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.

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.

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.