This is an application for a K23 Mentored Patient-Oriented Career Development Award for Dr. Charles Venuto, PharmD, an assistant professor at the University of Rochester Medical Center. Dr. Venuto has established a strong foundation in clinical research with an emphasis in clinical pharmacology of HIV antiretrovirals and clinical tril methodologies. These training experiences have led to a focused and clear career path towards establishing himself as an independent investigator in HIV antiretroviral and hepatitis C virus (HCV) antiviral clinical pharmacology. Liver disease caused by HCV has now become a leading cause of serious illness and death in people with HIV; however, treatment advances in novel HCV therapies are just beginning to take shape in co-infected individuals. Although these new direct acting antivirals bring promising treatment strategies to the co-infected population, there are challenges that must be addressed in order to establish their safety and effectiveness. Drug-drug interactions, overlapping drug toxicities, increased pill burden, and pharmacokinetic (PK) variability have made it difficult to translate clinical study conclusions from mono-infected to co infected patient populations. With this in mind, Dr. Venuto's interests are focused in studying the pharmacokinetic and pharmacodynamic (PK/PD) patterns of drugs in patients with HIV and HIV/HCV, and identifying how these patterns influence clinical outcomes. The training and research plans within this K23 award have been devised around the hypothesis that alternative in silico tools such as model- based pharmacokinetic and drug-drug interaction studies, and data-driven approaches using preclinical and clinical trial data can be used to predict drug exposure, interaction potential and antiviral effects within HIV mono-infected and HIV/HCV co-infected individuals. This K23 award will serve as a vehicle for investigating this hypothesis by taking advantage of existing infrastructure within the NIH-sponsored AIDS Clinical Trials Group Network. Additionally, new pilot data will also be collected to compare antiretroviral PK between HIV mono- and co-infected patients, and to validate modeling tools developed from the clinical trial data. Dynamic research environments and a mentoring team comprised of leaders in clinical trial methodologies, HIV clinical pharmacology, and PK/PD modeling and simulation will facilitate the achievement of each goal. In conclusion, the model-based clinical pharmacology approaches proposed offer comprehensive and efficient ways to learn more about emerging treatment strategies for HIV/HCV patients.

Public Health Relevance

The overall objective of this proposal is to provide advanced training for the career development of Dr. Charles Venuto, in pharmacokinetic/pharmacodynamic and viral kinetics modeling and simulation in patients with HIV and HIV/HCV co-infection. The research plan is dedicated to testing hypotheses for evaluating treatment outcome differences between mono- and co-infected patients and identifying the safest and most effective treatment strategies in co-infected patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23AI108355-05
Application #
9706710
Study Section
Acquired Immunodeficiency Syndrome Research Review Committee (AIDS)
Program Officer
Zhang, Hao
Project Start
2015-06-15
Project End
2020-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Rochester
Department
Neurology
Type
School of Medicine & Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Venuto, Charles S; Lim, Jihoon; Messing, Susan et al. (2018) Inflammation investigated as a source of pharmacokinetic variability of atazanavir in AIDS Clinical Trials Group protocol A5224s. Antivir Ther 23:345-351
Venuto, Charles S; Markatou, Marianthi; Woolwine-Cunningham, Yvonne et al. (2017) Paritaprevir and Ritonavir Liver Concentrations in Rats as Assessed by Different Liver Sampling Techniques. Antimicrob Agents Chemother 61:
Talal, Andrew H; Venuto, Charles S; Younis, Islam (2017) Assessment of Hepatic Impairment and Implications for Pharmacokinetics of Substance Use Treatment. Clin Pharmacol Drug Dev 6:206-212
Bednasz, Cindy J; Venuto, Charles S; Ma, Qing et al. (2017) Efavirenz Therapeutic Range in HIV-1 Treatment-Naive Participants. Ther Drug Monit 39:596-603
Bednasz, Cindy J; Venuto, Charles S; Ma, Qing et al. (2017) Pharmacokinetic Considerations for Combining Antiretroviral Therapy, Direct-Acting Antiviral Agents for Hepatitis C Virus, and Addiction Treatment Medications. Clin Pharmacol Drug Dev 6:135-139
Gupta, Samir K; Yeh, Eunice; Kitch, Douglas W et al. (2017) Bone mineral density reductions after tenofovir disoproxil fumarate initiation and changes in phosphaturia: a secondary analysis of ACTG A5224s. J Antimicrob Chemother 72:2042-2048
Verma, Anurag; Bradford, Yuki; Verma, Shefali S et al. (2017) Multiphenotype association study of patients randomized to initiate antiretroviral regimens in AIDS Clinical Trials Group protocol A5202. Pharmacogenet Genomics 27:101-111
Venuto, Charles S; Talal, Andrew H (2017) Intrahepatic Sampling for the Elucidation of Antiviral Clinical Pharmacology. Clin Pharmacol Drug Dev 6:169-175
Venuto, Charles S; Potter, Nicholas B; Dorsey, E Ray et al. (2016) A review of disease progression models of Parkinson's disease and applications in clinical trials. Mov Disord 31:947-956
Bednasz, Cindy J; Sawyer, Joshua R; Martinez, Anthony et al. (2015) Recent advances in management of the HIV/HCV coinfected patient. Future Virol 10:981-997