Patterns and characteristics associated with surface contamination of hazardous drugs in hospital pharmacies.

PURPOSE: The surface contamination levels of 5 commonly used hazardous drugs in hospital pharmacies are summarized, identifying practice patterns associated with contamination. METHODS: Contamination testing data were compiled to evaluate surface contaminants of 5 hazardous drugs (docetaxel, paclitaxel, cyclophosphamide, ifosfamide, and 5-fluorourcil). Data from 5,842 wipes over 6 years were collected from 338 hospital pharmacies. The contamination level for each drug was categorized as nondetectable (ND; ≤10 ng/ft2), low (between 10 and ≤100 ng/ft2), medium (between 100 and ≤1,000 ng/ft2) or high (>1,000 ng/ft2). Surface exposures for each drug were summarized based on location, contamination at first and subsequent wipe events, and the use of a closed system transfer device (CSTD). RESULTS: The majority of contamination results corresponded to locations at or near hazardous drug preparation, but also occurred in areas where hazardous drugs were not prepared. There was a higher incidence of contamination levels (high, medium, and low, respectively) at first wipe event (10.2%, 17.4%, and 17.7%) compared to subsequent wipe events (5.8%, 12.2%, and 13.6%) (p < 0.0001). There was a lower incidence of contamination levels at institutions that used CSTDs (6.3%, 12.8%, and 14.4%) compared to institutions that did not use CSTDs (14.2%, 17.9%, and 17.3%) (p < 0.0001). CONCLUSIONS: The majority of highest contamination levels corresponded to locations where hazardous drugs were prepared. While the rate of contamination was lower at subsequent wipe events and at institutions that used CSTDs, contamination was not completely eliminated in either scenario.

Technetium Tc 99m sulfur colloid phenotypic probe for the pharmacokinetics and pharmacodynamics of PEGylated liposomal doxorubicin in women with ovarian cancer.

PURPOSE: Significant variability in the pharmacokinetics and pharmacodynamics of PEGylated liposomal doxorubicin (PLD) exists. PLD undergoes clearance via the mononuclear phagocyte system (MPS). Technetium Tc 99m sulfur colloid (TSC) is approved for imaging MPS cells. We investigated TSC as a phenotypic probe of PLD pharmacokinetics and pharmacodynamics in women with epithelial ovarian cancer. METHODS: TSC 10 mCi IVP was administered and followed by dynamic planar and SPECT/CT imaging and blood pharmacokinetics sampling. PLD 30-40 mg/m(2) IV was administered with or without carboplatin, followed by plasma pharmacokinetics sampling. RESULTS: There was a linear relationship between TSC clearance and encapsulated doxorubicin clearance (R(2) = 0.61, p = 0.02), particularly in patients receiving PLD alone (R(2) = 0.81, p = 0.04). There was a positive relationship (ρ = 0.81, p = 0.01) between maximum grade palmar-plantar erythrodysesthesia toxicity developed and estimated encapsulated doxorubicin concentration in hands. CONCLUSIONS: TSC is a phenotypic probe for PLD pharmacokinetics and pharmacodynamics and may be used to individualize PLD therapy in ovarian cancer and for other nanoparticles in development.

Factors affecting the pharmacokinetics and pharmacodynamics of PEGylated liposomal irinotecan (IHL-305) in patients with advanced solid tumors.

IHL-305 is a PEGylated liposomal formulation of irinotecan (CPT-11). The objective of this study was to evaluate the factors associated with interpatient variability in the pharmacokinetics and pharmacodynamics of IHL-305 in patients with advanced solid tumors. IHL-305 was administered intravenously once every 4 weeks as part of a Phase I study. Pharmacokinetic studies of the liposomal sum total CPT-11, released CPT-11, SN-38, SN-38G, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin, and 7-ethyl-10-[4-amino-1-piperidino]-carbonyloxycamptothecin in plasma were performed. Noncompartmental and compartmental pharmacokinetic analyses were conducted using pharmacokinetic data for sum total CPT-11. The pharmacokinetic variability of IHL-305 is associated with linear and nonlinear clearance. Patients whose age and body composition (ratio of total body weight to ideal body weight [TBW/IBW]) were greater than the median age and TBW/IBW of the study had a 1.7-fold to 2.6-fold higher ratio of released CPT-11 area under the concentration versus time curve (AUC) to sum total CPT-11 AUC. Patients aged <60 years had a 1.3-fold higher ratio of percent decrease in monocytes at nadir to percent decrease in absolute neutrophil count at nadir as compared with patients aged ≥60 years. There was an inverse relationship between patient age and percent decrease in monocytes at nadir, ie, younger patients have a higher percent decrease in monocytes. Patients with a higher percent decrease in monocytes at nadir have a decreased plasma exposure of sum total CPT-11. The pharmacokinetics and pharmacodynamics of IHL-305 are consistent with those of other PEGylated liposomal carriers. Interpatient variability in the pharmacokinetics and pharmacodynamics of IHL-305 was associated with age, body composition, and monocytes.

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

A 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. FROM THE CLINICAL EDITOR: In 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 CPT-11 (IHL-305) in patients with advanced solid tumors.

PURPOSE: To investigate pharmacokinetics (PK) of encapsulated CPT-11, released CPT-11 and the active metabolite SN-38 following administration of IHL-305 and to identify factors that may influence IHL-305 PK. METHODS: Plasma samples from 39 patients with solid tumors were collected in a phase I study. IHL-305 was administered as a 1 h IV infusion with doses ranging from 3.5 to 210 mg/m(2). Plasma concentrations of encapsulated CPT-11, released CPT-11 and SN-38 were used to develop a population PK model using NONMEM®. RESULTS: PK of encapsulated CPT-11 was described by 1-compartment model with nonlinear clearance and PK of released CPT-11 was described by a 1-compartment model with linear clearance for all patients. PK of the active metabolite SN-38 was described by a 2-compartment model with linear clearance for all patients. Covariate analysis revealed that gender was a significant covariate for volume of distribution of encapsulated CPT-11. Vencap in male patients is 1.5-fold higher compared with female patients. CONCLUSIONS: The developed population PK modeling approach is useful to predict PK exposures of encapsulated and released drug and can be applied to the more than 300 other nanoparticle formulations of anticancer agents that are currently in development. The effect of gender on PK of IHL-305 needs to be further evaluated.

A review of study designs and outcomes of phase I clinical studies of nanoparticle agents compared with small-molecule anticancer agents.

PURPOSE: Nanoparticles or carrier-mediated agents have been designed to prolong drug circulation time, increase tumor delivery, and improve therapeutic index compared to their small-molecule counterparts. The starting dose for phase I studies of small molecules and nanoparticles anticancer agents is based on the toxicity profile of the most sensitive species (e.g., rat or canine), but the optimal animal model for these studies of nanoparticles is unclear. The objective of this study was to evaluate the design, progression, and outcomes of phase I studies of nanoparticles compared with small-molecule anticancer agents. EXPERIMENTAL DESIGN: In preclinical studies, the maximum tolerated dose (MTD) in rats and dogs was evaluated for nanoparticles and their respective small molecules. In phase I clinical trials in patients with advanced solid tumors, the basis for starting dose, the number of dose escalations, number of patients enrolled, and the ratio of MTD to starting dose was determined for nanoparticles and small molecules. RESULTS: The mean ratio of MTD to starting dose in clinical phase I studies was significantly greater for nanoparticles (13.9 ± 10.8) compared with small molecules (2.1 ± 1.1; P = 0.005). The number of dose levels in a clinical phase I study was also significantly greater for nanoparticles (7.3 ± 2.9) compared with small molecules (4.1 ± 1.5; P = 0.008). CONCLUSIONS: The degree of dose escalation from starting dose to MTD was significantly greater for nanoparticles as compared with small-molecule anticancer drugs. These findings necessitate the need to identify the most appropriate preclinical animal model to use when evaluating nanoparticles toxicity.

Mechanism-based model characterizing bidirectional interaction between PEGylated liposomal CKD-602 (S-CKD602) and monocytes in cancer patients.

S-CKD602 is a PEGylated liposomal formulation of CKD-602, a potent topoisomerase I inhibitor. The objective of this study was to characterize the bidirectional pharmacokinetic-pharmacodynamic (PK-PD) interaction between S-CKD602 and monocytes. Plasma concentrations of encapsulated CKD-602 and monocytes counts from 45 patients with solid tumors were collected following intravenous administration of S-CKD602 in the phase I study. The PK-PD models were developed and fit simultaneously to the PK-PD data, using NONMEM(®). The monocytopenia after administration of S-CKD602 was described by direct toxicity to monocytes in a mechanism-based model, and by direct toxicity to progenitor cells in bone marrow in a myelosuppression-based model. The nonlinear PK disposition of S-CKD602 was described by linear degradation and irreversible binding to monocytes in the mechanism-based model, and Michaelis-Menten kinetics in the myelosuppression-based model. The mechanism-based PK-PD model characterized the nonlinear PK disposition, and the bidirectional PK-PD interaction between S-CKD602 and monocytes.

Factors affecting the pharmacokinetics of pegylated liposomal doxorubicin in patients.

PURPOSE: There 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. METHODS: Pharmacokinetic 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. RESULTS: There was a 15.3-fold variability in PLD clearance. Body surface area-based dosing did not significantly reduce the variability in PLD clearance. The mean ± SD clearance for patients <60 years old and ≥60 years old were 54.6 ± 28.5 and 23.3 ± 10.8 mL/h/m(2), respectively (P < 0.0001), and for female and male patients were 23.7 ± 18.8 and 55.6 ± 26.8 mL/h/m(2), respectively (P < 0.0001). A reduction in pre-cycle monocyte count was associated with a greater reduction in PLD clearance. CONCLUSIONS: Age, 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.

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/m(2) . 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.

Pharmacologic and phenotypic study of docetaxel in patients with ovarian or primary peritoneal cancer.

PURPOSE: The objectives of this study were to determine whether the midazolam clearance predicted docetaxel pharmacokinetics, CA-125 change, and response and to assess the impact of cytochrome P450 (CYP) 3A5 and ATP-binding cassette, subfamily B, member 1 (ABCB1) genotypes on docetaxel pharmacokinetics and pharmacodynamics in ovarian or primary peritoneal cancer patients. METHODS: Thirty-four patients with advanced ovarian and primary peritoneal cancer were administered docetaxel at 75 mg/m(2) as a 1-h infusion in combination with carboplatin IV over 30 min at a target AUC of 5 mg/ml min. Cycles were repeated every 21 days for 6 cycles. Midazolam was administered at 2 mg as a 30-min IV infusion the day prior to cycle one of docetaxel administration. Pharmacokinetic studies of docetaxel and CYP3A5 and ABCB1 genotype studies were performed. RESULTS: There was an inverse relationship between midazolam clearance (CL) and CA-125 level after cycle 6 where a higher midazolam CL was associated with a CA-125 <10 U/ml (P = 0.007) and CA-125 <15 U/ml (P = 0.048). The CA-125 categories were associated with response achieved (complete response/partial response) (CR/PR), stable disease (SD), and progressive disease (PD) at the end of therapy (P = 0.0173). Docetaxel CL was not related to midazolam CL or genotype. Docetaxel exposure and genotypes were not related to toxicity or response (P > 0.05). CONCLUSIONS: The midazolam CL predicted CA-125 levels and response that was independent of other factors including docetaxel pharmacokinetics. Future studies need to evaluate the mechanism for the relationship between midazolam CL and response in patients with ovarian cancer.

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 (P < 0.0001). 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.

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

BACKGROUND: STEALTH(®) 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: As 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: For S-CKD602 in patients <60 years, the percent decrease in ANC and monocytes were 43 ± 31 and 58 ± 26%, respectively (P = 0.001). For S-CKD602 in patients ≥60, the percent decrease in ANC and monocytes were 41 ± 31 and 45 ± 36%, respectively (P = 0.50). For NL-CKD602 (n = 42), the percent decrease in ANC and monocytes were similar (P > 0.05). For S-CKD602, the relationship between the percent decrease in monocytes and CKD-602 recovered in urine was stronger in patients <60 (R(2) = 0.82), compared with patients ≥60 (R(2) = 0.30). CONCLUSIONS: Monocytes 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.

Conditional survival and the choice of conditioning set for patients with colon cancer: an analysis of NSABP trials C-03 through C-07.

PURPOSE: Colon 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]). PATIENTS AND METHODS: Using 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). RESULTS: For 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%). CONCLUSION: Prognosis 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.

Plasma and tissue disposition of non-liposomal DB-67 and liposomal DB-67 in C.B-17 SCID mice.

PURPOSE: DB-67 is a silatecan, 7-silyl-modified camptothecin, with enhanced lipophilicity and increased blood stability of the active-lactone ring. The generation of a liposomal formulation of DB-67 may be an attractive method of intravenous (IV) administration and may maintain DB-67 in the active-lactone form. We evaluated the tissue and plasma disposition of DB-67 lactone and hydroxy acid after administration of non-liposomal (NL) and liposomal (L) DB-67 in severe combined immunodeficient (SCID) mice. METHODS: NL-DB-67 and L-DB-67 10 mg/kg IV x 1 were administered via a tail vein in SCID mice. After dosing, mice (n = 3 per time point) were euthanized and blood ( approximately 1 ml) and tissue were collected from 5 min to 48 h after administration. DB-67 lactone and hydroxy acid concentrations in plasma and DB-67 total (sum of lactone and hydroxyl acid) concentrations in tissues were determined by high-performance liquid chromatography (HPLC) with fluorescence detection. RESULTS: Clearance of DB-67 lactone after administration of NL-DB-67 and L-DB-67 were 1.6 and 3.5 l/h/m(2), respectively; DB-67 lactone half-lives after administration of NL-DB-67 and L-DB-67 were 1.4 and 0.9 h, respectively. The percentages of DB-67 lactone in plasma after administration of NL-DB-67 and L-DB-67 were 92% and 89%, respectively. Liver, kidney, spleen, and lung tissues had longer exposure times to DB-67 after administration of L-DB-67 compared with NL-DB-67. CONCLUSION: In plasma, the majority of DB-67 remained in the lactone form after administration of NL-DB-67 and L-DB-67. The plasma disposition of DB-67 was similar after administration of NL-DB-67 and L-DB-67, suggesting that most of the DB-67 is immediately released from the L-DB-67 formulation. Following administration of L-DB-67, the higher and longer exposure of DB-67 in the spleen, as compared with NL-DB-67, is consistent with splenic clearance of liposomes by the reticuloendothelial system.

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 approximately 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.

Transgenic mice overexpressing hepatocyte growth factor in the airways show increased susceptibility to lung cancer.

Several studies have suggested a possible role of the hepatocyte growth factor (HGF)/c-Met system in lung tumor development and progression. Extent of expression of both HGF and c-Met have been shown to be negative prognostic indicators of survival and recurrence in non-small-cell lung cancer, especially adenocarcinoma. To further define a role for HGF in lung cancer development and growth, we have generated transgenic mice that overexpress HGF in the airway epithelium. HGF transgenic and wild-type mice were exposed to the tobacco carcinogen, nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), or saline control and killed 10-38 weeks after exposure. Lungs were formalin inflated, paraffin embedded and sectioned. It was verified that the HGF transgene was expressed only in the lungs of transgenic mice. The transgenic mouse lung histology exhibited congestion in the alveolar spaces, excess production of blood vessels and a convoluted pattern of airways with wide bifurcations. The number of lung tumors from NNK-treated transgenic animals versus the number of lung tumors from NNK-treated wild-type animals was significantly higher (P = 0.0001, Poisson regression). The percentage of animals with tumors was 75% in the transgenic group compared with 48.8% in the wild-type group. The main effect was an increase in tumor multiplicity; average size of tumors was not different between the groups. Additionally, the tumors that arose in the transgenic mice contained increased HGF protein compared with tumors from the wild-type mice. These results indicate that lung carcinogenesis induced by a tobacco carcinogen is enhanced by expression of the HGF transgene. This model recapitulates the phenotype of aggressive lung adenocarcinoma that overexpresses HGF and will be useful in evaluating antitumor agents that target either the HGF/c-Met pathway or downstream effects such as angiogenesis or invasion.

Phase I and pharmacokinetic study of weekly docetaxel, cisplatin, and daily capecitabine in patients with advanced solid tumors.

PURPOSE: Docetaxel, cisplatin, and capecitabine are three active chemotherapeutic agents with different mechanisms of action. This phase I study investigated the feasibility and pharmacokinetics of this combination given on a weekly schedule. EXPERIMENTAL DESIGN: Docetaxel and cisplatin were given i.v. over 30 minutes on days 1 and 8 and capecitabine was given orally bid on days 1 to 14 (every 21 days). Escalation occurred in cohorts of three patients until the maximum tolerated dose was defined. Pharmacokinetics studies of docetaxel and total and ultrafiltrate platinum after cisplatin administration were done on cycle 1 (with capecitabine) and cycle 2 (without capecitabine). RESULTS: Twenty-five patients were enrolled. Two of six patients at dose level 5 had a dose-limiting infection and diarrhea. One of six evaluable patients at dose level 4 (27 mg/m2 docetaxel, 27 mg/m2 cisplatin, 825 mg/m2 capecitabine) had a dose-limiting hypomagnesemia. Pharmacokinetics of docetaxel were similar on cycles 1 and 2. Area under the plasma concentrations versus time curves of total platinum was significantly greater in cycle 2 compared with cycle 1 (P = 0.001). There was no difference in the disposition of docetaxel on cycles 1 and 2. CONCLUSIONS: The recommended docetaxel, cisplatin, and capecitabine dose for phase II studies is 27/27/825 mg/m2. The alteration in total and ultrafiltrate platinum disposition on cycle 2 compared with cycle 1 may be inherent to sequential cisplatin administration; however, prior treatment with capecitabine cannot be ruled out as a factor.

The gender gap in a surgical subspecialty: analysis of career and lifestyle factors.

BACKGROUND: Although the percentage of women in surgical subspecialties is increasing, little is known about the experiences of these women compared with their male counterparts. OBJECTIVE: To identify career and lifestyle factors that distinguish female otolaryngologists. DESIGN, SETTING, AND PARTICIPANTS: Otolaryngologists were asked to respond to a confidential 119-item questionnaire. The instrument was sent to all 502 female members of the American Academy of Otolaryngology-Head and Neck Surgery who had finished their residency training and were practicing medicine. For response comparison, the survey was mailed to 2 male otolaryngologists who were matched to each female survey recipient for years since completion of training, geographic region, and practice type. RESULTS: Of the 673 respondents (52.6% response rate), women were more likely to be divorced or separated (P =.001) and have fewer children (P <.001). In contrast to men, women reduced their work hours in conjunction with having more children (P <.001). Controlling for professional hours and hours spent in the operating room per week, type of practice, and years since completion of residency, women earned 15% to 20% less per year than men (P <.001). Men relied more on their spouse or partner for household responsibilities and child care (P <.001), and 34.3% of the women (compared with 7.1% of the men) spent 21 to 40 h/wk on household management (P <.001). CONCLUSION: Although male and female otolaryngologists receive equal training opportunities, women earn less money for performing similar jobs and have increased family responsibilities, which may effect their career advancement.