Saul Yanovich

Safety and Pharmacokinetics of Oral Voriconazole in Patients at Risk of Fungal Infection: A Dose Escalation Study

The objective of this study was to investigate the safety, tolembility, and pharmacokinetics of oral voriconazole in subjects at high risk of developing fungal infections. This was a multicenter, randomized, double‐blind, double‐dummy, parallel‐group, dose escalation study with a fluconazole active control. Twenty‐four subjects with hematological malignancies, solid tumors, or autologous bone marrow transplants were randomized to receive voriconazole 200 mg q 12 h (n = 9), voriconazole 300 mgq 12 h (n = 9), or fluconazole 400 mg OD(n = 6) for a period of 14 days. Blood samples were taken for the assessment of voriconazole pharmacokinetics in plasma on Days 1 and 14. Using a 200 mgq 12 h dosing regimen, geometric mean voriconazole peak plasma concentrations (Cmsx) were 904 ng/ml on Day 1 and 2996 ng/ml on Day 14. Geometric mean voriconazole exposure, as measured by the area under the curve within a dosing interval (AUCπ, was 4044 and 20308 ng·h/ml on Days 1 and 14, respectively. On Day 1, geometric mean Cmax and AUC were 1.80‐ and 1.94‐fold higher in subjects receiving voriconazole 300 mg q 12 h than in those receiving 200 mg q 12 h. Similarly, on Day 14, geometric mean Cmax and AUC were 1.56‐ and 1.80‐fold greater in the high‐dose group. Although the confidence intervals are large, this trend suggests nonlinearity in pharmacokinetics with respect to dose as seen in healthy volunteers. The absorption of orally administered voriconazole was relatively rapid, with tmax achieved in 1.7 to 3.0 hours. There was a mean 5.4‐ and 5.0‐fold accumulation of voriconazole over the 14‐day study period in the 200 mg and 300 mg q 12 h dose groups, respectively. Voriconazole was generally safe and well tolerated. Mild, reversible visual disturbances were the most commonly reported adverse event but were not associated with treatment discontinuation. No patient developed a breakthrough fungal infection. It was concluded that in thisgroup of patients at risk of fungal infection, voriconazole pharmacokinetics was consistent with that reported in healthy volunteers.

Delivery of Lipophilic Drugs Using Lipoproteins

Low density lipoproteins (LDLs) and high density lipoproteins (HDLs), are spherical classes of particles 7 to 25 nm in diameter with oily, nonaqueous cores (FIGURE 1). Extensive studies have been performed throughout the years with respect to the structure, metabolism, and molecular biology of lipoproteins..* Recently lipoproteins, most notably LDL, have been examined experimentally as drug-delivery vehicle^.^-^ Advantages of lipoproteins as drug carriers include: (1) their being natural components able to survive in plasma and tissue fluids for significant time periods, ( 2 ) the small particle size, which allows diffusion from vascular to extravascular compartments, ( 3 ) their interaction via receptor-mediated endocytosis enabling intracellular uptake of drug, and (4) the oily core, which provides a domain for lipophilic drugs and prodrugs. Disadvantages of lipoproteins as drug carriers include their complex and unstable nature, a general lack of targeting since receptors for some lipoproteins reside on numerous tissues, and potential drug cytotoxicity to normal tissues. In the present studies, the preparation, composition, and stability of lipoproteindrug complexes are described. Interactions of these complexes with cells in vitro were performed to establish how the modified lipoprotein particles and drugs became cell associated and what biological effects occurred on the target cells.

Metabolism of adriamycin in hepatocytes isolated from the rat and the rabbit

Metabolism of adriamycin, an anthracycline antibiotic, was characterized in both rat and rabbit hepatocytes under aerobic conditions. Adriamycin was the predominant fluorescent species within the cell in hepatocytes from both the rat and the rabbit. In the rat hepatocyte, the primary intracellular metabolite was deoxyadriamycin aglycone, while significant levels of deoxyadriamycinol aglycone were also synthesized; little adriamycinol was observed in the cells or the incubation medium. In contrast, in the rabbit hepatocyte, significant levels of adriamycinol as well as deoxyadriamycinol aglycone were formed; deoxyadriamycinol aglycone was the primary intracellular metabolite while low levels of deoxyadriamycin aglycone were observed. The relative formation of deoxyadriamycinol aglycone and deoxyadriamycin aglycone suggests that adriamycinol may be metabolized more effectively to the deoxyaglycone derivative than the parent drug. Conjugates of adriamycin were not observed in hepatocytes from either the rat or the rabbit or in the incubation medium.

Magnetic resonance imaging of cardiac rhabdomyosarcoma. Quantifying the response to chemotherapy

This report illustrates the use of cardiac magnetic resonance imaging (MRI) to quantify the initial extent of a cardiac rhabdomyosarcoma and, more importantly, its response to chemotherapy. Image slices spanning the heart and adjacent structures were analyzed using Simpsons rule applied to the image slices to estimate the tumor volume initially, then after 5 weeks, and again after 4 months of chemotherapy. A substantial, progressive reduction in tumor volume during chemotherapy was shown. After chemotherapy was discontinued, an increase in tumor volume was shown. It is suggested that, in addition to being useful in patient care, the technique may be useful in clinical investigations by providing an objective, quantitative measure of tumor response to therapy.

Metabolism of the anthracycline antibiotic daunorubicin to daunorubicinol and deoxydaunorubicinol aglycone in hepatocytes isolated from the rat and the rabbit

In the rat and rabbit hepatocyte in suspension, daunorubicin was metabolized primarily to deoxydaunorubicinol aglycone and daunorubicinol. Little deoxydaunorubicin aglycone was observed in either species. High levels of daunorubicinol in the rabbit hepatocyte reflected the greater affinity of rabbit hepatic aldo-keto reductase for the substrate, daunorubicin. Conjugates of the anthracyclines were not observed with hepatocytes from either species. The relative formation of deoxydaunorubicinol aglycone and deoxydaunorubicin aglycone suggests that daunorubicinol is a preferred substrate for reductive deglycosidation. Consequently, the presence of daunorubicinol in the circulation of patients undergoing chemotherapy with daunorubicin may be a factor in the therapeutic efficacy of this antineoplastic agent.

Enhanced analytical sensitivity of a quantitative PCR for CMV using a modified nucleic-acid extraction procedure.

Accurate and rapid diagnosis of CMV disease in immunocompromised individuals remains a challenge. Quantitative polymerase chain reaction (QPCR) methods for detection of CMV in peripheral blood mononuclear cells (PBMC) have improved the positive and negative predictive value of PCR for diagnosis of CMV disease. However, detection of CMV in plasma has demonstrated a lower negative predictive value for plasma as compared with PBMC. To enhance the sensitivity of the QPCR assay for plasma specimens, plasma samples were centrifuged before nucleic‐acid extraction and the extracted DNA resolubilized in reduced volume. Optimization of the nucleic‐acid extraction focused on decreasing or eliminating the presence of inhibitors in the pelleted plasma. Quantitation was achieved by co‐amplifying an internal quantitative standard (IS) with the same primer sequences as CMV. PCR products were detected by hybridization in a 96‐well microtiter plate coated with a CMV or IS specific probe. The precision of the QPCR assay for samples prepared from untreated and from pelleted plasma was then assessed. The coefficient of variation for both types of samples was almost identical and the magnitude of the coefficient of variations was reduced by a factor of ten if the data were log transformed. Linearity of the QPCR assay extended over a 3.3‐log range for both types of samples but the range of linearity for pelleted plasma was 20 to 40,000 viral copies/ml (vc/ml) in contrast to 300 to 400,000 vc/ml for plasma. Thus, centrifugation of plasma before nucleic‐acid extraction and resuspension of extracted CMV DNA in reduced volume enhanced the analytical sensitivity approximately tenfold over the dynamic range of the assay. J. Clin. Lab. Anal. 14:32–37, 2000.

Variable effects of tamoxifen on human hematopoietic progenitor cell growth and sensitivity to doxorubicin

To determine the influence of tamoxifen on the drug sensitivity of normal human hematopoietic progenitor cells, T-cell- and adherent-cell depleted human bone marrow mononuclear cells (T−, Ad−) were exposed in vitro to 5 μM tamoxifen for 24 h. The effects of tamoxifen were highly variable, as exposure to tamoxifen produced an increase (97%±12.3%) in the growth of day-12 committed myeloid progenitors (CFU-GM) in only four of ten experiments utilizing bone marrow from different donors. When T−, Ad− myeloid progenitor cells treated with tamoxifen were subsequently exposed to doxorubicin, 7 of 14 experimental samples studied demonstrated a net increase in the number of surviving clonogenic cells as compared with cells exposed to doxorubicin alone. Tamoxifen also stimulated the growth of a more purified (CD34+-selected) progenitor cell population in four of four experiments (by 62.5%±4.9%) but did not increase the survival of these cells upon exposure to doxorubicin; in fact, in five of ten experimental samples, tamoxifen enhanced cell sensitivity to doxorubicin. Taken together, these observations indicate that tamoxifen produces variable stimulation of committed myeloid progenitor cell growth in vitro. Furthermore, while under some circumstances, tamoxifen appears to have the capacity to enhance CFU-GM survival in the presence of doxorubicin, this drug combination may also result in enhanced toxicity to normal bone marrow progenitors.