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Preclinical and Phase I Studies With Rhizoxin to Apply a Pharmacokinetically Guided Dose-Escalation Scheme M. A. Graham* D. Bissett, A. Setanoians, T. Hamilton, D. J. Kerr, R. Henrar, S. B. Kaye

rhea was universal at doses greater than 9 mg/m2, and hind Background: Rhizoxin is a new tnacrocyclic lactone isolated limb paralysis was observed 2in one of 10 mice, but only at from the fungus Rhizopus chinensis which displays broad- supralethal doses (18 mg/m ). Rhizoxin pharmacokinetics spectrum antitumor activity against murine and human were best described by a two-compartment open model tumor xenografts and has activity against a number of (half-life [tu2] a = 4.4 minutes ± 0.9 minute 2[mean ± SD], and vincristine-resistant tumors in vitro and in vivo. Purpose: '1/2P = 84 minutes ± 20 minutes at 12 mg/m ) and found to be with respect to dose. At doses of 1.2, 6, and 12 This study describes the preclinical and clinical pharmacol- nonlinear 2 mg/m , the respective AUC values were 1.3, 22.4, and 70.6 ogy of rhizoxin to apply a pharmacokinetically guided dose[lM x minute. From these data, a target AUC value of 28 |i/W escalation (PGDE) strategy during the phase I trial. x minute (40% of the LD 10 AUC) was derived. Rhizoxin was Methods: Rhizoxin was administered by a single intravenous not detectable in patient plasma ( o c .01 o o

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Fig. 3. Comparative pharmacokinetics of rhizoxin in mice (dotted line) treated at the LDIO (12 mg/m!; AUC = 71 \iM x minute) and in four patients (solid lines) treated at the MTD (2.6 mg/m!; AUCs = 0.41-1.01 \iM x minute). Lines represent computer-generated fits of the data as described in the "Materials and Methods" section.

Vol. 84, No. 7, April 1, 1992

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Clustering of Adverse Drug Events: Analysis of Risk Factors for Cerebellar Toxicity With High-Dose Cytarabine Heidi M. Jolson* Lynn Bosco, Marilyn G. Bufton, B. Burt Gerstman, Stephen S. Rinsler, Eliot Williams, Bridget Flynn, William D. Simmons, Bruce V. Stadel, Gerald A. Faich, Carl Peck

Background: Cerebellar toxicity is a severe, therapy-limiting adverse reaction of cytarabine given in high doses. The Food and Drug Administration received a report of an increased frequency of cerebellar toxicity at the University of Wisconsin Hospital and Clinics after a switch from the product (Cytosar-U) manufactured by The Upjohn Co., Kalamazoo, Mich., to the generic form made by Quad Pharmaceuticals, Inc., Indianapolis, Ind. Purpose: To compare the incidence of cerebellar toxicity in Quad-treated patients with Upjohntreated patients, a record-based cohort study was conducted at the University of Wisconsin Hospital and Clinics between January 1986 and August 1989. Methods: The incidence of cerebellar toxicity was studied in 63 leukemia patients according to the manufacturer of the product received (34 Upjohn only, 25 Quad only, and four both manufacturers). The relative risk of cerebellar toxicity was adjusted for other known risk factors. Results: Patients in the manufacturerdefined treatment groups did not differ significantly with respect to age, sex, type of leukemia, disease stage, calculated creatinine clearance, presence of abnormal liver function tests, or total dose received. The crude relative risk of cerebellar toxicity comparing the Quad product with the 500

Upjohn product was 5.0 (95% confidence interval = 1.813.7). Adjustment for potential confounders did not alter the association. Other risk factors for cerebellar toxicity, independent of manufacturer, were age greater than 50 years, type of leukemia, disease stage, total dose greater than or equal to 20 g/m2, abnormal pretreatment liver function, and reduced creatinine clearance. Conclusion: This study found a significantly higher incidence of cerebellar toxicity with high-dose cytarabine manufactured by Quad Pharmaceuticals when compared with the incidence of cerebellar toxicity with the Upjohn product. Further research at independent institutions would be necessary to allow generalization of this finding. In addition, our findings suggest that a dose reduction in high-dose cytarabine therapy may be indicated for patients with reduced glomerular filtration rates. [J Natl Cancer Inst 84:500-505,1992]

Cytarabine was approved by the Food and Drug Administration (FDA) in 1969. It is used for the treatment of acute leukemia, non-Hodgkin's lymphoma, and other solid tumors and for bone marrow ablation prior to transplantation. Conventional dosing for treatment of acute leukemias is in the range of 100Journal of the National Cancer Institute