A Pharmacokinetic and Safety Study of Trebananib, an Fc-Fusion Peptibody, in Patients With Advanced Solid Tumors and Varying Degrees of Renal Dysfunction.

Clearance of trebananib (AMG 386), a 64-kD antiangiogenic peptibody, has been associated with estimated glomerular filtration rate (eGFR). We prospectively evaluated trebananib pharmacokinetics and safety/tolerability in advanced solid tumor patients with varying degrees of renal function. Patients were assigned to normal renal function, mild, moderate, or severe renal dysfunction cohorts based on eGFR, received trebananib 15 mg/kg i.v. weekly, and underwent week 1 and week 5 pharmacokinetic and weekly safety assessments. For 28 patients, trebananib clearance decreased from normal renal function (1.52 mL/hr/kg), to mild (1.20 mL/hr/kg), moderate (0.79 mL/hr/kg), and severe (0.53 mL/hr/kg) renal dysfunction (P ≤ 0.001). Treatment-related adverse events showed no association with clearance. Trebananib clearance was proportional to eGFR and unrelated to pretreatment protein excretion. These data confirm a role for renal clearance of a recombinant peptibody with molecular weight <69 kD and support a longer dosing interval for patients with severe renal dysfunction.

Phase II study of oral docetaxel and cyclosporine in canine epithelial cancer.

The goal of the current study was to determine the efficacy of oral docetaxel in combination with cyclosporine in the treatment of canine epithelial cancer. Requirements for eligibility were histological confirmation of epithelial neoplasia, measurable disease, no chemotherapy treatment within 2 weeks, and a life expectancy of ≥ 3 months. Fifty-one dogs were enrolled. All dogs received 1.625 mg kg(-1) of docetaxel with 5 mg kg(-1) of cyclosporine (DT/CSA) by gavage. Ten dogs had progressive disease at 2 weeks, one dog died, and one dog was withdrawn from the study. Thirty-nine dogs were given a second dose of DT/CSA, three each receiving a third or fourth dose. Eight dogs had a dose reduction (1.5 mg kg(-1)) and six dogs had treatment delays primarily for gastrointestinal toxicity. The overall response rate was 16.7% (8/48 had a partial response there were no complete responses). The highest response rate was seen in dogs with oral squamous cell carcinoma (50%; 6/12).

An evaluation of the drug interaction potential of pazopanib, an oral vascular endothelial growth factor receptor tyrosine kinase inhibitor, using a modified Cooperstown 5+1 cocktail in patients with advanced solid tumors.

Pazopanib, an oral inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-kit kinases, inhibits multiple cytochrome P450 (CYP450) enzymes in vitro. This study in patients with advanced cancer evaluated the effect of pazopanib on CYP450 function by comparing the pharmacokinetics of CYP-specific probe drugs in the presence and absence of pazopanib. The probes used included midazolam (CYP3A specific), warfarin (CYP2C9 specific), omeprazole (CYP2C19 specific), caffeine (CYP1A2 specific), and dextromethorphan (CYP2D6 specific). The estimated ratios of the geometric means (90% confidence interval (CI)) for the area under the curve to the last measurable point (AUC(0-t)) for these probe drugs with/without pazopanib were as follows: midazolam, 1.35 (1.18-1.54); omeprazole, 0.81 (0.59-1.12); caffeine, 1.00 (0.77-1.30); and S-warfarin, 0.93 (0.84-1.03). The geometric least-squares (LS) mean ratio of urine dextromethorphan:dextrorphan ranged from 1.33 (0-4-h interval) to 1.64 (4-8-h interval). The data suggest that pazopanib is a weak inhibitor of CYP3A4 and CYP2D6 and has no effect on CYP1A2, CYP2C9, and CYP2C19 in patients with advanced cancer.

Bioequivalence study of a new oral topotecan formulation, relative to the current topotecan formulation, in patients with advanced solid tumors.

OBJECTIVE: The aims of this study were to investigate the bioequivalence of a new oral topotecan formulation (i.e., proposed commercial formulation) relative to the current oral formulation (formulation used in previous clinical trials), the effect of food on the absorption and disposition of the new oral topotecan and its safety and tolerability in patients with advanced solid tumors. PATIENTS AND METHODS: This was a multi-center, pharmacological Phase I, multiple-dose, randomized, open-label, cross-over bioequivalence study. In the bioequivalence part, 85 patients were randomized to receive either a 4 mg (4 x 1 mg) dose of the new or current formulation on Days 1 or 8. In the food-effect part, 23 patients received a 4 mg (4 x 1 mg) dose of the new formulation in a fasted and fed state. Total topotecan and topotecan lactone were determined and pharmacokinetic data were analyzed by non-compartmental method. RESULTS: Bioequivalence was demonstrated as the 90% confidence intervals of the ratio of the new to current formulation for both the area under the plasma concentration-time curve (AUC) and the maximal drug concentration (Cmax) for topotecan lactone were contained within the 0.8 - 1.25 boundary. The AUC and Cmax were similar in the fed and fasted state whilst food delayed the tmax for topotecan lactone and total topotecan. Safety data were collected on all subjects enrolled (n = 108) and were consistent with observations from previous studies of oral topotecan. All subjects experienced at least one adverse event, the majority of which were graded as mild to moderate in severity. CONCLUSION: The new oral topotecan formulation demonstrated bioequivalence to the current formulation and demonstrated it can be administered to patients with solid tumors in the fed or fasted state with similar systemic exposure.

Aplidin synergizes with cytosine arabinoside: functional relevance of mitochondria in Aplidin-induced cytotoxicity.

Aplidin (plitidepsin) is a novel marine-derived antitumor agent presently undergoing phase II clinical trials in hematological malignancies and solid tumors. Lack of bone marrow toxicity has encouraged further development of this drug for treatment of leukemia and lymphoma. Multiple signaling pathways have been shown to be involved in Aplidin-induced apoptosis and cell cycle arrest in G1 and G2 phase. However, the exact mechanism(s) of Aplidin action remains to be elucidated. Here we demonstrate that mitochondria-associated or -localized processes are the potential cellular targets of Aplidin. Whole genome gene-expression profiling (GEP) revealed that fatty acid metabolism, sterol biosynthesis and energy metabolism, including the tricarboxylic acid cycle and ATP synthesis are affected by Aplidin treatment. Moreover, mutant MOLT-4, human leukemia cells lacking functional mitochondria, were found to be resistant to Aplidin. Cytosine arabinoside (araC), which also generates oxidative stress but does not affect the ATP pool, showed synergism with Aplidin in our leukemia and lymphoma models in vitro and in vivo. These studies provide new insights into the mechanism of action of Aplidin. The efficacy of the combination of Aplidin and araC is currently being evaluated in clinical phase I/II program for the treatment of patients with relapsed leukemia and high-grade lymphoma.

Sublethal concentrations of gemcitabine (2',2'-difluorodeoxycytidine) alter mitochondrial ultrastructure and function without reducing mitochondrial DNA content in BxPC-3 human pancreatic carcinoma cells.

2',2'-Difluorodeoxycytidine (gemcitabine), a pyrimidine nucleoside analog, is used therapeutically in the treatment of pancreatic, non-small cell lung, and breast cancer. The cytotoxic effect of gemcitabine is thought to be due to masked chain termination after the triphosphorylated anabolite of the drug is incorporated into nascent DNA strands. We tested the hypothesis that sublethal concentrations of gemcitabine inhibit DNA polymerase gamma and reduce mitochondrial DNA content in BxPC-3 and MOLT-4 cell lines, and we used 2',3'-dideoxycytidine, a known inhibitor of DNA polymerase gamma as a positive control. The 6-day BxPC-3 cell growth IC(50) for gemcitabine and 2',3'-dideoxycytidine was 0.003 microM (SD +/- 0.0005) and 14.5 microM (SD +/- 4.7), respectively, and in MOLT-4 cells was 0.002 microM (SD +/- 0.001) and 0.86 muM (SD +/- 0.23), respectively. These drug concentrations were anti-proliferative but non-cytotocidal. Electron photomicrographic studies showed deranged mitochondrial cristae patterns in BxPC-3 cells treated with either gemcitabine or 2',3'-dideoxycytidine for 6 days. Mitochondrial oxidative phosphorylation dysfunction was observed as reflected by increased lactate concentration in the media of cells exposed to gemcitabine, but to a much greater extent in cells exposed to 2',3'-dideoxycytidine. PCR analysis showed that gemcitabine did not reduce mitochondrial DNA content in either BxPC-3 or MOLT-4 cells, but 2',3'-dideoxycytidine did. The effect of gemcitabine on mitochondrial ultrastructure and function did not concomitantly yield a reduction in mitochondrial DNA content. Therefore, the molecular target(s) by which gemcitabine and 2',3'-dideoxycytidine produce mitochondrial abnormalities in these cells appear to be different.

Two cases of rapid onset Parkinson's syndrome following toxic ingestion of ethylene glycol and methanol.

Ethylene glycol and methanol are toxic alcohols commonly found in a variety of commercial products. We report two cases, one associated with ethylene glycol and one with methanol poisoning, which both led to acute hemorrhagic necrosis of the basal ganglia and resulted in acute Parkinson's syndrome. It is unlikely that oxalate crystal deposition is the only mechanism for such basal ganglia necrosis, because similar findings were seen following methanol intoxication. We discuss other possible mechanisms that may contribute towards this unusual neurotoxicity. Both of our patients survived their toxic ingestions, but then developed acute Parkinson's syndrome within 10 days of the ingestion. However, the patient who ingested methanol developed respiratory muscle stiffness/weakness, which responded poorly to anti-Parkinsonian drug therapy. Treatment with carbidopa/levodopa improved cogwheel rigidity and bradykinesia in both patients. We conclude that acute Parkinsonism is one of the lesser-recognized devastating complications of both ethylene glycol and methanol poisoning.

Phase I and pharmacokinetic evaluation of the combination of orally administered docetaxel and cyclosporin A in tumor-bearing cats.

Intravenously administered docetaxel (DT) is problematic in cats because of the requirement for premedication to ameliorate acute vehicle-induced hypersensitivity reactions. Previously we have revealed that therapeutic plasma concentrations of DT can be achieved in normal and tumor-bearing dogs when DT is administered PO in combination with oral cyclosporin A (CSA). The purpose of this study was to identify the maximally tolerated dosage and characterize the pharmacokinetic disposition of oral DT combined with CSA in cats with tumors. Eighteen tumor-bearing cats were enrolled in this phase I dose escalation and pharmacokinetic study. DT was administered by gavage with CSA (5 mg/kg) twice over a 3-week period. The starting dose of DT was 1.0 mg/kg. Based on the clinical toxicity profile, with gastrointestinal adverse effects and hematologic toxicity the maximal tolerated dose of oral DT was 1.75 mg/kg in combination with 5 mg/kg CSA. Additional studies are necessary to determine the efficacy of DT/CSA in cats with epithelial tumors.

Ex vivo zidovudine (AZT) treatment of CD34+ bone marrow progenitors causes decreased steady state mitochondrial DNA (mtDNA) and increased lactate production.

Haematopoietic suppression is one of the dose-limiting side effects of chronic zidovudine (AZT) therapy. We tested the hypothesis that AZT would reduce mitochondrial DNA (mtDNA) content in haematopoietic progenitors causing impaired haematopoiesis and mitochondrial dysfunction. We studied the effects of AZT 0-50 microM in vitro, on normal human CD34+ haematopoietic progenitor cells cultured ex vivo for up to 12 days. The mean AZT IC50 for granulocyte (phenotype CD15+/CD14-) and erythroid (phenotype glycophorin+/CD45-) cell proliferation was 2.5 microM (SD+/-0.7) and 0.023 microM (SD+/-0.005), respectively. In myeloid-rich cell cultures, the mean lactate content of the media, compared to untreated controls, increased by 86% (SD+/-23) at 10 microM AZT and in erythroid-rich cultures it increased by 134% (SD+/-24) in the presence of 0.5 microM AZT. In myeloid-rich cultures the AZT IC50 for the reduction in the mitochondrial/nuclear DNA content ratio was 5.6 microM, whereas in erythroid rich cultures this AZT IC50 was < 0.0005 microM. AZT produced concentration-dependent inhibition of CD34+ progenitor proliferation into both myeloid and erythroid lineages; erythropoiesis was more sensitive than myelopoiesis. Concurrently, AZT reduced steady state mtDNA content, while increasing lactate production. These findings support the hypothesis that mtDNA is one of the intracellular targets involved in the pathogenesis of AZT-associated bone marrow progenitor cell toxicity.

Taxanes synergize with the bispecific antibody MDXH447 to enhance antibody-dependent cell-mediated cytotoxicity.

The interaction between antibody based therapy and cytotoxic chemotherapy is complex. To explore these interactions we investigated, in vitro, the effects of IC20 growth inhibitory concentrations of taxanes on bispecific antibody-mediated tumor cell cytotoxicity. MDXH447 is a bispecific antibody with specificity for the high affinity IgG receptor (CD64) and the type I epidermal growth factor receptor type (EGF-R). A431 cells, an epidermoid carcinoma cell line that over expresses EGF-R, were exposed to a range of IC20 growth inhibitory concentrations of paclitaxel or docetaxel. Interferon gamma activated monocytes were armed with MDXH447 and a standard chromium release antibody-dependent cell-mediated cytotoxicity (ADCC) assay was performed. Using the Chou and Talalay median effect analysis, we found that MDXH447-mediated ADCC was enhanced when A431 target cells were pretreated with paclitaxel or docetaxel. Median effect analysis of these interactions supported a synergistic interaction (CI < 1). Pretreatment of A431 cells with taxanes did not increase EGF-R expression compared to untreated controls. A431 epidermoid carcinoma cells pretreated with IC20 growth inhibitory concentrations of taxanes enhanced interferon gamma activated monocyte mediated ADCC killing through MDXH447.

Phase I study of twice-weekly gemcitabine and concomitant external-beam radiotherapy in patients with adenocarcinoma of the pancreas.

PURPOSE: To determine the maximum tolerated dose and dose-limiting toxicity associated with twice-weekly gemcitabine and concomitant external-beam radiotherapy in patients with adenocarcinoma of the pancreas. METHODS AND MATERIALS: Twenty-one patients with biopsy-proven adenocarcinoma of the pancreas were treated with external-beam radiotherapy to a dose of 50.4 Gy in 28 fractions, concurrent with gemcitabine, infused over 30 min before irradiation on a Monday and Thursday schedule. The dose of gemcitabine was escalated in 5 cohorts of 3--6 patients each. Initial gemcitabine dose was 10 mg/m(2), with dose escalation until dose-limiting toxicity was observed. RESULTS: The maximum tolerated dose of gemcitabine was 50 mg/m(2), when given in a twice-weekly schedule with radiation. Dose-limiting toxicity was seen in 2 patients at 60 mg/m(2), and consisted of severe upper gastrointestinal bleeding approximately 1 month after completion of treatment. Six patients had radiographic evidence of response to treatment, and 5 of these underwent complete surgical resection. Three patients who underwent complete resection had been deemed to have unresectable tumors before enrollment on trial. Four patients are alive, including 2 without evidence of disease more than 1 year after resection. CONCLUSION: The combination of external-beam radiation and twice-weekly gemcitabine at a dose of 50 mg/m(2) is well tolerated and shows promising activity for the treatment of pancreatic cancer. Our data suggest a higher maximum tolerated dose and different dose-limiting toxicity than previously reported. Further investigation of this regimen is warranted.

Phase I pilot trial of the bispecific antibody MDXH210 (anti-Fc gamma RI X anti-HER-2/neu) in patients whose prostate cancer overexpresses HER-2/neu.

The goal of this study was to evaluate, in patients with prostate cancer, the toxicity profile and biologic activity of the bispecific antibody MDXH210, which has specificity for the non-ligand-binding site of the high-affinity immunoglobulin G receptor (Fc gamma RI) and the extracellular domain of the HER-2/neu proto-oncogene product. Patients with prostate cancer that expressed HER-2/neu were entered into a phase I dose-escalation trial of MDXH210. Patients received an intravenous infusion MDXH210 during a period of 2 h three times per week for 2 weeks and were monitored for toxicity. Pharmacokinetic and pharmacodynamic parameters were measured and included the biologic end points of monocyte-bound MDXH210, cytokine production, and clinical response. Seven patients were treated with MDXH210 doses ranging from 1 to 8 mg/m2. In general, MDXH210 was well tolerated, with only mild infusion-related malaise, fever, chills, and myalgias. No dose-limiting toxic effects were observed. Biologic effects included induction of low plasma concentrations of tumor necrosis factor-alpha and interleukin-6 observed immediately after MDXH210 infusion and 70% saturation of circulating monocyte-associated Fc gamma RI with MDXH210 at a dose level of 4 to 8 mg/m2. Five of six patients had stable prostate-specific antigen levels during the course of 40 days or more. Circulating plasma HER-2/neu levels decreased by 80% at days 12 and 29 (p = 0.03 and 0.06, respectively, by the Wilcoxon signed rank test). MDXH210 can be given safely to patients with HER-2/neu-positive prostate cancer in doses of at least 8 mg/m2. At the doses studied, biologic activity was demonstrated and characterized by binding of MDXH210 to circulating monocytes, release of monocyte-derived cytokines, a decrease in circulating HER-2/neu, and short-term stabilization of prostate-specific antigen levels.

Pharmacokinetic-pharmacodynamic relationships of the bispecific antibody MDX-H210 when administered in combination with interferon gamma: a multiple-dose phase-I study in patients with advanced cancer which overexpresses HER-2/neu.

INTRODUCTION: MDX-H210 is a Fab'xFab' bispecific antibody (BsAb) constructed chemically by crosslinking Fab' mAb 520C9 (anti-HER-2/neu) and Fab' mAbH22 (anti-CD64). STUDY DESIGN AND OBJECTIVES: This was a dose escalation study of intravenous MDX-H210 (1-70 mg/m(2)), preceded 24 h beforehand by subcutaneous IFNgamma (50 microg/m(2) to up-regulate FcgammaRI) administered three times a week for 3 weeks. We investigated the pharmacokinetic-pharmacodynamic relationships between MDX-H210 C(max) and AUC and (i) MDX-H210 binding to peripheral blood monocytes and neutrophils, (ii) the peak plasma G-CSF, IL-6, IL-8 and TNFalpha concentrations, and (iii) the observed clinical toxicity. RESULTS: 23 patients (19F:4M; median age 51.5; range 25-72 y) with advanced HER-2/neu positive cancers (19 breast, three prostate and one lung) were studied. Plasma MDX-H210 concentrations over time, circulating numbers of monocytes and neutrophils, percent saturation of monocyte and neutrophil FcgammaRI, and plasma concentrations over time of G-CSF, IL-6, IL-8 and TNFalpha were measured and clinical toxicity monitored. The E(max) pharmacodynamic model best fitted the relationship of MDX-H210 C(max) and the maximum percent saturation of both monocytes (E(max)=74.6; EC(50)=0.9 microg/ml) and neutrophils (E(max)=66.2; EC(50)=2.3 microg/ml) on the first day of treatment. On the last day of treatment, day 19, these parameters were E(max)=57.0% and EC(50)=0.46 microg/ml for monocytes and E(max)=61.9% and EC(50)=0.26 microg/ml for neutrophils. No positive relationship was defined between the log MDX-H210 C(max) and the log peak plasma IL-6, G-CSF, TNF or IL-8 concentrations on day 1. On day 19 these plasma cytokine concentrations were undetectable post MDX-H210 therapy. There was no consistent relationship between MDX-H210 C(max) and the observed clinical toxicities. CONCLUSIONS: These data suggest that MDX-H210 C(max) and AUC could be related by the E(max) model to maximum percent FcgammaRI saturation on circulating monocytes and neutrophils in the patients studied. After day 1, the post MDX-H210 therapy cytokine response attenuated over time, consistent with desensitization. We did not find a relationship between log MDX-H210 C(max) and peak plasma cytokine concentrations or clinical toxicities.

Bispecific antibody-targeted phagocytosis of HER-2/neu expressing tumor cells by myeloid cells activated in vivo.

Studies from our laboratory and others have established that both mononuclear phagocytes and neutrophils mediate very efficient cytotoxicity when targeted through Fc receptors using a suitable monoclonal or bispecific antibody (BsAb). Cross-linking an Fc receptor for IgG (FcgammaR) triggers multiple anti-tumor activities including superoxide generation, cytokine and enzyme release, phagocytosis and antibody-dependent cellular cytotoxicity (ADCC). In this report, using unfractionated leukocytes and two color flow cytometric analysis, we describe the phagocytic capacity of peripheral blood polymorphonuclear cells (PMN) and monocytes isolated from patients enrolled in a phase I clinical trial of MDX-H210 given in combination with IFNgamma. MDX-H210 is a BsAb targeting the myeloid trigger molecule FcgammaRI and the HER-2/neu proto-oncogene product overexpressed on a variety of adenocarcinomas. In this trial, cohorts of patients received escalating doses of MDX-H210 3 times per week for 3 weeks. Interferon-gamma (IFNgamma) was given 24 h prior to each BsAb infusion. Our results demonstrate that monocytes from these patients were inherently capable of phagocytosing the HER-2/neu positive SK-BR-3 cell line and that addition of MDX-H210 into the assay significantly enhanced the number of targets phagocytosed. Two days after administration of an immunologically active dose of MDX-H210 (10 mg/m2), monocytes from these patients were able to phagocytose greater amounts of target cell material, indicating that these cells remained armed with functionally sufficient BsAb for at least 48 h. PMN from these patients very efficiently mediated phagocytosis through FcgammaRI after being treated with IFNgamma, but not before. We conclude that phagocytosis is not only an efficient mechanism of myeloid cell-mediated cytotoxicity, but may also be a mechanism by which antigens from phagocytosed cells can enter a professional antigen presenting cell for processing and presentation.

The role of polymorphonuclear neutrophils (PMNs) in clearance of granulocyte colony-stimulating factor (G-CSF) in vivo and in vitro.

Previous studies have suggested that in vivo granulocyte colony-stimulating factor (G-CSF) pharmacokinetics may change over time. We studied three patients treated with high-dose chemotherapy followed by autologous bone marrow transplantation (ABMT) for metastatic breast cancer after intravenous administration of recombinant human (rh) G-CSF (5 or 16 microg/kg/day). We investigated plasma G-CSF concentrations and absolute neutrophil counts (ANCs/pL) in these patients on three separate days. G-CSF plasma clearance increased with time post-ABMT with no change in the apparent volume of distribution (Vd) of G-CSF. Regression analysis of G-CSF plasma clearance and ANCs revealed a linear relationship, with r2 = 0.85 (p = 0.00025). We further investigated this phenomenon in vitro by estimating pharmacokinetic parameters for rhG-CSF using a model in which polymorphonuclear neutrophils (PMNs) were incubated with rhG-CSF. We found that, at low G-CSF concentrations in vitro, there was an increase in G-CSF clearance with increasing ANCs, but at higher G-CSF concentrations this relationship did not hold. We suggest that this finding resulted from aggregation and polymerization of G-CSF at high concentrations when kept at 37 degrees C for 24-48 hours in vitro. Using fluorescence staining techniques, our data suggest there are changes over time in the amount of G-CSF bound to PMNs. These changes may reflect reexpression or recycling of the G-CSF receptor, and could explain the continuing clearance of G-CSF by PMNs in vitro. The strong positive correlation between G-CSF plasma clearance and ANCs in vivo is compatible with the hypothesis that neutrophils mediate one of the major pathways for rhG-CSF clearance.

Olsalazine and 6-mercaptopurine-related bone marrow suppression: a possible drug-drug interaction.

A patient with refractory Crohn's disease had two separate episodes of bone marrow suppression while receiving 50 to 75 mg 6-mercaptopurine a day and 1000 to 1750 mg olsalazine a day. This adverse reaction necessitated dose reduction of 6-mercaptopurine on the first occasion and withdrawal of 6-mercaptopurine and olsalazine on the second occasion. The patient's red blood cell thiopurine methyltransferase (TPMT) activity was 1.2 U per milliliter red blood cells (low normal range) and her TPMT genotype was wild-type sequence for all known alleles of TPMT that result in low TPMT enzyme activity. In vitro enzyme kinetic studies confirmed the hypothesis that olsalazine and olsalazine-O-sulfate are potent noncompetitive inhibitors of recombinant human TPMT. We suggest that the patient's relatively low baseline level of TPMT activity was inhibited by olsalazine and olsalazine-O-sulfate, leading to decreased clearance of 6-mercaptopurine and its accumulation. This ultimately increased intracellular 6-thiopurine nucleotide levels to toxic concentrations, which caused bone marrow suppression.

Delayed sequelae after acute overdoses or poisonings: cranial neuropathy related to ethylene glycol ingestion.

A 31-year-old woman came to the hospital with breathlessness, confusion, and a refractory anion gap metabolic acidosis; acute renal failure subsequently developed. Her blood ethylene glycol concentration was 390 mg/L, and she was treated with an intravenous ethanol infusion and hemodialysis. During the tenth and eleventh day after admission bilateral seventh cranial nerve paralysis developed, as well as bilateral dysfunction of cranial nerves II, V, VIII, IX, X and XII. Magnetic resonance imaging of her head showed gadolinium enhancement of the fifth cranial nerve bilaterally and a communicating hydrocephalus. Over the subsequent 11 months she recovered full function of her cranial nerves V, VII, IX, X, and XII, and she had subjective clinical improvement to baseline function in cranial nerves II and VIII. This case serves to introduce a discussion of agents that cause delayed complications after their acute toxic ingestion.

A study of 5 day fractionated ifosfamide pharmacokinetics in consecutive treatment cycles.

1. Ifosfamide demonstrates increased clearance with time when administered daily for 5 days. The objectives of this study were to define whether the increased ifosfamide clearance was sustained between treatment cycles and whether it was reproducible in consecutive treatment cycles. 2. Seven patients with inoperable cancer received 1.5 g m-2 ifosfamide infused intravenously over 0.5 h, each day for 5 days, for two consecutive cycles. Urine and appropriately timed blood samples were collected for up to 24 h post ifosfamide infusion on day 1 and day 5. Plasma ifosfamide concentrations were assayed by gas liquid chromatography and pharmacokinetic parameters were imputed using non-compartmental analysis. 3. The difference in the mean (n = 7) total ifosfamide plasma clearance between day 5 and day 1 of Cycle I was an increase of 56.8 ml min-1 (99.8% CIs + 22.6-->+ 91.4). The difference in the mean (n = 7) total ifosfamide plasma clearance between day 1 of Cycle II and day 5 was a decrease of 61.9 ml min-1 (99.8% CIs -111.2 -->-12.6). The magnitude of the mean increase in total ifosfamide plasma clearance in Cycle II and Cycle I was similar because the difference between these means (0.9 ml min-1, 99.8% CIs -63.7-->+65.3) was not statistically significant. There was no change in the apparent volume of distribution of ifosfamide between the two study days in either of Cycle I or II, or between cycles. 4. The difference in the mean (n = 7) ifosfamide renal clearance between day 5 and day 1 of Cycle I was minus 0.4 ml min-1 (99.8% CIs -8.5-->+8.6); the means +/- s.d. wee 6.3 +/- 2.6 ml min-1 and 6.7 +/- 3.2 ml min-1 respectively. The difference in the mean (n = 4) ifosfamide renal clearance between day 5 and day 1 of Cycle II was -0.2 ml min-1 (99.8% CIs -5.7-->+5.2); the means +/- s.d. were 7.8 +/- 6.1 ml min-1 and 8.0 +/- 6.2 ml min-1 respectively. 5. These data suggest that the increase in total ifosfamide plasma clearance with time in a 5 day fractionated regimen was due to an increase in ifosfamide metabolism which was not sustained over the 21 days between cycles, but was reproducible and of a similar magnitude in the two consecutive treatment cycles studied.