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Center for Drug Development Science Pharmacometric Services (CDDS-PS)

A. Summary

The Center for Drug Development Science (CDDS), Department of Biopharmaceutical Sciences, proposes to offer Pharmacometric Services (CDDS-PS) to the UCSF clinical and translational investigators. CDDS-PS will provide study design and data analysis services for studies of pharmacokinetics, pharmacodynamics, clinical pharmacology, mechanism of pharmacological action, proof of concept, and any other translational, exploratory, learning or confirming studies of a preventive, therapeutic, and diagnostic agent. CDDS-PS promotes a mechanistic approach to drug evaluation and development, which can serve as an integrated link between translational and clinical investigators of various disciplines. CDDS-PS accomplishes its objective through utilization of state-of-the-art methods in design optimization, modeling and simulations.

B. Background

1. Needs to be Addressed

Knowledge of pharmacokinetics (PK; how the body handles a drug over time) and pharmacodynamics (PD; how a drug affects the body over a range of exposures) is indispensable for designing and conducting efficient and informative preclinical and clinical drug studies. Advanced data analysis, employing cutting-edge PK and PD approaches, is critical for maximizing the content and quality of information yielded. Translational and clinical investigators generally have limited practical knowledge of PK and PD, which restricts their ability to derive an integrated, whole-human drug-action knowledge base, a frequently cited problem of empirically oriented drug studies. Additionally, there is often an absence of knowledge of the quantitative link between i) biology, genomics, and molecular pharmacology, ii) PK and PD, and iii) quantitative mechanistic forecasting (in silico simulation). The goal of the CDDS-PS is to provide services in the way of expertise, resources, and technologies to fill these knowledge and technical gaps and, in doing so, optimize the drug-study and drug-development processes.

2. Role of CDDS Pharmacometric Services

Pharmacometrics is the science of designing, analyzing, and interpreting pharmacology in a quantitative fashion. Pharmacometrics is a key component to understanding the action of a drug from the mechanistic perspective, based on PK and PD models. A fully integrated model considers disease processes and progression, drug formulation and input, mechanistic drug action and response submodels, in which response can range from biomarker to clinical effect (e.g., blood pressure) to clinical outcome (e.g., survival).

Investigators involved in experimental therapeutics are best served by appropriately designing dosing regimens and sample collection times to optimize the evaluation of effectiveness and safety of therapeutic entities, including small molecules, biologics, and drug delivery systems. Particularly in clinical trials, design optimization can lead to a more informative, less costly and more ethical study. Deterministic and stochastic in silico simulations developed by CDDS-PS will help investigators gain deeper and more detailed knowledge of the expected distribution of exposure and/or effects of a therapeutic entity for a combination of various doses, regimens, and study settings. This process allows for information-based selection of dosage regimens in animal and human experiments.

Successful application of pharmacometrics requires extensive knowledge and skills of various disciplines, including, but not limited to: in vivo PK and PD, in vitro ligand binding and enzyme kinetics, mathematics, biostatistics, numerical science, computational science, clinical trial design, and in silico simulation. CDDS-PS will provide expertise in these areas as they relate to pharmacometrics, and will employ highly specialized software, such as NONMEM, WinNonlin, PC-BUGS, Trial Simulator, and WinPopt. The extent of the services will depend on the nature and scope of project, ranging from one time ad hoc consultation to multi-year extensive collaboration.

C. Specific Services To Be Provided

Traditionally, pharmacometric analysis has been focused on preclinical and clinical PK or PK-PD studies. However, with more clinical studies adopting PK and/or PD research components (e.g., sparsely sampled population PK screening approach), pharmacometric analysis can be extended to various clinical studies of late phases (i.e., phase 2 or 3). CDDS-PS understands the uniqueness of each phase or design, and offers advanced customer-tailored services in the following research areas.

1. Design of a Translational and Clinical Study

  • General design of a protocol
  • Selection of a therapeutic regimen
  • Selection of a dose or dose range
  • Optimal blood sampling time for PK and PD evaluation
  • Patient population including sample size
  • Data analysis plan specific to PK, PK-PD, and pharmacometric analysis

2. Advanced Pharmacometric Modeling and Simulations

  • Pharmacokinetics (Dose-concentration)
  • Pharmacodynamics (Concentration-response)
  • Disease progression
  • Covariate analysis, i.e., population analysis of individualÕs demographic (e.g., age), clinical (e.g., stage, concomitant drug), or genetic (genotype) effects on PK or PD parameters
  • Physiologically based PK-PD
  • Mechanistically based effect
  • Allometric scaling
  • Deconvolution

3. Conventional Pharmacokinetic and Pharmacodynamic Analysis

  • Model-independent analysis using rich-sample data
  • Bioavailability
  • Bioequivalence
  • In vivo drug interaction
  • Drug disease interaction
  • Mass balance

4. Training and Education

  • Training and education of translational and clinical investigators in PK, PD, and pharmacometrics. This can be tailored based on individualÕs need and understanding of the disciplines.

5. Resources and Services for Use of Advanced Pharmacometric Software

  • Upon agreement with individual investigators or organizations, CDDS-PS offers license management, installation, management, update, and technical assistance of the following advanced software programs.
    • NONMEM
    • WinNonlin
    • PC-BUG
    • WinPopt
D. Meet Our Faculty and Staff

1. Howard Lee, MD, PhD

Dr. Howard Lee is Associate Adjunct Professor, Department of Biopharmaceutical Sciences, School of Pharmacy. He is a graduate of the Seoul National University College of Medicine (MD and PhD in epidemiology). Dr. Lee completed a two-year postdoctoral drug development and regulatory science fellowship at the CDDS. Dr. Lee also serves as Director, CDDS, and has extensive experiences in pharmacometric and mathematical modeling with human and animal data. Prior to the current position, Dr. Lee was an Assistant Professor, University of Pittsburgh School of Medicine, affiliated with the Center for Clinical Pharmacology, where Dr. Lee also developed the Clinical Investigation Core, providing tailored translational and clinical research services for underserved investigators. Dr. Lee was the Co-PI of clinical pharmacology for the Washington Obstetric Pharmacology Research Unit grant, awarded by the National Institute of Child Health and Human Development, where Dr. Lee also directed the development of the Pharmacometric Core. Dr. Lee is currently providing pharmacometric consulting and data analysis services for the Pharmacologic Support for CDC funded Phase II/III Safety and Efficacy Trials of Tenofovir Disoproxil Fumarate (TDF) in Botswana and Thailand. Dr. Lee has strong expertise in NONMEM, Trial Simulator, WinNonlin, S-PLUS, and SAS. Dr. Lee extensively uses these software programs for his pharmacometric and mathematical modeling research projects.

2. Nancy Sambol, PharmD

Dr. Nancy Sambol is Associate Professor Biopharmaceutical Sciences & Clinical Pharmacy, School of Pharmacy, UCSF. She obtained a B.S. in pharmacy at the University of Illinois and a Pharm.D. degree at the University of Texas prior to completing a fellowship in oncology and pharmacokinetics at UCSF in 1986. From 1988-1993, Dr. Sambol served as an Associate Director of the Drug Studies Unit, a (former) clinical trial unit in the School of Pharmacy. During and since that time, she has provided pharmacometric data analysis and a variety of consulting services to industrial and academic collaborators, providing input to well over 100 trials. The primary goal of Dr. SambolÕs research group is to advance methods of new drug development as they relate to PK and PD, particularly population approaches (those that consider patient traits and variability). Pharmaceutical companies and other investigators provide real-life issues and challenges on which their work is based. Ongoing and future investigations include the following issues: 1) population PK-PD study design and analysis when data are censored (e.g., analgesic trials and bronchoprovocation studies); 2) population PK-PD study design and analysis for investigating genetic variables; and 3) methodologic issues of population modeling and simulations. Secondarily, Dr. SambolÕs research group strives to gain specific knowledge about drugs that contribute to their improved clinical usage. They use a variety of PK-PD and statistical software including NONMEM, S-Plus and WinNonlin. Dr. Sambol also coordinates a course on Study Design in the School of Pharmacy.

3. Carl Peck, MD, PhD (hon)

Dr. Carl Peck is a world renowned expert in science-based drug regulations. Dr. Peck joined the FDA as Director, Center for Drug Evaluation and Research, in October 1987. He was promoted to Assistant Surgeon General in the Public Health Service in October 1990. Dr. Peck obtained a B.A. in mathematics and chemistry from the University of Kansas in 1963 and the M.D. in 1968. Following training in internal medicine, he undertook a research fellowship in clinical pharmacology at the University of California San Francisco (1972-74). From 1974 to 1980, Dr. Peck was employed at the Letterman Army Institute of Research, San Francisco, CA, as Chief of the Army Blood Preservation Research Program. In 1980, Dr. Peck became Director of the Division of Clinical Pharmacology and, Professor, Departments of Medicine and Pharmacology, Uniformed Services University, Bethesda, Maryland. Retiring from FDA in late 1993, Dr. Peck was appointed ŌBoerhaaveĶ Professor of Clinical Drug Research at Leiden University in The Netherlands. In 1994 Professor Peck joined the faculty of the Georgetown University Medical Center, as the founding Director of the Center for Drug Development Science. In 1999, Dr. Peck received the FDA Distinguished Alumnus Award. SwedenÕs University of Uppsala conferred an honorary doctorate degree (Doctor Honoris Causa) to Dr. Peck in January 2002 in recognition of "outstanding contributions to the science of drug development". Dr. Peck founded NDA Partners LLC in 2003 and in 2004, CDDS moved to UCSF, located in the UC-Washington Center. His research interests center on optimizing drug development and regulation. He is an author of more than 100 original research papers, chapters and books. Dr. Peck serves on numerous scientific advisory boards to industry and government

4. Thuy Vu, PharmD

Dr. Thuy Vu is a Postdoctoral Fellow in the Center for Drug Development Science, UCSF School of Pharmacy. Dr. Vu received the Excellent Pharmaceutical Sciences Research Project Award in 2005 from UCSF for her work on population pharmacokinetics of enoxaparin (Lovenox¨) in obese patients undergoing bariatric surgery. Dr. Vu has built a strong foundation in pharmaceutical sciences, and has a primary interest in population PK-PD modeling and its value in prospective decision-making in trial designs and clinical therapeutics. Dr. Vu received her Bachelors of Science in Biochemistry from UC Davis, and has held positions in the clinical research management in both a university and industry settings.

5. Julie Nelson, MBA

Ms. Nelson joined CDDS in 1995 and is responsible for overseeing the operations, planning, and development of the research, education, and technical assistance programs of the Center including management of the Technical Assistance Program (TAP), projects sponsored by pharmaceutical industry, government agencies & academic institutions, Research on Contemporary Drug Development Program, contracts, grants and other sources of funding, strategic planning, project proposals, center plans, and staff resourcing. She initiated the NDA study, which aimed to assess the content of contemporary clinical development programs of new molecular entities and co-authored the post-marketing dosage change study.

Ms. Nelson obtained a M.B.A. from PACE University, New York and a B.S. from the University of Minnesota. She came to CDDS from Dugan. Farley Communications., Inc. where she was Vice President, Account Management. Previous to that she held positions in marketing and development of medical devices, diagnostics, and pharmaceuticals at Becton Dickinson, Union Carbide, and the American Hospital Supply Corporation.

6. Other Adjunct Faculty

The CDDS-PS has reached and worked closely with many internationally acclaimed experts in PK-PD, pharmacometrics, and drug regulatory science, who are also available for the consulting services included in this proposal. They are Drs. Les Benet (UCSF, USA), Malcolm Rowland (Manchester University, UK), Nick Holford (University of Auckland, New Zealand), Stephen Duffull (University of Otago, Australia), David Feigal (NDA Partners, Former Director of CDRH, FDA, USA), and Charlie Grudzinskas (NDA Partners, Former Director, National Institute of Drug Abuse, USA).

E. Major Accomplishments and Solutions

The Center for Drug Development Science (CDDS), established in late 1994 at Georgetown University and with the UCSF School of Pharmacy since October, 2004, is a unique academic center dedicated to advancing the science, strategic planning, and management processes of drug development and to establishing clinical drug development science as a rigorous academic discipline through four programs, i.e., research, education, public policy and technical assistance program. CDDS has pioneered innovative drug development methodologies, e.g., pharmacometrics, physiologically-based pharmacokinetic analysis, microdosing techniques, and good clinical trial simulation practices and has closely worked with many academic clinical and translational investigators. CDDS has advised over 80 firms on a total of over 200 Investigational New Drug applications to the Food and Drug Administration (FDA). CDDS is the only academic institute that provides integrated drug development science, drug development science management, and regulatory science services.

The collective examples of past pharmacometric accomplishments and solutions by CDDS are listed below, and related publications are shown in "H. Selected Publications".

  • Theory and practice of concentration-controlled trials
  • Evaluation of study designs for dose-ranging
  • Evaluating historical labeling failures w/r to dosing
  • Methods for analyzing repeated-measures categorical data (pain studies)
  • Interaction between structural, statistical & covariate components of mixed effects models
  • PK/PD Characterization of Numerous Drugs/Outcomes/Variables
    • Antihypertensives, including 24-hour monitoring & Placebo effect (ß-blockers, Ca-channel blockers)
    • Antiepiletics
    • Antidiabetic agents (metformin)
    • Antirheumatoid agents (enteracept) in both juvenile & adult RA with logistic regression methods and disease progression model
    • Anticoagulation agents (antithrombin inhibitor, enoxaparin in morbidly obese patients)
    • Analgesics (ketoprofen, ibuprofen, naratriptan)
    • Anti-congestive heart failure agent (nesiritide)
    • Anti-inflammatory (anti B-lymphocyte stimulating agent) indirect model
    • Cell mobilizing agent
    • Mixed effect modeling of twin-study data
    • Dosage form evaluations
    • Unique absorption profiles (non-linear, combination of inputs)
  • Clinical Trial Simulations for Evaluation of Study Designs or Therapeutic Regimen
    • VMAC trial of nesiritide
    • Anti-stroke and CHD trial using baseline hazard function
    • Placebo effect of antirheumatic agents
    • Antihypertensive agents
    • Anti-HIV agents
F. Service Fees

There are two service fee schemes: collaboration-based and fee-for-service-based.

In the collaboration-based fee scheme, CDDS-PS anticipates the CDDS pharmacometric experts actively participate in a research project at any stage to tailor the need of the clinical and translational investigators. Some examples include, but are not limited to, grant writing, protocol design, and development of a pharmacometric data analysis plan. The CDDS-PS asks support for salary of personnel, travel (when necessary), equipment (e.g., a desk-top exclusively assigned for pharmacometric analysis), and license maintenance fee of a software program. These kinds of support will be budgeted based on the extent of the CDDS-PS involvement. A typical research collaboration project requires 20-35% of time of one or two pharmacometric experts and 10% of a supporting staff person.

In the fee-for-service-based fee scheme, the pharmacometric experts of the CDDS-PS will provide tailored research services for the UCSF clinical and translational investigators, ranging from a single ad hoc consultation to a full range data analysis project.

More information on the fees will be provided upon request.

G. Contact

If you want to know more about the CDDS-PS, please contact Julie Nelson.

Julie Nelson
Associate Director
CDDS-UCSF
1608 Rhode Island Ave. NW
Washington, DC 20036
E-mail: Julie.Nelson@ucsf.edu
Phone: 202-785-5450
Fax: 202-822-5040
Cell: 410-991-7428

H. Selected Publications
  1. Lee H, Kimko HC, Rogge M, Wang D, Nestorov I, Peck CC. Population pharmacokinetic and pharmacodynamic modeling of etanercept using logistic regression analysis. Clinical Pharmacology & Therapeutics 2003; 73:348-365.
  2. Lee H, Yim DS, Zhou H, Peck CC. Evidence of effectiveness: how much can we extrapolate from existing studies? AAPS.J 2005; 7:E467-E474.
  3. Yim DS, Zhou H, Buckwalter M, Nestorov I, Peck CC, Lee H. Population pharmacokinetic analysis and simulation of the time-concentration profile of etanercept in pediatric patients with juvenile rheumatoid arthritis. J Clin Pharmacol 2005; 45:246-256.
  4. Lee H, Yim D. Disease progression model is useful to characterize the pattern of placebo response in patients with rheumatoid arthritis (RA) using the numeric American College of Rheumatology Improvement Criteria (ACR-N). Clinical Pharmacology & Therapeutics 2006; 79:3.
  5. Sheiner LB, Beal S and Sambol NC. Study designs for dose ranging. Clin Pharmacol Ther 1989; 46: 63-77.
  6. Sambol NC and Sheiner LB. Population dose vs. response of betaxolol and atenolol: A comparison of potency and variability. Clin Pharmacol Ther 1991; 49: 4-31.
  7. Publication Committee for the VMAC Investigators (Vasodilatation in the Management of Acute CHF). Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. JAMA 2002; 287:1531-1540.
  8. Sambol NC, Harper C, Kim L. Liu CY, Darney P, Raine TR. Pharmacokinetics of single dose levonorgestrel in adolescents. Contraception 2006; 74:104-109.
  9. Kraiczi H, Jang T, Ludden T, Peck CC. Randomized concentration-controlled trials: motivations, use, and limitations. Clin Pharmacol Ther. 2003 Sep;74(3):203-14
  10. Peck CC, Rubin DB, Sheiner LB. Hypothesis: a single clinical trial plus causal evidence of effectiveness is sufficient for drug approval. Clin Pharmacol Ther. 2003 Jun;73(6):481-90
  11. Kimko HC, Reele SS, Holford NH, Peck CC.Prediction of the outcome of a phase 3 clinical trial of an antischizophrenic agent (quetiapine fumarate) by simulation with a population pharmacokinetic and pharmacodynamic model. Clin Pharmacol Ther. 2000 Nov;68(5):568-77.
  12. Lesko LJ, Rowland M, Peck CC, Blaschke TF. Optimizing the science of drug development: opportunities for better candidate selection and accelerated evaluation in humans. J Clin Pharmacol. 2000 Aug;40(8):803-14.

Latest News

Improving Drug Development Using Patient Adherence Data in Clinical Trials, May 6-7, 2008.
Brochure (PDF)
Registration site

Advanced NONMEM workshop – March 17–19, 2008 at Mission Bay Conference Center, San Francisco, CA.
More information >

UCSF-CDDS to launch The American Course on Drug Development and Regulatory Science- September 2007
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CDDS – Pharmacometric Services is available to drug researchers
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Howard Lee, MD, PhD, named Director of CDDS
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Lewis B. Sheiner Memorial. Symposium held at CDDS in December 2006
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If you have any questions or comments please contact cdds@ucsf.edu.
Last updated: April 25 2007 16:19.

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