Shiew Mei Huang

Membrane transporters in drug development

Membrane transporters can be major determinants of the pharmacokinetic, safety and efficacy profiles of drugs. This presents several key questions for drug development, including which transporters are clinically important in drug absorption and disposition, and which in vitro methods are suitable for studying drug interactions with these transporters. In addition, what criteria should trigger follow-up clinical studies, and which clinical studies should be conducted if needed. In this article, we provide the recommendations of the International Transporter Consortium on these issues, and present decision trees that are intended to help guide clinical studies on the currently recognized most important drug transporter interactions. The recommendations are generally intended to support clinical development and filing of a new drug application. Overall, it is advised that the timing of transporter investigations should be driven by efficacy, safety and clinical trial enrolment questions (for example, exclusion and inclusion criteria), as well as a need for further understanding of the absorption, distribution, metabolism and excretion properties of the drug molecule, and information required for drug labelling.

Drug metabolizing enzymes

D h n a p F s i ( t m s p t n t n d f r C i i l rom Clinical Pharmacology, AstraZeneca, Mölndal; Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis; Department of Biology (Galton Lab), University College London, London; Center for Drug Evaluation and Research, Food and Drug Administration, Rockville; School of Pharmacy, University of California San Francisco, San Francisco; Pharmacogenomics, Pfizer Global Research and Development, Groton; University of Chicago, Chicago; and University of Washington, Seattle. his commentary was based on presentations made at a Food and Drug Administration/Johns Hopkins University/Pharmaceutical Research and Manufacturers of America educational workshop, September 13, 2004, Rockville, Md. he views presented in this article do not necessarily reflect those of the Food and Drug Administration. eceived for publication June 6, 2005; accepted Aug 12, 2005. eprint requests: Shiew-Mei Huang, PhD, FCP, Deputy Office Director for Science, Office of Clinical Pharmacology and Biopharmaceutics, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, MD 20993-0002. -mail: huangs@cder.fda.gov lin Pharmacol Ther 2005;78:559-81. 009-9236/

The utility of modeling and simulation in drug development and regulatory review

30.00 opyright

Drug interactions with herbal products and grapefruit juice: A conference report

US Food and Drug Administration (FDA) has identified innovation in clinical evaluations as a major scientific priority area. This paper provides case studies and updates to describe the efforts by the FDAs Office of Clinical Pharmacology in its development and application of regulatory science, focusing on modeling and simulation. Key issues and challenges are identified that need to be addressed to promote the uptake of modeling and simulation approaches in drug regulation. Published 2013. This article is a U.S. Government work and is in the public domain in the USA. 102:2912-2923, 2013.

Quantitative Evaluation of Pharmacokinetic Inhibition of CYP3A Substrates by Ketoconazole : A Simulation Study

Shiew-Mei Huang, PhD, Stephen D. Hall, PhD, Paul Watkins, MD, Lori A. Love, MD, PhD, Cosette Serabjit-Singh, PhD, Joseph M. Betz, PhD, Freddie Ann Hoffman, MD, Peter Honig, MD, Paul M. Coates, PhD, Jonca Bull, MD, Shaw T. Chen, MD, PhD, Gregory L. Kearns, PharmD, PhD, and Michael D. Murray, PharmD, MPH Rockville and Bethesda, Md, Indianapolis, Ind, Chapel Hill and Research Triangle Park, NC, Morris Plains, NJ, West Point, Pa, and Kansas City, Mo

Evaluation of exposure change of nonrenally eliminated drugs in patients with chronic kidney disease using physiologically based pharmacokinetic modeling and simulation.

The US Food and Drug Administration draft drug interaction guidance recommends that 400 mg ketoconazole (KTZ) be administered once daily for several days (QD400) for maximal CYP3A inhibition. Some investigators suggest that a single dose of 400 mg (SD400) KTZ is sufficient given its short half‐life (t1/2 ∼ 3–5 hr). To determine the impact of KTZ regimens on CYP3A inhibition, we simulated AUC fold‐change (AUCR) in the presence of SD400, QD400, or 200 mg twice‐daily (BID200) KTZ for theoretical CYP3A substrates. Ratios of AUCR (AUCRQD400/AUCRSD400 and AUCRBID200 AUCRQD400) increase with increasing bioavailability and increasing substrate t1/2. The SD400 KTZ regimen may provide maximal inhibition only for a subset of substrates (ie, low bioavailability and short t1/2). For substrates with t1/2 longer than that of KTZ, multiple KTZ dosing is critical and BID200 appears to provide greater inhibition than QD400. Also, timing of KTZ administration should be optimized to allow maximal presystemic enzyme inhibition prior to substrate administration.

A Systematic Comparison of Cockcroft-Gault and Modification of Diet in Renal Disease Equations for Classification of Kidney Dysfunction and Dosage Adjustment

Chronic kidney disease, or renal impairment (RI) can increase plasma levels for drugs that are primarily renally cleared and for some drugs whose renal elimination is not a major pathway. We constructed physiologically based pharmacokinetic (PBPK) models for 3 nonrenally eliminated drugs (sildenafil, repaglinide, and telithromycin). These models integrate drugdependent parameters derived from in vitro, in silico, and in vivo data, and system‐dependent parameters that are independent of the test drugs. Plasma pharmacokinetic profiles of test drugs were simulated in subjects with severe RI and normal renal function, respectively. The simulated versus observed areas under the concentration versus time curve changes (AUCR, severe RI/normal) were comparable for sildenafil (2.2 vs 2.0) and telithromycin (1.6 vs 1.9). For repaglinide, the initial, simulated AUCR was lower than that observed (1.2 vs 3.0). The underestimation was corrected once the estimated changes in transporter activity were incorporated into the model. The simulated AUCR values were confirmed using a static, clearance concept model. The PBPK models were further used to evaluate the changes in pharmacokinetic profiles of sildenafil metabolite by RI and of telithromycin by RI and co‐administration with ketoconazole. The simulations demonstrate the utility and challenges of the PBPK approach in evaluating the pharmacokinetics of nonrenally cleared drugs in subjects with RI.

Biomarkers in drug development and regulation: a paradigm for clinical implementation of personalized medicine.

BACKGROUND: The dosing of drugs in patients with kidney dysfunction is often based on the estimates of kidney function. OBJECTIVE: To systematically compare the performance of the Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault (CG) equations for dosage adjustment. METHODS: We assessed agreement (concordance, kappa statistics [κ,κω]) between CG and MDRD using a Food and Drug Administration database to evaluate the effect of renal function on the pharmacokinetics of 36 approved drugs. Across the approved drugs, we compared the correlation between these 2 equations for renal drug clearance (Clren) and area under the concentration-time curve. For 26 approved drugs that require renal dose adjustment, we also compared dosing regimens and expected exposure using these equations. Sensitivity analyses were performed by adjusting the MDRD estimates for individualized body surface area and/or range of serum creatinine assay calibration errors. RESULTS: In the pharmacokinetic database with 973 subjects (age 18-95 years, weight 35-153 kg, female 33%), we found that the CG and the MDRD classification of renal function generally agreed (64.2%, κ = 0.54, κω = 0.73). Among the subjects studied for drugs requiring renal dose adjustment, dosages in 12% were changed to a higher or lower dosing category by the MDRD compared to the CG equation. In particular, using MDRD in place of CG for dosage modification yielded higher dosing recommendations for subjects with a combination of age >80 years, weight <55 kg, and serum creatinine >0.7 and ≤1.5 mg/dL; the coefficient of determination was also higher by CG than MDRD in trials that enrolled these or similar patients. CONCLUSIONS: For patients with advanced age, low weight, and modestly elevated serum creatinine, further work is needed before the MDRD equations can replace the CG equation for dose adjustment in the labeling.

Pharmacokinetic assessment in patients receiving continuous RRT: perspectives from the Kidney Health Initiative.

The post-genomic era has been hallmarked by significant enthusiasm for therapeutic individualization through the use of pharmacogenomic and other biomarkers. This enthusiasm has been dampened by limited examples of widespread clinical adoption. The current clinical implementation paradigm may not be adequate to facilitate uptake of pharmacogenetics for a variety of reasons. This paper discusses certain limitations of the classical clinical implementation paradigm and describes the drug development paradigm as an additional, powerful mechanism to facilitate clinical implementation of individualized therapeutics.

Recommendations for selecting drug–drug interactions for clinical decision support

The effect of AKI and modern continuous RRT (CRRT) methods on drug disposition (pharmacokinetics) and response has been poorly studied. Pharmaceutical manufacturers have little incentive to perform pharmacokinetic studies in patients undergoing CRRT because such studies are neither recommended in existing US Food and Drug Administration (FDA) guidance documents nor required for new drug approval. Action is urgently needed to address the knowledge deficit. The Kidney Health Initiative has assembled a work group composed of clinicians and scientists representing academia, the FDA, and the pharmaceutical and dialysis industries with expertise related to pharmacokinetics, AKI, and/or CRRT. The work group critically evaluated key considerations in the assessment of pharmacokinetics and drug dosing in CRRT, practical constraints related to conducting pharmacokinetic studies in critically ill patients, and the generalizability of observations made in the context of specific CRRT prescriptions and specific patient populations in order to identify efficient study designs capable of addressing the knowledge deficit without impeding drug development. Considerations for the standardized assessment of pharmacokinetics and development of corresponding drug dosing recommendations in critically ill patients with AKI receiving CRRT are proposed.