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.

A performance evaluation of 90Y dose-calibrator measurements in nuclear pharmacies and clinics in the United States.

A blind performance test was conducted to evaluate dose-calibrator measurements at nuclear pharmacies in the United States (US). Two test-sample geometries were chosen to represent those used for measurements of 90Y-ibritumomab tiuxetan (ZEVALIN). The radioactivity concentration of test-samples was verified by the US National Institute of Standards and Technology. Forty-five results were reported by 10 participants. Eighty percent of reported values were within the US Pharmacopoeia content standard (+/-10%) for 90Y-ZEVALIN. All results were within US Nuclear Regulatory Commission conformance limits (+/-20%) for defining therapeutic misadministrations.

Successful in vivo recovery and extended storage of additive solution (AS)-5 red blood cells after deglycerolization and resuspension in AS-3 for 15 days with an automated closed system.

BACKGROUND: Previously, cryopreserved red blood cell (RBC) units derived from CPD/AS-5 whole-blood (WB) collections have been limited to 24 hours postthaw storage (1-6 degrees C). STUDY DESIGN AND METHODS: Sixty-four leukoreduced (LR) and 54 nonleukoreduced (NLR) AS-5 (n = 118) RBC units from 500-mL WB collections were stored for 6 days, glycerolized, frozen (-70 +/- 5 degrees C) for at least 14 days, thawed, deglycerolized, and stored (1-6 degrees C) for 15 days resuspended in AS-3, using an automated closed-system cell processor (ACP 215, Haemonetics). Frozen units were stored in either ethylene vinyl acetate (EVA) or polyvinylchloride (PVC) bags. In vitro parameters were tested in all units 15 days after deglycerolization. In vivo 24-hour recovery was measured in 77 of 118 donors. RESULTS: Postdeglycerolization in vitro RBC mass recoveries (mean +/- SD) were 96.8 +/- 5.7 and 94.7 +/- 5.6% for EVA LR and NLR units, respectively, and 97.3 +/- 6.2 and 94.7 +/- 6.2% for PVC LR and NLR units, based on unit weight and hematocrit after sampling for in vitro testing, immediately before glycerolization. Hemoglobin content (g/unit, mean +/- SD) after deglycerolization was 40.4 +/- 5.6 and 42.6 +/- 6.0 for EVA LR and NLR units, respectively, and 40.7 +/- 4.8 and 43.0 +/- 7.7 for PVC LR and NLR units. Hemolysis was 0.61 +/- 0.23 and 0.54 +/- 0.16% for EVA LR and NLR units, and 0.47 +/- 0.14 and 0.43 +/- 0.12% for PVC LR and NLR units. In vivo 24-hour recoveries on Day 15 were 83.0 +/- 6.7% (PVC NLR) up to 86.2 +/- 5.7% (EVA NLR). CONCLUSION: With processing on the ACP 215 system, CPD/AS-5 LR and NLR thawed RBC units can be stored for up to 14 days after frozen storage at -65 degrees C or colder in EVA or PVC bags with acceptable in vivo and in vitro RBC quality.

Determination of the biliary excretion of piperacillin in humans using a novel method.

AIM: To evaluate the applicability of a novel method to determine the biliary excretion of piperacillin. METHODS: Healthy volunteers were administered piperacillin i.v. Duodenal aspirates were collected via a custom-made oroenteric catheter; blood and urine also were collected. Gallbladder ejection fraction (EF) was determined by gamma scintigraphy and pharmacokinetic parameters were calculated using noncompartmental analysis. RESULTS: The fraction of the piperacillin dose excreted unchanged into bile was 1.1 +/- 0.3% (biliary clearance corrected for EF was 0.032 +/- 0.008 ml min(-1) kg(-1)). CONCLUSIONS: This methodology can be used to determine reliably the biliary clearance of drugs that are excreted only marginally into bile. Normalization of biliary clearance for EF significantly reduces intersubject variability of this parameter.

Extended storage of AS-1 and AS-3 leukoreduced red blood cells for 15 days after deglycerolization and resuspension in AS-3 using an automated closed system.

BACKGROUND: The utilization of cryopreserved red blood cell (RBC) units had been limited by a maximum postdeglycerolization storage of 24 hours at 1 to 6 degrees C until the recent development of a closed system for the glycerolization and deglycerolization process. STUDY DESIGN AND METHODS: Sixty leukoreduced additive solution (AS), AS-1 (n = 30) and AS-3 (n = 30) RBC units from 500-mL whole blood (WB) collections were stored for 6 days, glycerolized, frozen at -70 +/- 5 degrees C for at least 14 days, thawed, deglycerolized, and stored for 15 days at 1 to 6 degrees C. Glycerolization and deglycerolization were performed with the ACP 215. In-vitro variables were tested before glycerolization, on Day 0, and Day 15 after deglycerolization storage. Forty donors were assessed for double-label 24-hour percent recovery, and T1/2 survival time was measured for 20 donors. RESULTS: Postdeglycerolization mean +/- standard deviation in-vitro RBC mass recoveries were 93 +/- 5 percent for AS-1 and 95 +/- 4 percent for AS-3. Mean hemoglobin +/- standard deviation after deglycerolization was 50.5 +/- 5.5g for AS-1 and 50.1 +/- 3.5g for AS-3. Mean hemolysis (Day 15) was 0.36 +/- 0.11 percent for AS-1 and 0.38 +/- 0.13 percent for AS-3. Double-label 24-hour in-vivo recoveries were 82.5 +/- 7.8 percent for AS-1 and 81.4 +/- 7.1 percent for AS-3. The 51Cr T1/2 value was 41.8 +/- 3.97 for AS-1 and 40.6 +/- 7.11 for AS-3. Other in-vitro variables were as expected. CONCLUSION: Leukoreduced AS-1 and AS-3 RBCs after frozen storage at -70 +/- 5 degrees C can be stored for up to 14 days when processing is performed with the ACP 215 system with resuspension of deglycerolized RBCs in AS-3.

A novel method for the determination of biliary clearance in humans.

Biliary excretion is an important route of elimination and the biliary tract is a potential site of toxicity for many drugs and xenobiotics. Quantification of biliary excretion in healthy human volunteers is logistically challenging and is rarely defined during drug development. The current study uses a novel oroenteric tube coupled with a specialized clinical protocol to examine the pharmacokinetics of 99mTechnetium (Tc-99m) mebrofenin, a compound that undergoes rapid hepatic uptake and extensive biliary excretion. A custom-made multilumen oroenteric tube was positioned in the duodenum of healthy human volunteers. Subjects were positioned under a gamma camera and 2.5 mCi of Tc-99m mebrofenin was administered intravenously. Duodenal aspirates, blood samples, and urine were collected periodically for 3 hours. Two hours after Tc-99m mebrofenin administration, the gallbladder was contracted with an intravenous infusion of cholecystokinin-8. Gamma scintigraphy was used to determine the gallbladder ejection fraction in each subject. Total systemic clearance of Tc-99m mebrofenin approximated liver blood flow (Cl(total) 17.3 degrees 1.7 mL/min/kg), and 35% to 84% of the Tc-99m mebrofenin dose was recovered in bile. However, when the data were corrected for the gallbladder ejection fraction, 71% to 92% of the excreted Tc-99m mebrofenin dose was recovered. This novel oroenteric tube and clinical protocol provide a useful method to quantify biliary excretion of xenobiotics in healthy human volunteers.