CLINICAL PHAILMACOLOGY & THERAPEUTICS VOLUME 73, NUMBEK2 American Society for Clinical Pharmacology and Therapeutics P 6 7

PIII-18 REDUCED EFFECT OF FOOD ON THE PHARMACOKINET-

ICS OF LONAFARNIB FOLLOWING MULTIPLE ORAL DOSES. Y. Zhu, MS, P. Statkevich, PhD, D. L. Cutler, MD, A. Calzetta, MA, L. S. Rosen, MD, D. Curtis, MS, V. K. Batra, PhD, Schering Plough, UCLA School of Medicine, Kenilworth, NL

Lonafamib (L), a tricyclic farnesyl protein transferase inhibitor, is being developed for the treatment of various cancers. A multiple- dose, randomized, two-way crossover study to evaluate the effect of food on the steady state L pharmacokinetics (PK) was performed. Patients (n= 12; 9 evaluated for PK) received L 200 rag, twice daily (BID), for two 28-day cycles; one cycle was under fasted and the other was under fed conditions. Each cycle was separated by a two-week washout period. Plasma samples were collected on Day 15 of each cycle and L concentrations were determined by a LC-MS/MS assay. Mean (%CV) PK parameters at steady state are:

Fasted Fed Relative BA Confidence Interval

Cmax 0xg/mL) 2.77 (76) 2.27 (57) 87.2% 75-102% Tmax (hr) 4 (2-6) 4 (0-8) - - AUC (p,g - hr/mL) 24.1 (85) 21.6 (67) 95.5% 82-111%

There were no statistically significant differences in the PK (AUC) of L between the fasted and fed states after multiple doses. L 200 mg, BID, was safe and generally well tolerated under both fasted and fed conditions. Previously in a single dose study, food decreased the rate and extent of L absorption by -- 50 and 23%, respectively. The observed food effect diminished upon multiple doses. For L, a highly lipophilic drug with rate-limiting absorption, the multiple dose food effect results are those that are clinically relevant.

PIII-19 A POPULATION ANALYSIS OF DATA OBTAINED IN

PHASE I-III CLINICAL TRIALS OF HBOC-201. W. KnebeL PharmD, PhD~ L. B. Pearce, PhD, M. S. Gawryl, PhD, H. S. Pentikis, PhD, GloboMax, Biopure, Hanover, MD.

The pharmacokinetics of HBOC-201 based on Hb concentrations were investigated using a population analysis of data from 18 Phase I-lII studies and included the assessment of the pharmacokinetics of HBOC-201 in 726 patients undergoing various surgical procedures. The pharmacokinetics of HBOC-201 following an intravenous infu- sion is described by a one-compartment model with linear elhnination and endogenous levels of Hb. Estimates of the pharmacokinetic parameters are similar to those obtained in previous studies: clearance CL=0.122 L/hr , volume V=3.36 L, and baseline endogenous level ENDO=0.0536 g/dL. The T~/2 of HBOC-201 was estimated to be approximately 19 hrs. The inter-patient variability in clearance was related to patient body weight and one study which involved the administration of HBOC-201 pre-operatively. Clearance decreased by 81% as patient weight increased and V increased by 80% as patient weight increased thereby supporting the weight based dosing for HBOC-201. Clearance and volume were not influenced by any other demographic covariates including age or gender. In addition, across all of the surgical settings studied, no real differences were observed between patients based on surgical procedure. Therefore, it can be concluded that the exposure to HBOC-201, when dosed based on patient body weight, to patients undergoing a variety of surgical procedures is consistent. Based on these data HBOC-201 dosed on a body weight basis can be used in a predictable fashion.

PIII-20 A POPULATION PHARMACOKINETIC MODEL FOR

ZOLEDRONIC ACID (ZOMETA) IN PATIENTS WITH BONE METASTASES. B. P. Booth, PhD= A. Rahman, PhD, A. Ibrahim, MD, N. Scher, MD, G. Williams, MD, H. Schran, PhD, P. Ma, C. Hsu, J. V. Gobburu, Ph.D., FDA\CDER\OCPB, FDA\CDER\OND, Novartis Pharmaceuticals Inc., Rockville,. MD.

Purpose: Zoledronic acid is a bisphosphonate indicated for the treatment of bone metastases and hypercalcemia of malignancy. The objective of the study was to characterize the population pharmaco- kinetics (PPK) of zotedronic acid in patients with bone metastases.

M e t h o d s : Data were obtained from 64 patients who were treated with either a 5 or 15 minute infusion of 2 to 16 mg zoledronic acid once every tour weeks for up to three cycles. Eleven samples were taken over the course of the first day of dosing, and once on days 8, 15 and 29 in the first cycle of therapy. NONMEM was used to develop a PPK model for zole&'onic acid.

Results: Zoledronic acid PK was characterized by a 3-compartment model with systemic clearance (CL) of 6.53 L/h for a 70 kg patient with creatinine clearance (CLcr) of 90 mL/min, central compartment volume of 7.9 L/70kg, a high volume of the peripheral compartment presumably representing bone, of 173L/70kg, and a tong terminal half-life of 146 hours. CLcr was the most influential cowtriate of CL, where CL = 6.53"(CLcr/90) °'3s7. The unexplained variability was about 30% for CL and V. Simulations were conducted to qualify the model for predicting the time course of zoledronic acid concentrations in bone metastases patients with varying CLcr.

Conclusion: The PPK model adequately characterized the phar- macokinetic behavior of zoledronic acid. The findings of the study were incorporated in the labeling.

PIII-21 MEVALONATE DEPLETION INDUCES UP-REGULATION

OF RAS AND RAS-RELATED PROTEINS. R.J. Hohl, MD, PhD, S. A. Holstein, BA, C. L. Wohtford-Lenane, BS, University of Iowa, Iowa City, IA.

Ras-related proteins are small GTPases that play important roles in regulating diverse cellular processes including cell growth, differen- tiation, and cytoskeletal organization. These proteins are post- translationally modified with mevalonate-derived isoprenoids. Al- though the effects of inhibition of isoprenylation on protein function have been examined, the consequences of depletion of isoprenoid pools on regulation of expression of isoprenylated proteins have yet to be investigated. In these studies we have shown that depletion of mevalonate results in increased total levels of Ras, Rapla, RhoA, and RhoB in K562 cells. [35S]methinnine pulse/pulse-chase and cyclo- heximide experiments reveal that mevalonate depletion increases the de novo synthesis of Ras and RhoA and decreases the degradation of existing Ras and RhoA protein. Experiments with actinomycin D revealed that inhibition of transcription completely prevents the in- duced up-regulation of RhoB and only partially prevents the up- regulation of Ras, Rapla, and RhoA. Although depletion of mevaI- onate does not alter steady state levels of Ras or RhoA nlRNA, there is a significant increase in RhoB mRNA. Our results demonstrate that mcvalonate depletion induces up-regulation of Ras and Ras-related proteins by discrete mechanisms that include modulation of transcrip- tional, translational, and post-translational processes. The isoprenoids contributing to this modulation will be discussed.