ACTG Pharmacology Support Laboratory

Abstract

The UBPSL is committed to the mission of the Adult ACTG at it implements its domestic agenda and expands to include an international agenda of antiretroviral (ARV) therapeutics in HIV infection. The UBPSL has grown since the epidemic started and has retained a focus of research activities that provide the ACTG with a core group of dedicated researchers with an emphasis on translational HIV pharmacology and therapeutics optimization strategies. The growth of the UBPSL to include multiple analytical approaches (HPLC, LCMSMS, CE), as well as the implementation of innovative assays, provides the adult ACTG with a resource that can contribute to innovative clinical trial design, approach innovation from the analytical perspective as well as through novel modeling aspects of data analysis and genomics in support of Translational Research and Drug Development. Pharmacologic themes:Primary: TDM and HIV Resistance: The UBPSL has fostered innovative application of antiretroviral assays to real-time study design approaches and therapeutic drug monitoring in prior and ongoing ACTG protocols (A260, A261, A5135, A5146) and integration of drug concentrations with HIV resistance tests (e.g., Inhibitory Quotient (IQ), Normalized IQ) (5135, 5146). Secondary: a) TDM in patients with Co-Infection and in patients with complex drug regimens, b) ARV pharmacokinetic drug interaction studies in patients (A368, 372, 388-733/5060, 384) and sero-negative volunteers (A5043, TMC 125 concept proposal) including pharmacodynamics such as metabolic changes (A5043), c) Quality assurance-quality control of antiretroviral assays including proficiency testing, clinical pharmacology study conduct and AVR-SOP peer review process, and d) Intracellular antiretroviral quantitation including NRTI-tri phosphates, NNRTIs and PIs (A384-5006, PR444). The ACTG agenda is focused on domestic research with a growing contribution to an international agenda. In support of this direction, the UB PSL has developed initiatives that contribute to technology transfer to resource-poor countries.ACTG Leadership Role: The UB PSL investigators have contributed to the ACTG as protocol pharmacologists, protocol chairs, protocol vice-chairs, DACS chair, Concept Proposal PI, and through leadership roles as pharmacology committee chair and vice-chair, PSL committee chair and chair of the pharmacology quality assurance program.

 

ACTG Pharmacology Support Laboratory QA/QC

Abstract

The adult and pediatric AIDS Clinical Trials Groups (ACTGs) Pharmacology Specialty Laboratories (PSLs) are involved in measuring all currently available antiretroviral drugs for both domestic and international clinical trial studies. This may involve therapeutic drug monitoring (TDM) which requires a laboratory to be in compliance with the Clinical Laboratory Improvement Amendments of 1988 (CLIA’88). Proficiency Testing (PT) is a CLIA requirement and is also an essential ingredient of Quality Control/Quality Assurance (QA/QC) and Good Laboratory Practice (GLP) programs. The ACTG QA/QC program is actively involved in proficiency testing for adult and pediatric PSLs, and designed its own PT program in 2001. There is no CLIA-approved PT program for antiretrovirals however the ACTG PT program fulfils CLIA requirements as an acceptable alternative. In 2001 there was an initial single round of PT and since then PSLs have been challenged twice a year (for a total of seven rounds) with PT samples containing all antiretroviral drugs currently used in ACTG studies. Results from the first four rounds have been published including indinavir (IDV), saquinavir (SQV), nelfinavir (NFV), ritonavir (RTV), nevirapine (NVP), efavirenz (EFV), amprenavir (APV) and lopinavir (LPV), atazanavir (ATV), abacavir (ABC), lamivudine (3TC), zidovudine (ZDV), didanosine (ddI) and stavudine (d4T).

In 2002-2003, the AIDS Clinical Trials Group’s (ACTG) Pharmacology Quality Assurance Subcommittee (PQA) designed a web-based Clinical Pharmacology tutorial. The tutorial was installed on the ACTG website, making it available to all AIDS Clinical Trial Unit (ACTU) staff participating in ACTG trials with pharmacology components. The purpose of the tutorial was to address concerns about the conduct of ACTG pharmacokinetic studies, such as: 1) Assurance that dosing of study drug(s) in the days leading up to the pharmacokinetic visit had been executed per protocol, 2) Proper administration of study drug at the pharmacokinetic visit, 3) Recording of actual clock times of samples (e.g., 8:04) rather than scheduled sample times (e.g., 08:00), 4) Accuracy and completion of specimen collection forms, 5) Matching of the sample time recorded on the specimen collection form (case report form, CRF) to the time recorded on the sample collection tube, 6) Assurance that the next scheduled dose of study drug was not administered prior to collection of the final pharmacokinetic sample (sample to be taken at the end of the dosing interval).

 

University at Buffalo ACTG Clinical Research Site

Abstract

History of the Subunit

The University at Buffalo (UB) subunit is located in the Immunodeficiency Services (IDS) program at the Erie County Medical Center (ECMC), the regional New York State HIV referral center for Western New York and teaching affiliate of UB. The subunit was established in 1987 as a component of the original ACTG network in collaboration with the University of Rochester main unit.

The UB ACTU subunit has consistently enrolled patients into a variety of ACTG protocols over the 1987-2005 period. In June 2004, the long-term PI for the UB subunit, Dr. Ross Hewitt, retired and the PI role was assumed by Dr. Gene D. Morse. Dr. Morse is also one of the original ACTG investigators having been the PI of an ACTG Specialty Pharmacology Laboratory and Co-Investigator in the University of Rochester ACTU since 1987. Dr. Morse and Dr. Hewitt collaborated on a number of HIV clinical protocols with numerous abstracts and publications resulting from this clinical research program. In 1998, Dr. Morse and other UB investigators established an Adherence-Pharmacology Unit within the IDS at the ECMC. This unit has become integrated into both the clinical care programs and the clinical research program of IDS as described below.

A. Personnel

Site Leader: Gene D. Morse, Pharm.D., is the Principal Investigator of the UB ACTU subunit. Dr. Morse a Professor of Pharmacy Practice, Medicine and Pediatrics. Dr. Morse is responsible for providing leadership within the subunit with regard to IRB protocol submissions, patient enrollment strategies, clinical research and administrative personnel within the subunit, mentoring clinical faculty in clinical trials and organizing a bi-weekly research committee meeting.

Dr. Morse, Principal Investigator, is currently the Associate Dean, Clinical Education and Research in the School of Pharmacy and Pharmaceutical Sciences. Dr. Morse is also Professor in the Department of Pharmacy Practice. Dr. Morse has been a faculty member at the University at Buffalo since 1983 and has a joint appointment as a Research Professor of Medicine and Pediatrics in the UB School of Medicine and Biomedical Sciences and the Department of Medicine at the University of Rochester (UR) School of Medicine and Dentistry.

Clinical facilities

The UB/ECMC Adherence/Pharmacology Consultation Form

These health care providers are part of our planned Western New York HIV Pharmacotherapy Research Network. The mechanism by which providers in these regional health care centers will be networked is via the Western New York section of the UB HIV ePharmacotherapy Network (www.hiv.buffalo.edu).

2. Research Pharmacy: The UB subunit, located in ECMC, is provided with research pharmacy services an ECMC pharmacist responsible for all investigational drug studies. The pharmacy component of the UB subunit is well established and the pharmacist is a member of the IDS HIV Pharmacotherapy Research Committee. Prior ACTG QA audits have found the pharmacy to be a strong component of the subunit.

3. Routine laboratory testing: Routine protocol laboratory tests are conducted in the Erie County Laboratories, the primary lab resource for the Erie County Medical Center . There has been an excellent working collaboration with ECMC laboratories with regard to ACTG protocols.

Plan for community involvement

The HIV Clinic at ECMC has had a peer education team since 2002 that provides support to patients, assist with education activities, administer patient satisfaction surveys, and provide feedback to the multidisciplinary care team on patient issues of concern. This team is being expanded to include additional community members, including AIDS Community Services, and will comprise the Community Advisory Board of the UB Subunit.

 

TDM & Drug Interactions in HIV Infected Substance Abusers

Abstract

This application is for the renewal of R01DA015024-04, “TMD & Drug Interactions in HIV-Infected Substance Abusers.” The impact of drug interactions in HIV-infected, substance users continues to be of utmost significance for the US epidemic and on a global basis. In both settings drug interactions contribute to clinical dilemmas in patients with a number of factors making successful antiretroviral (ARV) therapy, as well as the management of long-term complications, a difficult challenge. The Specific Aims of the renewal are: 1) Utilize a newly established HIV therapeutic drug monitoring (TDM) network to investigate PI and NNRTI pharmacokinetics and drug interactions in HIV-infected, substance users receiving ARVs and develop a longitudinal database for pharmacodynamic analysis with antiviral and toxicity parameters, 2) Determine the influence of selected interacting medications (methadone, buprenorphine, lipid-lowering drugs, antidepressants, hepatitis C antivirals, and traditional African medicines) on ARV pharmacokinetics in HIV-infected substance users, 3) Determine the pharmacokinetics of these interacting medications to identify interactions requiring more intensive pharmacokinetic evaluation and 4) Examine pharmacogenetic factors that may identify individuals at greater risk for insufficient or excessive systemic drug exposure while receiving regimens with multiple drug-drug interactions. Our preliminary findings indicate that this approach is able to identify drug-drug interactions in substance users which, in turn, allows more rigorous follow up through intensive pharmacokinetic studies. Our specific aims will be accomplished through our NIDA Drug Interactions and Therapeutic Drug Monitoring collaborative research group which is comprised of six HIV treatment centers, a central pharmacology laboratory with a website that supports remote clinical and laboratory data entry and the conduct of protocol-driven pharmacokinetic and pharmacogenetic studies. The data obtained from this research plan will provide new insight into factors that influence ARV pharmacokinetics and drug interactions that impact on the quality of care for HIV-infected substance users. In addition, the integration of pharmacokinetic data with important co-morbidities such as hepatitis C or opioid addiction treatment with buprenorphine or methadone will provide additional data for the development of guidelines for optimizing HIV management in substance users.

Opioids and HIV Medications: Interactions in Drug Abusers

 

Abstract

This application presents a research plan for R01 DA 13004 "Opioids and HIV Medications- Interactions in Drug Abusers". The overall objective of this work is to improve the clinical care of human immunodeficiency virus (HlV)-infected, substance-abusing patients by identifying significant interactions that occur between drugs commonly used to treat HIV disease and opioid therapies used in treatment of opioid dependence. The currently funded project has identified drug interactions of clinical importance between opioid therapies and HIV medications (nelfinavir, ritonavir, lopinavir/ritonavir, efavirenz and delavirdine).The ongoing project continues a series of drug interaction studies with buprenorphine, the newest opioid used for maintenance treatment of opioid dependence and antiretroviral medications frequently used in HAART regimens. The study design is a cost-effective method for rapid determination of the presence and of the clinical significance of drug interactions between buprenorphine and antiretroviral therapies. The project includes a within-subject component in which buprenorphine plasma concentrations are determined prior to and following antiretroviral administration to reveal whether the pharmacokinetics of buprenorphine are altered by co administration of any of the following HIV medications: nevirapine, atazanavir, atazanavir/ritonavir, fosamprenavir, fosamprenavir/ritonavir, tenofovir, or didanosine. Antiretroviral medication pharmacokinetics alone and in the presence of buprenorphine will be determined using a between-subjects study design and will elucidate the presence and significance of buprenorphine effects on the HIV therapeutics of study. Drug interaction studies have been identified as a priority research area for NIDA because of their importance to optimizing the clinical care of HIV disease in opioid dependent patients.

 

UB-UZ AIDS International Training & Research Program Training Grant

Abstract

This revised AITRP application is for the “Implementation of an International HIV/AIDS Pharmacology Post-Doctoral Research and Training Program.” The training program seeks to promote intellectual and technology transfer to developing countries in the area of Antiretroviral Clinical Pharmacology (including drug procurement, medication adherence support, pharmacogenetics, drug interactions and adverse drug reaction monitoring) in order to support HIV/AIDS research and information dissemination. The trainees will participate in ongoing activities of research funded by the National Institutes of Health. NIAID-supported antiretroviral pharmacology research is conducted through the University at Buffalo Adult ACTG Pharmacology Support Laboratory while Drug Interactions and Substance Abuse research is conducted under an RO-1 from the National Institute of Drug Abuse. Dr. Gene Morse is the PI for both grants. An initial University at Buffalo-University of Zimbabwe Pharmacology Fellowship was established through the AIDS Clinical Trials Group to initiate a training program and establish a pharmacology support laboratory in Harare . Dr. Chiedza Maponga, the first fellow, has completed a two-year fellowship. In Harare , a volunteer, lay worker-based adherence program in support of the introduction of antiretrovirals into Zimbabwe has been implemented. In collaboration with CDC, IACTG and CIPRA an infrastructure has been built to support clinical pharmacology studies. This program will focus on training independent researchers to expand our international pharmacology initiative to achieve 1) The promotion of intellectual and technology transfer through international collaboration in the area of Clinical Pharmacology, and 2) Develop programs to support generic antiretroviral drug use with a bioequivalence surveillance system, accountable drug procurement and distribution, medication adherence support, pharmacogenetics and drug interaction research through the conduct of sound clinical pharmacology research.

Drug Interactions Studies of Buprenorphine and HAART in HIV Infected Patients

Abstract

This is a supplement to R01DA015024 (PI- GD Morse), the primary grant that is investigating drug interactions and therapeutic drug monitoring in HIV-infected substance users and nonusers. Since this grant was implemented buprenorphine treatment programs have been initiated some of which are based within HIV treatment programs. However, there are minimal pharmacokinetic data in HIV-infected patients receiving HAART and buprenorphine. Therefore, this supplement proposes to extend the limited sampling strategy in the main study to conduct intensive (over 12 hours) pharmacokinetic and pharmacodynamic studies in patients who will be co-enrolled in the University of Miami buprenorphine treatment program.This supplemental application is consistent with the specific aims of the primary RO-1 application, and has the following additional aims; 1)Examine buprenorphine interactions with antiretrovirals in patients with HIV infection who are enrolled in a combined HIV treatment and buprenorphine program, 2) Develop and validate a multi-analyte assay for buprenorphine, nor-buprenorphine and naloxone that has no interference from antiretrovirals, 3)Conduct pharmacogenetic SNP analysis to examine drug metabolizing enzyme and efflux transporter genotypes and identify possible predictors for patients at greatest risk for drug interactions between buprenorphine and antiretrovirals. Part 1: For HIV-infected patients receiving antiretroviral therapy prior to the initiation of buprenorphine, antiretroviral pharmacokinetic evaluations will be performed prior to initiating buprenorphine treatment for opioid addiction and then after buprnorphine is started. Antiretroviral pharmacokinetic evaluations will be performed at four time points, prior to the initiation of buprenorphine (antiretrovirals only) and following the initiation of buprenorphine at weeks 2, 6 and 24 (buprenorphine and antiretrovirals). Part 2: For subjects without prior antiretroviral experience or those not having received antiretroviral therapy for more than one month prior to the initiation of buprenorphine, buprenorphine pharmacokinetic evaluation will be performed prior to initiating antiretroviral treatment and following antiretroviral therapy initiation at weeks 2,6 and 24 weeks. These pharmacokinetic studies will provide information upon which chronic dosing can be recommended for safe and effective opioid addiction treatment and also optimize antiretroviral therapy.

Drug Interactions & Antiretrovirals in Resource-Poor Countries

Abstract

As the HIV pandemic continues to expand, the use of antiretrovials among a diverse group of countries has emerged as a key challenge to the research community. This proposal seeks to extend a currently funded RO-1 grant (5R015024-02) that is examining pharmacologic aspects of complex drug interactions with antiretrovirals (ARV) among HIV-1 infected substance abusers on a domestic basis. While substance abuse is also an important co-morbidity in HIV-infected individuals in developing countries, the substances of abuse vary and the drug interaction situation is made more complex by regional “traditional” medicines that are prescribed by local healers and the need for opportunistic infection treatment (e.g., TB). 5R01DA015024-02 addresses drug interactions between antiretrovirals and opiod addiction therapies such as methadone and buprenorphine, with an emphasis on pharmacogenetics, plasma protein binding and therapeutic drug monitoring (TDM). This supplement seeks to extend the project to examine complex drug interactions in HIV-infected subjects in Zimbabwe . In this setting, cannabis is the primary substance of abuse, traditional medicine (“muti”) is also prescribed along with nucleoside analog reverse transcriptase inhibitors (NRTIs) and nonnucleoside RTIs (NNRTIs). Specific aims include: 1) Conduct antiretroviral pharmacology studies in Harare, Zimbabwe that are integrated with ongoing access to antiretrovirals in substance abusers, 2) Investigate TEM focusing on plasma NRTI and NNTRI concentrations and intracellular NRTI-tri-phosphate and NNRTIs, 3) Determination of ARV pharmacokinetics and pharmacodynamics in individuals also taking anti-tuberculosis medications, drugs of abuse (mainly cannabinoids and other traditional psychoactive substances used in these settings) and traditional African medicines (multi) compared to those without substance abuse, and 4) Examine pharmacogenetic factors that may identify individuals at greater risk for insufficient drug exposure or excessive exposure leading to toxicity.

Optimizing Dosing of Colistin for Infections Resistant to all other Antibiotics

Abstract

Infections with Gram negative bacilli resistant to all antibiotics except colistin have become increasingly common. This is a worldwide problem, with substantial issues being noted in South America and Asia . No new antibiotic classes with activity against these resistant Gram negative organisms are likely to be commercially available in the next 5 years. Yet, the pharmacokinetics (PK) of the only remaining antibiotic option, colistin, were studied in the 1960s when many of the modern principles of antibiotic dosing were not known. The Product Information of the drug suggests dosing regimens which may not be optimal for the management of serious infections. Furthermore, many patients with multiply resistant Gram negative infections are critically ill requiring renal replacement therapy and the Product Information gives no recommendations for dosing in this scenario.

 

Although most physicians refer to "colistin", the only form available for intravenous use is sodium colistin methanesulfonate (CMS). In the body, CMS is partially hydrolyzed to colistin. CMS and colistin differ in their antibacterial and PK characteristics. We were the first to develop HPLC assays which can separately measure both CMS and colistin. We aim to measure the levels of CMS and generated colistin in plasma in all patients and at the site of infection in patients with pneumonia (lung epithelial lining fluid) in a multicenter cohort of 238 patients. We will also measure the clearance of CMS and colistin in those patients in the cohort who are undergoing dialysis or continuous renal replacement therapy. We will determine outcome of these patients and correlate outcome with pharmacodynamic parameters such as the ratio of area under the plasma concentration-time curve:minimal inhibitory concentration (MIC) or peak concentration:MIC. The primary outcome measures will be bacteriologic and clinical response. Mathematical modeling techniques such as Monte Carlo simulation will be used to integrate the PK/PD and outcome data in order to establish optimal dosing regimens. Resistance or intolerance to CMS/colistin leaves physicians with no antibiotic options - therefore, we will secondarily explore the relationships between PK, treatment duration and patient characteristics on resistance to colistin or advent of toxicity.

Targeted Neuro-Protection of HIV-1 Associated Neurologic Diseases

Abstract

Cognitive impairment is a common complication of HIV-1 infection that can lead to dementia. The use of potent antiretroviral therapy has dramatically improved survival and decreased the incidence of systemic HIV complications, including neurological complications. However, the increased survival is likely responsible for the unchanged prevalence of neurological disorders shown recently in longitudinal studies (NEAD cohort). The implication of these findings are that although controlling HIV-1 replication remains the most important goal in the treatment of HIV infection and its neurological sequelae, pathological mechanisms indirectly linked to HIV infection may persist despite optimal viral suppression. This may explain why the presence of macrophage activation in the brain correlates best with dementia. This suggests that the best approach to treat cognitive impairment should consist of best antiretroviral therapy and adjunctive therapy aimed at indirect mechanisms of neuronal injury. In the background of a systemic disease such as HIV infection treated with multiple drugs that have complex interactions, there are two important steps in the development of novel compounds for the treatment of cognitive impairment. The first step is to assess the pharmacokinetic interaction of a study drug with antiretrovirals (Phase Ia). The second step is to assess the safety and tolerability profile of a study drug in the HIV infected population (Phase Ib) rather than the normal HIV negative population. In such Phase I trials, in vivo brain metabolism (magnetic resonance spectroscopy) may be an important adjunctive tool to detect early cerebral changes that may not be evident clinically. We have established a Phase I Clinical Trials Unit to perform hypothesis driven clinical trials of agents shown by our in vitro and in vivo models to favorably act on mechanisms thought to be critical in the pathogenesis of HIV dementia. The specific aims of this Clinical Trials Unit are: 1. to conduct a series (yearly) of Phase Ia pharmacokinetic interaction studies in HIV infected individuals; 2. to conduct a series (yearly) of Phase Ib clinical trials in HIV infected patients at risk for HIV dementia to ascertain safety and tolerability, and to assess the impact on cognitive performance and brain metabolism of novel therapeutic agents; 3. to operate a Clinical Trials Coordination Center to support and promote the rapid and efficient conduct of the Phase I trials. An infrastructure for conducting Phase II and III trials is already in place and would therefore fast track the transition from Phase I to later stages of drug development.