CLINICAL PHARMACOLOGY & THEI~M'EUTICS VOLUME 73, NUMBER2 American Society for Clinical Pharmacology and Therapeutics P 3 3

PII-13 AN INFORMAL SURVEY OF PHARMACOGEN ETICS/PHAR-

MACOGENOMICS (PGTX) IN A SAMPLE OF IND'S AND NDA'S. W. Chou, PharmD, PhD, S. Huang, PhD, C. G. Sahajwalla, PhD, L. J. Lesko, PbD, US Food and Drug Administration, USFDA, US FDA, Rockville, MD.

PGtx is positioned to be an important scientific tool in drug development and regulatory decision-making to improve the efficacy of new drugs, to personalize drug dosing, and to mhiimize adverse drug reactions. In order to gain insight into how companies are utilizing PGtx in drug development, we examined a subset of INDs and NDAs submitted to the Agency over the past 10 years. The following information was collected: therapeutic class, genetic vari- ations, methods of testing, types of study, metabolic fates of the drug, results, and the clinical utility. A total of 70 INDs and or NDAs have been reviewed. Overall, genes encoding CYP2D6 activity are the most frequently examined and accounted for 73% of all tests, fol- lowed by CYP2C19, CYPCYP3A4, transferases, CYP1A2, certain receptors, CYP2C9, and Pgp. In marly occasions, multiple genetic variations were tested and both phenotyping--and genotyping methods were used in the same submission.

CYP CYP CYP CYP CYP Phase 2D6 2C19 2C9 3A4/5 1A2 II Pgp Receptors Others

Total 51 10 3 10 5 8 3 5 16 Genotyping 27 3 3 6 3 7 3 5 16 Phenotyping 20 4 0 2 1 1 0 0 0 Not available 4 3 0 2 l 1 0 0 0

This informal survey indicated increased integration of PGtx in the drug development process over the last two to three years. Recent, major advancement in PGtx technologies and wide availability of routine PGtx testing appear to contribute to this increased integration.

PII-14 QUANTITATIVE RISK-BENEFIT ANALYSIS OF A CAL-

CIUM CHANNEL ANTAGONIST DURING REGULATORY RE- VIEW. B. Nguven, PharmD, P. J. Marroum, PhD, J. V. Gobburu, PhD, FDA, Rockville, MD.

Purpose To characterize the risk-benefit of a calcium channel blocker.

Methods The clinical database, comprising of hundreds of pa- tients, was utilized to construct an exposure-effectiveness (ambula- tory blood pressure data) and adverse events (QTc, tachycardia, palpitations and edema) relationship. Mixed effects modeling was employed to model continuous response variables and logistic regres- sion was used to model discrete response variables. The developed models were then used to explore the appropriateness of the proposed dosing regimen and the clinical relevance of changes in the pharma- cokinetics due to intrinsic and extrinsic factors.

Results Modeling allowed testing of various scenarios of drug exposure and its influence on the effectiveness and safety. Simula- tions allowed determination of the probabilities of each of the adverse events for important extrinsic (e.g.: concomitant medications) factors. The simulations also allowed appreciation of the inadequacy of the proposed dosing regimen over the dosing interval.

Conclusions Quantifying the risk-benefit profile aids in determin- ing the approvability of a new drug entity.

PII-15 EFFECTS OF DRUG TREATMENT ON OSTEOPOROSIS US-

ING A DISEASE PROGRESS MODEL. S. Chung, PhD, H. Ahn, PhD, X. Wei, MD, PhD, U.S. FDA, Rockville, MD.

Objectives: To define models for disease progression in osteopo- rosis; to evaluate drug treatment effects using a disease progress model; to compare drug effects with different mode of action. Meth- od: Three components were characterized in postmenopausal wom- en: progression of osteoporosis, effect of placebo treatment, and drug treatment effect. Lumbar spinal bone minerai density (BMD) was used as the surrogate endpoint for the disease progress and response. The data were obtained from publications and new drug applications. Drugs with different modes of action were investigated, namely inhibition of bone loss such as hormone mimetics and bisphospho- nares, and stimulation of bone building with drug X. Doses were limited to the clinically relevant range. A physiological model was employed since osteoporosis is a function of bone building and bone resorption. Results: Global kinetic pattern of effect was nonzero asymptotic for all the drugs. The patterns indicate that the drugs affect disease progress. The detailed time course of the response was distinctive among drugs having different modes of action within the study. Conclusion: The study results indicate that the time course of drug effect can be better characterized based on the given mode of action and a knowledge of the kinetics can improve drug develop- ment plans as well as regulatory decisions.

PII-16 MISDIAGNOSIS OF ISCHEMIC COLITIS AS IRRITABLE

BOWEL SYNDROME. A. Bdnker, MD, MS, J. Senior, MD, J. Beitz, MD, FDA, CDER, Office of Drug Safety, DDRE, Rockville, MD.

Randomized, double-blind, placebo-controlled studies conducted in the U.S. have shown that treatment with aiosetron HC1 in patients with irritable bowel syndrome (IBS) is associated with an increased relative risk (RR >6) for development of ischemic colitis (IC). From observational data submitted to the FDA from the Ingenix Research Database within United HeaithGroup, it can b-e shown that in the 5 years before marketing of aiosetron HCL, patients with a claim for IBS were at risk for underlying (misdiagnosed) IC. In this associa- tion, IBS is best described as a risk marker for IC (analogous to cough and lung cancer) as examination of the association through Bradford-Hill criteria does not support a causal role for IBS in IC. We hypothesize that some U.S. clinicians use the broad ICD-9 code that includes IBS as an interim diagnosis. Distinguishing IC as a causal effect of Lotronex therapy from a potential "cause" of an IBS diagnosis presents additional limitations for study of an association between Lotxonex and IC in observational settings.