Biomedical subjects

D J Murry

Publications and source records attributed to D J Murry.

23 records · Page 2Linked to original sources

PubMed1993

Pharmacokinetics and acute renal effects of continuously infused carboplatin.

Carboplatin was given as a 24-hour infusion at high doses to pediatric patients with cancer (n = 11) and pharmacokinetic parameters and renal effects were determined. Median carboplatin clearance for course 1 (151 ml/min per 1.73 m2;) was not significantly different from clearance for course 2 (144 ml/min per 1.73 m2; p = 0.33). The median glomerular filtration rate measured before (159 ml/min per 1.73 m2) and after course 1 (161 ml/min per 1.73 m2) did not differ significantly (p = 0.4). Binding was time dependent but modest with a median free fraction at the end of infusion of 0.82. Pharmacokinetic parameters for continuous-infusion carboplatin are similar to those reported for short infusions, but the median dose of 817 mg/m2 required to achieve an acceptable systemic exposure in these patients was 45% greater than the previously suggested maximum tolerated dosage. Continuous infusion carboplatin did not alter carboplatin clearance or adversely effect glomerular filtration rate during a second course, showing the feasibility of this alternative dosage strategy to enhance therapeutic effects.

Adolescent↗

PubMedDate not supplied

Pharmacokinetics and cerebrospinal fluid penetration of daunorubicin, idarubicin, and their metabolites in the nonhuman primate model.

PURPOSE: Idarubicin (4-demethoxy-daunorubicin) is more potent and less cardiotoxic than the commonly used anthracyclines, doxorubicin and daunorubicin. In addition, idarubicin is metabolized to an active metabolite, idarubicinol, in contrast to other anthracyclines whose alcohol metabolites are much less active than the parent drug. The current study was performed in nonhuman primates to determine the plasma and cerebrospinal fluid (CSF) pharmacokinetics of idarubicin and idarubicinol and to compare them to the pharmacokinetics of daunorubicin and daunorubicinol. METHODS: A dose of 30 mg/m2 of daunorubicin or 8 mg/m2 of idarubicin was administered intravenously over 15 minutes. Plasma and CSF were sampled frequently from the end of the infusion to 72 to 96 hours after infusion. Drug and metabolite concentrations were measured using high-pressure liquid chromatography (HPLC). RESULTS: Daunorubicin elimination from plasma was triphasic with a terminal half-life of 5.9 +/- 1.8 hours, area under the concentration-time curve (AUC) 22.5 +/- 9.2 mumol/L.min, and clearance 2790 +/- 960 mL/min/m2. Daunorubicinol elimination was biphasic with a terminal half-life 10.2 +/- 2.3 hours and an AUC 74.5 +/- 5.3 mumol/L.min. Idarubicin elimination was triphasic with terminal half-life of 12.3 +/- 11.4 hours, a AUC 10.8 +/- 3.7 mumol/L.min, and clearance 1650 +/- 610 mL/min/m2. Idarubicinol elimination was biphasic with a terminal half-life 28.7 +/- 4.2 hours and AUC 67 +/- 9.8 mumol/L.min. CSF penetration was low for both parent drugs and their metabolites. CSF idarubicin was measurable at a single time point (1 hour after administration) for 2 animals, and was not measurable for the third. The CSF to plasma concentration ratio at that time point was 8% in 1 animal and 15% in the other. Idarubicinol was detected in 2 to 4 samples at various times, appearing as early as 1 hour in 1 animal and persisting as late as 48 hours in another. The CSF to plasma concentration ratio at corresponding time points was 1.9 +/- 0.6%. Daunorubicin was measurable for < 6 hours after intravenous administration. For individual animals, the mean CSF to plasma concentration ranged from 4% to 12%. Daunorubicinol was detectable by 1 hour in 2 of 3 animals and by 3 hours in the other, and remained detectable at 24 hours in 2 of 3. The terminal half-life of daunorubicinol in CSF was 8.8 +/- 1.3 hours, the AUC was 1.8 +/- 1.5 mumol/L.min, and the AUCCSF to AUCplasma ratio was 2.4 +/- 1.9%. CONCLUSION: Idarubicin, idarubicinol, daunorubicin, and daunorubicinol penetrate poorly into the CSF after intravenous administration.

Animals↗

PubMedDate not supplied

Renal function and methotrexate clearance in children with newly diagnosed leukemia.

STUDY OBJECTIVES: To determine whether glomerular filtration rate (GFR) changes during induction chemotherapy in children with leukemia, and to examine GFR as a determinant of pharmacokinetic variability of methotrexate clearance. DESIGN: Prospective, unblinded observational study in consecutive patients. SETTING: A research hospital. PATIENTS: Thirty-eight children newly diagnosed with acute lymphoblastic leukemia. INTERVENTIONS: The patients received either high-dose methotrexate 1 g/m2 intravenously over 24 hours or low-dose methotrexate 30 mg/m2 orally every 6 hours for six doses; both regimens were followed by an intensive six-drug chemotherapy regimen given over 6 weeks. Glomerular filtration rate was determined in each subject before and at the conclusion of induction therapy. MEASUREMENTS AND MAIN RESULTS: The GFR was determined from 99mTc-DTPA serum clearance in all patients, and methotrexate clearance was estimated from serial serum concentrations in 18 of these children who received high-dose methotrexate. Median values for GFR at diagnosis (131 ml/min/1.73 m2) and after induction therapy (120 ml/min/1.73 m2) were not significantly different (p = 0.26) but were highly variable (range 49-274 ml/min/1.73 m2). Body size, age, and serum creatinine were correlated significantly with GFR at diagnosis. Amphotericin B therapy (6 patients) significantly decreased GFR (p = 0.046) without a corresponding increase in serum creatinine. Methotrexate clearance (58-155 ml/min/m2) was significantly (p = 0.007) correlated with GFR, but GFR accounted for only 37% of the variability of methotrexate clearance. CONCLUSIONS: The GFR was normal but highly variable in these children with leukemia and was significantly altered by amphotericin. Our results explain little of the intersubject variability in methotrexate clearance.

Administration, Oral↗

PubMedDate not supplied

Formation of platinum-DNA adducts in pediatric patients receiving carboplatin.

STUDY OBJECTIVE: To determine the extent of platinum-DNA (Pt-DNA) adduct formation in peripheral white blood cells of children with cancer. DESIGN: Prospective study. SETTING: Pediatric research hospital. PATIENTS: Twenty-seven children receiving carboplatin as part of therapy as defined by clinical research protocols. INTERVENTIONS: Patients received various dosages of carboplatin over 1, 3, or 24 hours as a primary component of combination chemotherapy for pediatric solid tumors, brain tumors, or large cell lymphoma. MEASUREMENTS AND MAIN RESULTS: The Pt-DNA adducts were detectable in 10 (37%) of 27 patients. The median value was 3.4 fmol Pt/micrograms DNA (range 1.7-31.2 fmol) in patients with measurable values. CONCLUSION: The Pt-DNA adducts were detected less frequently in pediatric patients than reported in adults. Variables that influenced their detection were higher carboplatin dosages or systemic exposure and short (1-3 hrs) versus prolonged (24 hrs) infusions.

Adult↗

PubMedDate not supplied

Comparative clinical pharmacology of cisplatin and carboplatin.

The platinum compounds cisplatin and carboplatin are active against a wide range of adult and pediatric malignancies. Whereas both exert their cytotoxic effect by incorporating into DNA, they have substantially different systemic and cellular pharmacology. In addition, their toxicity profiles are much different. Substantial interpatient pharmacokinetic variability and narrow therapeutic indexes of the two agents led to the development of several dosing strategies. Although these strategies reduce pharmacokinetic variability, their effect on improving patient outcome remains to be determined.

Animals↗