This grant proposal develops methods to address the complexity of modern PKPD population studies.
AIM 1 Design will investigate population experimental design. We will develop novel methodology to increase the reliability of methods for sample size calculation, develop a novel semi-parametric approach to PK and PKPD sample size calculations, generalize currently available methods for sample size calculation and optimal experimental design to arbitrary parametric models, and develop and investigate design for multi-response multi-input studies.
AIM 2 Model Selection will investigate the selection of competing structural models as well as factors such as covariates. The algorithms we propose are based on Bayesian model selection and on reversible jump Markov Chain Monte Carlo. They apply to parametric models, as well as to novel generalized models that use flexible representations (splines) for the relationship between parameters and covariates.
AIM 3 Modeling will develop complex parametric models for: Post-Operative Pain, HIV-1 Plasma/CNS T-cells trafficking, and drug induced Haematotoxicity. We will also develop a novel class of models generalizing indirect and direct action PKPD models and capable of representing a large variety of PKPD experiments. We will develop novel general mixed effect semi-parametric models that can incorporate fixed or time-varying covariates and can be used for final analysis or to aid in the development of parametric models.
AIM 4 Software implements the methodologies we propose as self-standing computer programs as well as interfaces with the widely used computer program NONMEM.

Public Health Relevance

of the research we propose consists in providing state of the art methodology to aid in the development of drugs, increasing the understanding of their PKPD and the factors that explain their action in populations and individuals. This grant proposal develops methods to address the complexity of modern pharmacokinetics and pharmacodynamics (PKPD) population studies. We propose novel methodology for optimal experimental design, novel approaches to model selection, models applying to specific scientific problems ( Post-Operative Pain, HIV-1 Plasma/CNS T-cells trafficking, drug induced Haematotoxicity), and provide novel generalized PKPD representations which can be applied to a large variety of PKPD data. We also develop publicly available software implementing our design and model selection methodologies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI050587-09
Application #
8081105
Study Section
Biostatistical Methods and Research Design Study Section (BMRD)
Program Officer
Gezmu, Misrak
Project Start
2002-09-30
Project End
2013-05-31
Budget Start
2011-06-01
Budget End
2013-05-31
Support Year
9
Fiscal Year
2011
Total Cost
$264,995
Indirect Cost
Name
University of California San Francisco
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Frymoyer, Adam; Meng, Lina; Bonifacio, Sonia L et al. (2013) Gentamicin pharmacokinetics and dosing in neonates with hypoxic ischemic encephalopathy receiving hypothermia. Pharmacotherapy 33:718-26
Frymoyer, Adam; Verotta, Davide; Jacobson, Pamala et al. (2013) Population pharmacokinetics of unbound mycophenolic acid in adult allogeneic haematopoietic cell transplantation: effect of pharmacogenetic factors. Br J Clin Pharmacol 75:463-75
Frymoyer, A; Lee, S; Bonifacio, S L et al. (2013) Every 36-h gentamicin dosing in neonates with hypoxic-ischemic encephalopathy receiving hypothermia. J Perinatol 33:778-82
Dong, Betty J; Zheng, Yu; Hughes, Michael D et al. (2012) Nevirapine pharmacokinetics and risk of rash and hepatitis among HIV-infected sub-Saharan African women. AIDS 26:833-41
Verotta, Davide (2010) Fractional dynamics pharmacokinetics-pharmacodynamic models. J Pharmacokinet Pharmacodyn 37:257-76
Verotta, Davide (2010) Fractional compartmental models and multi-term Mittag-Leffler response functions. J Pharmacokinet Pharmacodyn 37:209-15; discussion 217-20
Chabas, D; Ness, J; Belman, A et al. (2010) Younger children with MS have a distinct CSF inflammatory profile at disease onset. Neurology 74:399-405
Schwartz, J B; Verotta, D (2009) Population analyses of atorvastatin clearance in patients living in the community and in nursing homes. Clin Pharmacol Ther 86:497-502
Perger, Ludwig; Rentsch, Katharina M; Kullak-Ublick, Gerd A et al. (2009) Oral heroin in opioid-dependent patients: pharmacokinetic comparison of immediate and extended release tablets. Eur J Pharm Sci 36:421-32
Kshirsagar, Smita; Gear, Robert; Levine, Jon et al. (2008) A mechanistic model for the sex-specific response to nalbuphine and naloxone in postoperative pain. J Pharmacokinet Pharmacodyn 35:69-83

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