CLINICAL PHAIhV'.~a~COLOGY & THERAPEUTICS VOLUME 73, NUMBER2 American Society for Clinical Pharmacology and Therapeutics P 8 5

PIII-83 POPULATION PHARMACOKINETICS OF MEROPENEM IN

FEBRILE NEUTROPENICS USING NPEM AND OPTIMAL SAMPLING DESIGN R. Ariano, A. Nyblen, J. Donnelly, G. Har- ding, S. Zelenitsky, D. Sitar, Clin. Pharmacol. Section, Univ of Manitoba, Winnipeg, Manitoba, Canada.

We evaluated optimal sampling design and a population-modeling program (NPEM) compared to a standard individual modeling method (SIM) for the estimation of meropenem pharmacokinetics in 12 febrile neutropenic patients. NPEM population modeling (USC*PACK) with a full data set (72 concentrations) was compared to a sparse data set with D-optimal sampling design (44 concentra- tions). All patients were initiated on meropenem 1 g IV q8h and plasma concentrations for modeling were obtained subsequent to the first dose. Median parameter values and respective 25-75% quartiles were:

SIM NPEM NPEM (full set) (full set) (sparse set)

CLp 0.14 0.15 0.14 (L/h) 0.12-0.16 0.12-0.17 0.12-0.17 CLd 0.15 0.13 0.24 (L/h/kg) 0.10-0.29 0.08-0.21 0.i2-0.26 Vc 0.13 0.13 0.12 (L/kg) 0.12-0.15 0.11-0.17 0.11-0.15 Vp 0.12 0.09 0.08 (L/kg) 0.04-0.23 0.07-0. I 1 0.06-0.11

The different models were considerably consistent, except fbr the estimation of CLd with sparse sampling. Our findings suggest that D-optimal sparse sampling is a reasonable approach to population PK/PD studies during drug development.

PIII-84 INITIAL DISTRIBUTION VOLUME ESTIMATES AFFECT

THE KINETIC MODEL AND TARGETED INFUSIONS. Michael J. Avram, PhD, Tom C. Krejcie, MD, Department of Anesthesiology, Northwestern University, Feinberg School of Medicine, Chicago, IL.

Recirculatory kinetic models describe drug disposition from the moment of injection. The present study compared 3-compartment kinetic models with the recirculatory model and the effect of model differences on the predicted drug concentration v e r s u s time relation- ships when they were used to design target-controlled drug infusions that were simulated using the recirculatory model parameters. Thio- pental concentrations of blood samples collected frequently after rapid IV administration to five dogs anesthetized with 1.5% halothane in an IACUC-approved study were measured by HPLC. All kinetic modelling and simulations were done with SAAM I1. With V c fixed to the sum of V c and VND from the recirculatory model, the descrip- tion of peripheral drug distribution was consistent with that of the recirculatory model; the target-controlled drug infusion based on this model produced a thiopental concentration history predicted by the recirculatory model that deviated minimally from the target concen- tration. Three-compartment models with Vcs estimated from frequent or intermittent early plasma concentrations overestimated Vc, VF, ~md elF; the target-controlled infusions based on these models pro- duced thiopental drug concentration histories predicted by the recir- culatory model that significantly overshot the target concentration until long after the infusion had begun, as is commonly observed clinically with computer-controlled infusions based on traditional mammillary models.

PIII-85 LIFE-THREATENING BRADYCARDIA: THE CLINICAL

RELEVANCE OF PROPOXYPHENE INHIBITION OF CYP2D6. J. Marraffa, PharmD, G. Ong, MD, D. F. Lehmann, MD, PharmD, SUNY Upstate Medical University, University Hospital, Syracuse, NY.

Propoxyphene is a commonly used opioid analgesic that has been shown to have an hfftibitory effect on CYP 2D6 in microsomal preparations. However, the clinical relevance of this effect is un- known. We report the index clinical case of this inhibition in a patient receiving a CYP 2D6 substrate, metoprolol, used for rate control in atrial fibrillation. Case Report: A 48 year old Caucasian male presented to the emergency department with complaints of dizziness approximately three hours after ingesting metoprolol, at his usual dose, and two tablets of propoxyphene, newly begun post- operatively. Four hours after ingestion, of both drugs, the patient was noted to have a ventricular rate in the 30's/minute with underlying atrial fibrillation. The patient's hepatic function panel was normal. The patient's ventricular response returned to normal within 11 hours of ingestion and was discharged home. Discussion: We report a case of life-threatening bradycardia in a male from his normal dose of metoprolol following ingestion of propoxyphene, confirming the clinical relevance of CYP 2D6 inhibition by propoxyphene. Since metoprolol has a high extraction ratio, CYP 2D6 inhibition would be expected to increase its peak concentration after oral ingestion, con- sistent with our observation. CYP 2D6 genotype and HPLC deter- minations of metoprolol and propoxyphene in this patient are pend- ing.

PIII-86 QUALIFICATION OF AN OSTEOPOROSIS BIOMARKER

MODEL FOR SIMULATION. P. Girard, PhD, L. Claret, PhD, W. Ebling, PhD, S. Forgue, PhD, M. A. Heathman, MD, A. Ghosh, PhD, C. T. Benson, MD, PhD, Pharsight, Eli Lilly & Co, Indianapolis IN, Mountain View, CA.

Purpose: Osteocalcin (OC) is a biomarker of drug effect on osteoporosis progression. A posterior predictive check (PPC) tech- nique was used to qualify a model of OC as a prerequisite for trial simulation.

Methods: Data were combined across 1,456 postmenopausal women who received placebo (calcium or Ca+vitamin D) or the SERM raloxifene (30, 60 or 150 mg) in 4 parallel-group trials. Serum OC and covariates measured at 0 to 12 months were fitted to an integrated indirect response model: OC(t)= Ki/Ko (1- f(D) (l-e -K° t)). Here, Ki and Ko are 0- and 1-order rate constants, and f(D)= Emax-D/(D50+D) if dose D > 0 and f(D)=PL if D=0. Parameters and between-patient variability in Ki, Emax and PL were estimated with NONMEM. Observed OC values were compared to values simulated with a degenerate posterior distribution or a multivariate normal one, with means set to their point estimates and covariance matrix set to the precision matrix.

Results: The best model included effects of urinary type 1 colla- gen on input rate K~ and osteopenia status on maximal SERM effect Em~ x. Common goodness-of-fit plots suggested an excellent fit; how- ever, both PPC techniques revealed misspecification that could po- tentially undermine trial simulations. The specific problem was cor- rected by constraining placebo to have a beneficial effect.

Conclusions: PPC accounts for all sources of randomness and is a powerful technique to qualify any population pharmacodynamic model intended to support clinical trial simulation.