Beth A. Zamboni

Factors affecting the pharmacokinetics of pegylated liposomal doxorubicin in patients

PurposeThere is significant inter-patient variability in the pharmacokinetics of pegylated liposomal doxorubicin (PLD). Identification of factors affecting the pharmacokinetics of PLD would enable personalization of therapy. We previously reported that age, gender, body composition, and monocytes affect the clearance of other liposomal agents. Therefore, we evaluated how these factors affect the pharmacokinetics of PLD.MethodsPharmacokinetic studies of PLD were performed as part of phase I and II studies in 70 patients with solid tumors or Kaposi’s sarcoma. The effects of monocyte count, age, gender, and body composition on PLD clearance were examined.ResultsThere was a 15.3-fold variability in PLD clearance. Body surface area-based dosing did not significantly reduce the variability in PLD clearance. The meanxa0±xa0SD clearance for patients <60xa0years old and ≥60xa0years old were 54.6xa0±xa028.5 and 23.3xa0±xa010.8xa0mL/h/m2, respectively (Pxa0<xa00.0001), and for female and male patients were 23.7xa0±xa018.8 and 55.6xa0±xa026.8xa0mL/h/m2, respectively (Pxa0<xa00.0001). A reduction in pre-cycle monocyte count was associated with a greater reduction in PLD clearance.ConclusionsAge, gender, and monocyte counts appear to correlate with PLD clearance. Further investigation of the association between these factors, PLD pharmacokinetics, and clinical outcomes (efficacy and toxicity) is warranted. These effects on the pharmacokinetics of PLD may be an approach for personalizing PLD therapy and may affect other pegylated liposomes and nanoparticle agents.

Plasma, Tumor, and Tissue Disposition of STEALTH Liposomal CKD-602 (S-CKD602) and Nonliposomal CKD-602 in Mice Bearing A375 Human Melanoma Xenografts

Purpose: S-CKD602 is a STEALTH liposomal formulation of CKD-602, a camptothecin analogue. The cytotoxicity of camptothecin analogues is related to the duration of exposure in the tumor. STEALTH liposomal formulations contain lipid conjugated to methoxypolyethylene glycol and have been designed to prolong drug circulation time, increase tumor delivery, and improve the therapeutic index. For STEALTH liposomal formulations of anticancer agents to achieve antitumor effects, the active drug must be released into the tumor extracellular fluid (ECF). Experimental Design: S-CKD602 at 1 mg/kg or nonliposomal CKD-602 at 30 mg/kg was administered once via tail vein to mice bearing A375 human melanoma xenografts. Mice (n = 3 per time point) were euthanized at 0.083 to 24 h, 48 h, and 72 h after S-CKD02 and from 0.083 to 24 h after nonliposomal CKD-602. Plasma samples were processed to measure encapsulated, released, and sum total (encapsulated plus released) CKD-602, and tumor and tissue samples were processed to measure sum total CKD-602. Microdialysis samples of tumor ECF were obtained from 0 to 2 h, 4 to 7 h, and 20 to 24 h after nonliposomal CKD-602 and from 0 to 2 h, 24 to 27 h, 48 to 51 h, and 72 to 75 h after S-CKD602. A liquid chromatography-mass spectrometry assay was used to measure the total (sum of lactone and hydroxyl acid) CKD-602. The area under the concentration-versus-time curves (AUC) from 0 to infinity and time >1 ng/mL in tumor were estimated. Results: For S-CKD602, the CKD-602 sum total AUC in plasma and tumor and the CKD-602 AUC in tumor ECF were 201,929, 13,194, and 187 ng/mL h, respectively. For S-CKD602, 82% of CKD-602 remains encapsulated in plasma. For nonliposomal CKD-602, the CKD-602 AUC in plasma and tumor and the CKD-602 AUC in tumor ECF were 9,117, 11,661, and 639 ng/mL·h, respectively. The duration of time the CKD-602 concentration was >1 ng/mL in tumor ECF after S-CKD602 and nonliposomal CKD-602 was >72 and ∼20 h, respectively. For S-CKD602, the CKD-602 sum total exposure was 1.3-fold higher in fat as compared with muscle. The ratio of CKD-602 sum total exposure in fat to muscle was 3.8-fold higher after administration of S-CKD602 compared with nonliposomal CKD-602. Conclusion: S-CKD602 provides pharmacokinetic advantages in plasma, tumor, and tumor ECF compared with nonliposomal CKD-602 at 1/30th of the dose, which is consistent with the improved antitumor efficacy of S-CKD602 in preclinical studies. The distribution of S-CKD602 is greater in fat compared with muscle whereas the distribution of nonliposomal CKD-602 is greater in muscle compared with fat. These results suggest that the body composition of a patient may affect the disposition of S-CKD602 and released CKD-602.

Conditional Survival and the Choice of Conditioning Set for Patients With Colon Cancer: An Analysis of NSABP Trials C-03 Through C-07

PURPOSEnColon cancer overall survival (OS) is usually computed from the time of diagnosis. Survival gives the initial prognosis but does not reflect how prognosis changes with changing hazard rates over time. Conditional survival (probability of surviving y additional years given they have survived x years [CS or OS|OS]) is an alternative measure that accounts for elapsed time since diagnosis, providing more relevant prognostic information. We extend the concept of CS to condition on the set of patients alive, recurrence-free, and second primary cancer-free (disease-free survival [OS|DFS]).nnnPATIENTS AND METHODSnUsing data from National Surgical Adjuvant Breast and Bowel Project trials C-03 through C-07, 5-year OS|DFS was calculated on patients who were disease free up to 5 years after diagnosis, stratified by age, stage, nodal status, and performance status (PS).nnnRESULTSnFor stage II, OS|DFS improved from 87% to 92% at 5 years. For stage III, OS|DFS improved from 69% to 88%. Patients younger than 50 years showed OS|DFS improvement from 79% to 95%; those older than 70 years showed no sustained increase in OS|DFS. Node-negative patients with > or = 12 nodes resected showed little change (89% to 94%); those with more than four positive nodes showed an improvement (57% to 86%). Patients with a PS of 0 or 1 demonstrated a small improvement; those with a PS of 2 did not (64% to 58%).nnnCONCLUSIONnPrognosis improves over time for almost all groups of patients with colon cancer, especially those with positive nodes. OS|DFS is a more relevant measure of prognosis for those who have already survived disease free a period of time after diagnosis.

Phase I and Pharmacokinetic Study of Pegylated Liposomal CKD-602 in Patients with Advanced Malignancies

Purpose: S-CKD602 is a pegylated liposomal formulation of CKD602, a semisynthetic camptothecin analogue. Pegylated (STEALTH) liposomes can achieve extended drug exposure in plasma and tumor. Based on promising preclinical data, the first phase I study of S-CKD602 was done in patients with refractory solid tumors. Experimental Design: S-CKD602 was administered i.v. every 3 weeks. Modified Fibonacci escalation was used (three to six patients/cohort), and dose levels ranged from 0.1 to 2.5 mg/m2. Serial plasma samples were obtained over 2 weeks and total (lactone + hydroxyl acid) concentrations of encapsulated, released, and sum total (encapsulated + released) CKD602 measured by liquid chromatography-tandem mass spectrometry. Results: Forty-five patients (21 males) were treated. Median age, 62 years (range, 33-79 years) and Eastern Cooperative Oncology Group status, 0 to 1 (43 patients) and 2 (2 patients). Dose-limiting toxicities of grade 3 mucositis occurred in one of six patients at 0.3 mg/m2, grade 3 and 4 bone marrow suppression in two of three patients at 2.5 mg/m2, and grade 3 febrile neutropenia and anemia in one of six patients at 2.1 mg/m2. The maximum tolerated dose was 2.1 mg/m2. Partial responses occurred in two patients with refractory ovarian cancer (1.7 and 2.1 mg/m2). High interpatient variability occurred in the pharmacokinetic disposition of encapsulated and released CKD602. Conclusions: S-CKD602 represents a promising new liposomal camptothecin analogue with manageable toxicity and promising antitumor activity. Phase II studies of S-CKD602 at 2.1 mg/m2 i.v. once every 3 weeks are planned. Prolonged plasma exposure over 1 to 2 weeks is consistent with STEALTH liposomes and provides extended exposure compared with single doses of nonliposomal camptothecins.

Bidirectional pharmacodynamic interaction between pegylated liposomal CKD-602 (S-CKD602) and monocytes in patients with refractory solid tumors.

Background:u2002STEALTH® liposomal CKD-602 (S-CKD602), a camptothecin analog, is eliminated by the reticuloendothelial system (RES), which consists of cells, including monocytes. We evaluated the relationship between monocyte and absolute neutrophil counts (ANCs) in the blood and pharmacokinetic disposition of S-CKD602 and nonliposomal CKD-602 (NL-CKD602) in patients. Methods:u2002As part of a phase I study of S-CKD602 and phase I and II studies of NL-CKD602, the percent decreases in ANC and monocytes at their nadir were calculated. After S-CKD602, the amount of CKD-602 recovered in urine was measured. Results:u2002For S-CKD602 in patients <60 years, the percent decrease in ANC and monocytes were 43u2009±u200931 and 58u2009±u200926%, respectively (Pu2009=u20090.001). For S-CKD602 in patients ≥60, the percent decrease in ANC and monocytes were 41u2009±u200931 and 45u2009±u200936%, respectively (Pu2009=u20090.50). For NL-CKD602 (nu2009=u200942), the percent decrease in ANC and monocytes were similar (Pu2009>u20090.05). For S-CKD602, the relationship between the percent decrease in monocytes and CKD-602 recovered in urine was stronger in patients <60 (R2u2009=u20090.82), compared with patients ≥60 (R2u2009=u20090.30). Conclusions:u2002Monocytes are more sensitive to S-CKD602, compared with neutrophils, and the increased sensitivity is related to the liposomal formulation, not CKD-602. These results suggest that monocytes engulf S-CKD602, which causes the release of CKD-602 from the liposome and toxicity to the monocytes, and that the effects are more prominent in patients <60.

Pharmacokinetic study of pegylated liposomal CKD-602 (S-CKD602) in patients with advanced malignancies

S‐CKD602 is a pegylated liposomal formulation of CKD‐602. This study is the first to evaluate the factors affecting the high interpatient variability in the pharmacokinetic disposition of S‐CKD602. S‐CKD602 was administered intravenously (i.v.) every 3 weeks as part of a phase I study. Pharmacokinetics studies of the liposomal encapsulated and released CKD‐602 in plasma were performed. The pharmacokinetic variability of S‐CKD602 is associated with both linear and nonlinear clearances. Patients ≥60 years of age have a 2.7‐fold higher exposure of S‐CKD602 as compared with patients <60 years of age (P = 0.02). Patients with a lean body composition have a higher plasma exposure of S‐CKD602 (P = 0.02). Patients who have received prior therapy with pegylated liposomal doxorubicin (PLD) have a 2.2‐fold higher exposure of S‐CKD602 as compared with patients who have not received PLD (P = 0.045). Prolonged exposure of the encapsulated drug in plasma over 1–2 weeks provides significant pharmacologic advantages. The high interpatient variability in the pharmacokinetic disposition of S‐CKD602 was associated with age, body composition, saturable clearance, and prior PLD therapy.

Genetically Engineered Cancer Models, But Not Xenografts, Faithfully Predict Anticancer Drug Exposure in Melanoma Tumors

BACKGROUNDnRodent studies are a vital step in the development of novel anticancer therapeutics and are used in pharmacokinetic (PK), toxicology, and efficacy studies. Traditionally, anticancer drug development has relied on xenograft implantation of human cancer cell lines in immunocompromised mice for efficacy screening of a candidate compound. The usefulness of xenograft models for efficacy testing, however, has been questioned, whereas genetically engineered mouse models (GEMMs) and orthotopic syngeneic transplants (OSTs) may offer some advantages for efficacy assessment. A critical factor influencing the predictability of rodent tumor models is drug PKs, but a comprehensive comparison of plasma and tumor PK parameters among xenograft models, OSTs, GEMMs, and human patients has not been performed.nnnMETHODSnIn this work, we evaluated the plasma and tumor dispositions of an antimelanoma agent, carboplatin, in patients with cutaneous melanoma compared with four different murine melanoma models (one GEMM, one human cell line xenograft, and two OSTs).nnnRESULTSnUsing microdialysis to sample carboplatin tumor disposition, we found that OSTs and xenografts were poor predictors of drug exposure in human tumors, whereas the GEMM model exhibited PK parameters similar to those seen in human tumors.nnnCONCLUSIONSnThe tumor PKs of carboplatin in a GEMM of melanoma more closely resembles the tumor disposition in patients with melanoma than transplanted tumor models. GEMMs show promise in becoming an improved prediction model for intratumoral PKs and response in patients with solid tumors.

Meta-analysis of inter-patient pharmacokinetic variability of liposomal and non-liposomal anticancer agents.

UNLABELLEDnA meta-analysis was conducted to evaluate the inter-patient pharmacokinetic (PK) variability of liposomal and small molecule (SM) anticancer agents. Inter-patient PK variability of 9 liposomal and SM formulations of the same drug was evaluated. PK variability was measured as coefficient of variance (CV%) of area under the plasma concentration versus time curve (AUC) and the fold-difference between AUCmax and AUCmin (AUC range). CV% of AUC and AUC ranges were 2.7-fold (P<0.001) and 16.7-fold (P=0.13) greater, respectively, for liposomal compared with SM drugs. There was an inverse linear relationship between the clearance (CL) of liposomal agents and PK variability with a lower CL associated with greater PK variability (R(2)=0.39). PK variability of liposomal agents was greater when evaluated from 0-336 h compared with 0-24h. PK variability of liposomes is significantly greater than SM. The factors associated with the PK variability of liposomal agents need to be evaluated.nnnFROM THE CLINICAL EDITORnIn this meta-analysis, the inter-patient pharmacokinetic variability of 9 liposomal and small molecule anti-cancer agents was studied. The authors determined that several parameters are in favor of the liposomal formulation; however, the PK variability of the formulation was higher compared with small molecule agents, the reason for which remains to be determined in future studies.

Population Pharmacokinetics of Pegylated Liposomal CKD‐602 (S‐CKD602) in Patients With Advanced Malignancies

S‐CKD602 is a pegylated long‐circulating liposomal formulation of CKD‐602, a potent topoisomerase I inhibitor. A population pharmacokinetic (PK) model for encapsulated and released CKD‐602 following administration of S‐CKD602 was developed to assess factors that may influence S‐CKD602 PK. Plasma samples from 45 patients with solid tumors were collected in a phase 1 study. S‐CKD602 was administered as a 1‐hour intravenous infusion with doses ranging from 0.1 to 2.5 mg/m2. Plasma concentrations of encapsulated and released CKD‐602 were used to develop a population PK model using NONMEM. PK of encapsulated CKD‐602 was described by a 1‐compartment model with nonlinear clearance, and PK of released CKD‐602 was described by a 2‐compartment model with linear clearance for all patients. Covariate analysis revealed that tumor in the liver was a significant covariate for clearance of encapsulated CKD‐602 and that age significantly influenced the release rate of CKD‐602 from S‐CKD602. Maximum elimination rate in patients with liver tumor is 1.5‐fold higher compared with patients without liver tumor. Release rate of CKD‐602 from S‐CKD602 in patients less than 60 years old was 2.7‐fold higher compared with patients 60 years old or older. These observations have potential implications in the optimal dosing of liposomal agents.

Tumor disposition of pegylated liposomal CKD-602 and the reticuloendothelial system in preclinical tumor models

Liposomes, such as pegylated-liposomal CKD-602 (S-CKD602), undergo catabolism by macrophages and dendritic cells (DCs) of the reticuloendothelial system (RES). The relationship between plasma and tumor disposition of S-CKD602 and RES was evaluated in mice bearing A375 melanoma or SKOV-3 ovarian xenografts. Area under the concentration-time curves (AUCs) of liposomal encapsulated, released, and sum total (encapsulated + released) CKD-602 in plasma, tumor, and tumor extracellular fluid (ECF) were estimated. A375 and SKOV-3 tumors were stained with cd11b and cd11c antibodies as measures of macrophages and DC. The plasma disposition of S-CKD602 was similar in both xenograft models. The ratio of tumor sum total AUC to plasma sum total AUC was 1.7-fold higher in mice bearing human SKOV-3 xenografts, compared with A375. The ratio of tumor ECF AUC to tumor sum total AUC was 2-fold higher in mice bearing human SKOV-3 xenografts, compared with A375. The staining of cd11c was 4.5-fold higher in SKOV-3, compared with A375 (Pu2009<u20090.0001). The increased tumor delivery and release of CKD-602 from S-CKD602 in the ovarian xenografts, compared with the melanoma xenografts, was consistent with increased cd11c staining, suggesting that variability in the RES may affect the tumor disposition of liposomal agents.