Helen Kastrissios

Phase I and Pharmacokinetic Study of Irinotecan and Docetaxel in Patients With Advanced Solid Tumors: Preliminary Evidence of Clinical Activity

PURPOSE The goals of this study were to determine the maximum-tolerated dose and describe the toxicities of the combination of irinotecan and docetaxel administered every 3 weeks to patients with advanced malignancies and, also, to evaluate the effect of irinotecan on the disposition of docetaxel and describe preliminary evidence of antitumor activity. PATIENTS AND METHODS Eighteen patients received 85 courses (median, two courses; range, one to 15 courses) of treatment with irinotecan, administered over 90 minutes by intravenous infusion, followed by docetaxel, administered over 60 minutes by intravenous infusion. Four escalating dose levels of irinotecan/docetaxel (160/50 mg/m(2), 160/65 mg/m(2), 200/65 mg/m(2), and 200/75 mg/m(2)) were studied. Pharmacokinetic analyses were performed to evaluate the effect of irinotecan on the disposition of docetaxel. RESULTS The most common and dose-limiting toxicity was myelosuppression, which consisted of neutropenia that was severe (National Cancer Institute common toxicity criteria [NCI CTC] grade 4) but brief (< 5 days) in 11 patients, with three episodes of febrile neutropenia. Nonhematologic toxicities of anorexia, nausea, and stomatitis were mild to moderate (NCI CTC grades 1 and 2), but there was one incidence each of both CTC grade 3 anorexia and nausea. All patients had total alopecia. Diarrhea was dose-dependent and severe in four patients who failed to take adequate antidiarrhea therapy. Five out of 16 assessable patients, one with cholangiocarcinoma, one with leiomyosarcoma, and three with non-small-cell lung cancer, achieved partial remissions. CONCLUSION The combination of irinotecan and docetaxel causes significant reversible myelosuppression, which was dose limiting but led to no serious sequelae. There was no evidence of a clinically significant interaction using these two agents in this sequence. The combination showed antitumor activity at all the dose levels tested and should be further studied in a number of tumor types. The recommended phase II dose on this schedule is irinotecan 160 mg/m(2) and docetaxel 65 mg/m(2).

Population pharmacokinetic model for irinotecan and two of its metabolites, SN‐38 and SN‐38 glucuronide

The objective of the study was to develop and validate a population pharmacokinetic model for irinotecan and 2 of its metabolites, SN‐38 and SN‐38 glucuronide (SN‐38G).

Novel, biocompatible, and disease modifying VIP nanomedicine for rheumatoid arthritis.

Despite advances in rheumatoid arthritis (RA) treatment, efficacious and safe disease-modifying therapy still represents an unmet medical need. Here, we describe an innovative strategy to treat RA by targeting low doses of vasoactive intestinal peptide (VIP) self-associated with sterically stabilized micelles (SSMs). This spontaneous interaction of VIP with SSM protects the peptide from degradation or inactivation in biological fluids and prolongs circulation half-life. Treatment with targeted low doses of nanosized SSM-VIP but not free VIP in buffer significantly reduced the incidence and severity of arthritis in an experimental model, completely abrogating joint swelling and destruction of cartilage and bone. In addition, SSM associated VIP, unlike free VIP, had no side-effects on the systemic functions due to selective targeting to inflamed joints. Finally, low doses of VIP in SSM successfully downregulated both inflammatory and autoimmune components of RA. Collectively, our data clearly indicate that VIP-SSM should be developed to be used as a novel nanomedicine for the treatment of RA.

Screening for Sources of Interindividual Pharmacokinetic Variability in Anticancer Drug Therapy: Utility of Population Analysis

Most cytotoxic drugs are characterized by a narrow therapeutic index, such that clinically effective doses are associated with some degree of acute or delayed toxicity. In cancer chemotherapy, the optimal dose is the dose that maximizes the likelihood of a successful treatment outcome and minimizes the risk of toxicity. An increasing number of studies have shown that in comparison to drug dose, measures of exposure to anticancer drug therapy, such as the area under the plasma concentration vs. time curve (AUC), are superior predictors of cytotoxicity, including therapeutic and toxic effects (1,2). Thus, understanding pharmacokinetic and pharmacodynamic relationships in cancer chemotherapy should allow better utilization of anticancer drugs and ultimately enhance patient care (3). The optimal dose of many cytotoxic drugs varies among individuals because variability in systemic expo-

Pharmacokinetics of diaspirin cross-linked haemoglobin in a rat model of hepatic cirrhosis

The aim of the study was to evaluate the effect of cirrhosis on the disposition of the haemoglobin‐based oxygen carrier, diaspirin cross‐linked haemoglobin (DCLHb). Cirrhosis was induced in male Sprague‐Dawley rats (200–250 g) by inhalational exposure to carbon tetrachloride (CCl4), over a period of 6 weeks. Pharmacokinetic evaluation was performed after a single intravenous bolus administration of DCLHb (400 mg kg−1). Serum biochemistry, including aspartate transaminase, alkaline phosphatase, bile acids, serum albumin, and serum creatinine, were measured in CCl4‐treated (n = 6) and age‐matched control (n = 6) rats. After 6 weeks, the jugular vein and carotid artery were cannulated for bolus DCLHb administration (400 mg kg−1) and blood sampling, respectively, in both groups of rats. Cirrhosis produced significant (P < 0.05) elevations in alkaline phosphatase (497.4 ± 84.8 U L−1 vs 241.2 ± 5.1 U L−1), aspartate transaminase (920.5 ± 190.9 U L−1 vs 238.2 ± 118.1 U L−1) and bile acids (333.8 ± 77.3 mg dL−1 vs 43.8 ± 4.2 mg dL−1) compared with the control group. No significant renal dysfunction was observed as a result of CCl4 exposure. Plasma DCLHb concentrations declined approximately log‐linearly. Systemic clearance of DCLHb was estimated to be 2.2 ± 0.7 mL h−1 in the treatment group and was slightly, but not significantly, less in the control group (3.6 ± 1.7 mL h−1). There was also a trend toward a longer elimination half‐life in the treatment group (4.7 ± 2.2 h) compared with the control group (3.8 ± 0.8 h), although this difference was not statistically significant. Cirrhosis does not significantly alter the disposition of DCLHb perhaps due to increased extra‐hepatic metabolism by the reticulo‐endothelial system.

Disposition of morphine in plasma and cerebrospinal fluid varies during neonatal development in pigs

The pharmacological effects of morphine are mediated via the central nervous system (CNS) but its clearance from the CNS in neonates has not been investigated. We have proposed that neonatal development of the blood‐brain barrier affected CNS clearance mechanisms and CNS exposure to morphine. Male piglets (n=5) aged one, three and six weeks were given morphine sulfate (0.5 mg kg−1, i.v.). Serial blood and cerebrospinal fluid (CSF) samples were withdrawn over 360 min after morphine administration. Morphine concentration was measured by radioimmunoassay. A three‐compartment model was fitted to individual data. Estimated parameters were reported as median and range. The peak morphine concentrations in plasma were not significantly different in the one‐, three‐ or six‐week‐old piglets. Plasma clearance at one week (4.5, 3.8‐8.6 mL min−1 kg−1) was significantly lower than at three weeks (30.0, 19.1‐ 39.0 mL min−1 kg−1) and six weeks (37.0, 29.7–82.8 mL min−1 kg−1). The peak morphine concentration in CSF at one week (59.84, 31–67 ng mL−1) was higher than at three weeks (18.8, 17.7–25 ng mL−1) and six weeks (24.51, 16.5–84 ng mL−1), while CSF clearance was lower at one week (1.0, 0.18‐9 mL min−1 kg−1) compared with three weeks (6.2, 2.3–9.3 mL min−1 kg−1) and six weeks (3.95, 1.3–85.7 mL min−1 kg−1). Apparent plasma: CSF transfer ratio at one week was greater than at three and six weeks. The reduced plasma and CSF morphine clearance in early infancy resulted in elevated systemic and central morphine exposure in neonatal pigs.