomal drugs is complicated by large intra- and interindividual variability in their pharmacokinetics (PK) and pharmacodynamics (PD). Thus, it is important to understand the factors affecting the PK/PD of the liposomal formulation of drugs and to elucidate the mechanisms underlying the variability in the PK/PD of liposomal drugs. In this review article, we describe the characteristics of liposome formulations and discuss the effects of various factors, including liposome-associated factors, host-associated factors, and treatment on the PK/PD of liposomal agents.

Effects of tumor microenvironment heterogeneity on nanoparticle disposition and efficacy in breast cancer tumor models.

Purpose: Tumor cells are surrounded by a complex microenvironment. The purpose of our study was to evaluate the role of heterogeneity of the tumor microenvironment in the variability of nanoparticle (NP) delivery and efficacy. Experimental Designs: C3(1)-T-Antigen genetically engineered mouse model (C3-TAg) and T11/TP53Null orthotopic syngeneic murine transplant model (T11) representing human breast tumor subtypes basal-like and claudin-low, respectively, were evaluated. For the pharmacokinetic studies, non-liposomal doxorubicin (NL-doxo) or polyethylene glycol tagged (PEGylated) liposomal doxorubicin (PLD) was administered at 6 mg/kg i.v. x1. Area under the concentration versus time curve (AUC) of doxorubicin was calculated. Macrophages, collagen, and the amount of vasculature were assessed by IHC. Chemokines and cytokines were measured by multiplex immunochemistry. NL-doxo or PLD was administered at 6 mg/kg i.v. weekly x6 in efficacy studies. Analyses of intermediary tumor response and overall survival were performed. Results: Plasma AUC of NL-doxo and PLD encapsulated and released doxorubicin was similar between two models. However, tumor sum total AUC of PLD was 2-fold greater in C3-TAg compared with T11 (P < 0.05). T11 tumors showed significantly higher expression of CC chemokine ligand (CCL) 2 and VEGF-a, greater vascular quantity, and decreased expression of VEGF-c compared with C3-TAg (P < 0.05). PLD was more efficacious compared with NL-doxo in both models. Conclusion: The tumor microenvironment and/or tumor cell features of breast cancer affected NP tumor delivery and efficacy, but not the small-molecule drug. Our findings reveal the role of the tumor microenvironment in variability of NP delivery and therapeutic outcomes. Clin Cancer Res; 20(23); 6083–95. ©2014 AACR.

Nanoparticles and the Mononuclear Phagocyte System: Pharmacokinetics and Applications for Inflammatory Diseases

Nanoparticles (NPs) provide several advantages over the small molecule drugs including prolonged circulation time and enhanced delivery to targeted sites. Once a NP enters the body, it interacts with hosts immune system and is engulfed by cells of the mononuclear phagocyte system (MPS). The interaction between NPs and the immune cells can result in immunosuppression or immunostimulation, which may enhance or reduce the treatment effects of NPs. Therefore, it is critical to understand the interactions between NPs and the immune system in order to optimize the treatment benefit and minimize the undesirable toxicities of NPs. This review elaborates on the interaction between NP and the MPS and its impacts on the pharmacokinetics (PK) and pharmacodynamics (PD) of NPs and applications for inflammatory diseases. This review also encompasses an overview of NPs being developed for treatment of inflammatory diseases.

The effects of nanoparticle drug loading on the pharmacokinetics of anticancer agents

Major advances in carrier-mediated agents, which include nanoparticles, nanosomes and conjugates, have revolutionized drug delivery capabilities over the past decade. While providing numerous advantages, such as greater solubility, duration of exposure and delivery to the site of action over their small-molecule counterparts, there is substantial variability in systemic clearance and distribution, tumor delivery and pharmacologic effects (efficacy and toxicity) of these agents. This review provides an overview of factors that affect the pharmacokinetics and pharmacodynamics of carrier-mediated agents in preclinical models and patients.

Roles of chemokines CCL2 and CCL5 in the pharmacokinetics of PEGylated liposomal doxorubicin in vivo and in patients with recurrent epithelial ovarian cancer.

UNLABELLED Nanoparticles (NPs) are cleared by monocytes and macrophages. Chemokines CCL2 and CCL5 are key mediators for recruitment of these immune cells into tumors and tissues. The purpose of this study was to investigate effects of CCL2 and CCL5 on the pharmacokinetics (PKs) of NPs. Mice deficient in CCL2 or CCL5 demonstrated altered clearance and tissue distribution of polyethylene glycol tagged liposomal doxorubicin (PLD) compared to control mice. The PK studies using mice bearing SKOV3 ovarian cancer xenografts revealed that the presence of tumor cells and higher expression of chemokines were significantly associated with greater clearance of PLD compared to non-tumor bearing mice. Plasma exposure of encapsulated liposomal doxorubicin positively correlated with the total exposure of plasma CCL2 and CCL5 in patients with recurrent epithelial ovarian cancer treated with PLD. These data emphasize that the interplay between PLD and chemokines may have an important role in optimizing PLD therapy. FROM THE CLINICAL EDITOR The use of nanoparticles as drug delivery carriers is gaining widespread acceptance in the clinical setting. However, the underlying pharmacokinetics of these novel drugs has not really been elucidated. In this interesting article, the authors carried out experiments using mice deficient in CCL2 or CCL5 to study the clearance of liposomal system. They showed the important role the immune system played and would enable better designs of future drug delivery systems.

Gulp1 is associated with the pharmacokinetics of PEGylated liposomal doxorubicin (PLD) in inbred mouse strains

Nanoparticles (NP) including liposomes are cleared by phagocytes of the mononuclear phagocyte system. High inter-patient variability in pharmacokinetics of PEGylated liposomal doxorubicin (PLD) has been reported. We hypothesized that genetic factors may be associated with the variable disposition of PLD. We evaluated plasma and tissue disposition of doxorubicin after administration of PLD at 6mg/kg IV ×1 via tail vein in 23 different male inbred mouse strains. An approximately 13-fold difference in plasma clearance of PLD was observed among inbred strains. We identified a correlation between strain-specific differences in PLD clearance and genetic variation within a genomic region encoding GULP1 (PTB domain containing engulfment adapter 1) protein using haplotype associated mapping and the efficient mixed-model association algorithms. Our results also show that Gulp1 expression in adipose tissue was associated with PLD disposition in plasma. Our findings suggest that genetic variants may be associated with inter-individual pharmacokinetic differences in NP clearance.

Profiling the relationship between tumor-associated macrophages and pharmacokinetics of liposomal agents in preclinical murine models

The mononuclear phagocyte system (MPS) has previously been shown to significantly affect the clearance, tumor delivery, and efficacy of nanoparticles (NPs). This study profiled MPS cell infiltration in murine preclinical tumor models and evaluated how these differences may affect tumor disposition of PEGylated liposomal doxorubicin (PLD) in models sensitive and resistant to PLD. Significant differences in MPS presence existed between tumor types (e.g. ovarian versus endometrial), cell lines within the same tumor type, and location of tumor implantation (i.e. flank versus orthotopic xenografts). Further, the differences in MPS presence of SKOV-3 ovarian and HEC1A endometrial orthotopic cancer models may account for the 2.6-fold greater PLD tumor exposure in SKOV-3, despite similar plasma, liver and spleen exposures. These findings suggest that profiling the presence of MPS cells within and between tumor types is important in tumor model selection and in tumor types and patients likely to respond to NP treatment.

Abstract 754: The effect of CC chemokine ligand-2 (CCL2/MCP-1) and CC chemokine ligand-5 (CCL5/RANTES) on the pharmacokinetics (PK) and the pharmacodynamics (PD) of pegylated liposomal CKD602 (S-CKD602) in patients with advanced solid tumors

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Introduction: S-CKD602, pegylated liposomal formulation of CKD-602, a camptothecin analog, is cleared by the mononuclear phagocyte system (MPS). A phase I study of S-CKD602 reported high interpatient variability in the PK of encapsulated and released CKD-602. In addition, there was a bi-directional interaction between S-CKD602 and monocytes (MO), primary cells of MPS. The exact mechanisms underlying these interactions are unknown. Chemokine ligands play essential roles in migration and activation of MO. These factors may have important effects on nanoparticle PK and PD but have not been evaluated. Thus, we assessed the relationship of chemokines on the PK and PD of S-CKD602 in patients with refractory solid tumor. Methods: S-CKD602 was given IV over 1 h q 3 weeks. The doses ranged from 0.10 to 2.5 mg/m2. PK studies of encapsulated and released CKD-602 in plasma were performed on cycle 1. Blood was collected prior to dose, at the end of the infusion, and from 3 h to 336 h post infusion. The % decrease in MO at their nadir was calculated. The concentrations of CCL2, CCL3, CCL4, and CCL5 in plasma at baseline, 48 h and 96 h post infusion were determined using the Bio-Plex system and analyzed using Bio-Plex software. Quartile distribution was assessed and used for Spearmans correlation coefficient to determine the association between chemokine baseline level and area under the concentration versus time curve (AUC) of chemokines with S-CKD602 PK and PD. The Kruskal-Wallis test was used for comparison among chemokines and cancer types. Results: The CCL5 baseline concentration [CCL5: 10,457 ± 11,549; CCL2: 182.44 ± 104.70; CCL3: 53.00 ± 19.60; CCL4: 42.88 ± 18.64 pg/ml (P<0.0001)] and the CCL5 AUC [CCL5: 770,880 ± 516,880; CCL2: 19,195 ± 9,407; CCL3: 5,388 ± 2,454; CCL4: 3,804 ± 1,476 pg/ml·h (P<0.0001)] were elevated in patients compared with other chemokines. The CCL5 baseline and the CCL5 AUC were elevated in patients with sarcoma [24,267 ± 15,108 pg/ml (P=0.0097)] and colon cancer [1,227,720 ± 486,142 pg/ml·h (P=0.0082)], respectively, compared to other types of solid tumors. The CCL5 AUC was shown to be inversely correlated with the CCL2 AUC (P=0.028). The encapsulated CKD-602 AUC was correlated with the CCL5 baseline level (P=0.0121), the CCL2 AUC (P=0.0324), the CCL4 AUC (P<0.0001), and the CCL5 AUC (P=0.0012). The % decrease in MO was correlated with released CKD-602 AUC (P=0.0004) and clearance of encapsulated CKD-602 (P=0.0223). Conclusions: This is the first report that CCL2 and CCL5 are associated with the PK and PD of a pegylated liposomal drug. These results suggest that chemokine production may have a significant impact on the PK and PD of pegylated liposomal formulation of anticancer agents. In addition, the type of solid tumor may influence the interaction. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 754. doi:1538-7445.AM2012-754

Abstract 2673: Relationship between serum hormone levels and pharmacokinetics (PK) of PEGylated liposomal doxorubicin (PLD) in patients with refractory ovarian cancer

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Background: Pharmacokinetics (PK) of nanoparticle agents, such as PEGylated liposomes, are dependent upon the carrier and not the encapsulated drug. Previous studies have demonstrated a high degree of interpatient variability in the PK of PEGylated liposomal doxorubicin (PLD). We have previously demonstrated that circulating monocytes play a major role in clearance (CL) of PEGylated liposomes in patients. Estrogen and testosterone, which are largely secreted via the gonads, have been shown to modulate monocyte function and chemotaxis. In addition, estrone is converted from other steroid hormones in adipose tissue. Thus, we evaluated the relationship between serum hormone concentrations in blood samples and PK of PLD in patients with refractory ovarian cancer. Methods: PLD was administered at 30 or 40mg/m2 IV every 28 days with or without concurrent carboplatin at an AUC = 5 in patients (n = 10) with recurrent ovarian cancer. All patients had undergone bilateral salpingo-oophorectomy (BSO). Serial PK samples were obtained from time 0 h to 168 h and day 28 post PLD dose. Plasma was processed to measure encapsulated and released doxorubicin using solid phase separation and HPLC with fluorescence detection. CL of encapsulated doxorubicin in plasma was calculated by non-compartmental methods. Prior to administration of PLD, serum samples were collected and concentrations of estrone, estrogen, testosterone, and dihydrotestosterone were measured. Results: There was a direct linear relationship between encapsulated doxorubicin CL and both testosterone (R2 = 0.72) and estrone concentrations (R2 = 0.54) in all patients. When patients were subdivided based on PLD monotherapy (n = 6) or PLD + carboplatin (n = 4), there was a stronger relationship between encapsulated doxorubicin CL and both testosterone (R2 = 0.88) and estrone concentrations (R2 = 0.86) in patients receiving PLD monotherapy. Estrogen and dihydrotestosterone concentrations were below quantification limits for the majority of patients and thus were not evaluated. There was no relationship between patient body weight and BMI and estrone concentrations (R2 = 0.25 and R2 = 0.13 respectively). Conclusions: These findings indicate that serum hormone concentrations are associated with encapsulated doxorubicin CL and thus may be useful for individualizing PLD therapy in patients with ovarian cancer and other malignancies. Patient body weight and BMI were not associated with estrone concentrations in patients with ovarian cancer, suggesting phenotypic and/or genotypic differences in estrone production in adipose tissue. Low estrogen concentrations are consistent with the patients undergoing BSO surgery as standard treatment of ovarian cancer. The relationship between hormone levels and PK of nanoparticles needs to be further evaluated as a method to individualize nanoparticle therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2673. doi:1538-7445.AM2012-2673