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The overarching goal of the Clinical Pharmacology and Analytical Chemistry (CPAC) Core is to facilitate the development of safe, effective strategies for HIV prevention, treatment, and cure. To achieve this goal, the CPAC Core provides expertise in small molecule drug development to assist investigators in nearly all aspects of HIV pharmacology research. This full-spectrum support, unique to our Core facility, helps advance preclinical and clinical HIV research towards ending the HIV epidemic.

Members of the CPAC Core work with investigators to identify and deliver services that best meet their research needs. Through highly interactive collaboration, the Core helps progress activities at each stage of HIV research, from study design and grant writing, to bioanalysis and mass spectrometry imaging, to data modeling and simulation, to publication and future work. The Core’s activities are augmented by institutional support from the UNC Eshelman School of Pharmacy, which links the Core with faculty renowned for their expertise in specialized fields of pharmacology.

The CPAC Core supports the global community of HIV researchers through fundamental services in drug quantification. These services are performed within a CAP/CLIA-accredited environment using six redundant AB Sciex instruments for LC-MS/MS analysis and two IR-MALDESI systems for small-molecule imaging. Redundancy allows for rapid resulting for studies with large sample numbers, as well as simultaneous assay development and sample analysis activities performed on consistent platforms. The Core’s bioanalytical capacity helps sustain collaborations within every inhabited continent.

Global CPAC Core Collaborations (Aug 2016-July 2020)

Core Services

Clinical Pharmacology Services

Expertise in clinical pharmacology is the bedrock of the CPAC Core and the central mechanism by which the Core executes its Mission. This guiding principle drives the Core’s research agenda, strategic plan, and service framework in effort to advance NIH HIV research priorities spanning prevention, treatment, and cure. Services in clinical pharmacology are available at nearly every stage of preclinical and clinical HIV research, making the CPAC Core a unique resource outside the industry setting.

  • Planning & Study Design: The CPAC Core has over 20 years of experience in pharmacology to facilitate the development of preclinical and clinical research approaches through collaborative study design. Services include assistance with hypothesis framing, experimental factor identification, bioanalytical method comparison, and strategy justification, as well as pharmacokinetic/pharmacodynamic (PK/PD) study design, planning, and optimization.
  • Grantsmanship: In the most recent CFAR funding cycle, the CPAC Core helped develop and submit >71 grant applications to the NIH, non-profit organizations such as the Bill and Melinda Gates Foundation, and investigator-sponsored research programs. Grantsmanship services include multi-year budget planning, writing of major sections, collaborative editing, constructive critique of existing proposals, and resubmission strategizing. Letters of support, biosketches, and other support pages are also available upon request.
  • Coordination & Project Management: To support investigators throughout the trajectory of long-term and/or large-scale pharmacology studies, the CPAC Core offers consultative services in protocol implementation, operation, and adherence monitoring, in addition to guidance for timeline logistics, coordination, and communication.
  • Abstract & Manuscript Preparation: The CPAC Core strives to maximize scientific impact and promote research fellowship through communicating advancements in HIV pharmacology research. Core personnel routinely assist with abstract and manuscript composition, drafting figures and tables, selecting appropriate conferences/journals for submission, and responding to reviewer comments.
  • PK/PD Computation & Pharmacometrics: The CPAC Core offers PK/PD data analysis, interpretation, and modeling, as well as services in Monte-Carlo simulations, optimal study design calculations, and clinical trial simulation. To expand provision of computational services, the CPAC Core recently partnered with Dr. Julie Dumond and the UNC Pharmacometrics Core Facility.
  • Therapeutic Drug Monitoring: The CPAC Core offers therapeutic drug monitoring (TDM) with interpretive reports for nearly all FDA-approved antiretrovirals in a CAP/CLIA-accredited environment. Please contact Lauren Tompkins or Mackenzie Cottrell with TDM inquiries.
  • Training & Mentoring: Fostering the next generation of scientific leadership is critical for encouraging progress towards ending the HIV epidemic. The Core offers consultative services such as teaching or clarification of essential concepts in pharmacology, training in theory and use of bioanalytical techniques for drug detection, and software tutorials (SigmaPlot, WinNonlin, Agilent ChemStation). To support early-stage investigators and investigators new to HIV, Core personnel serve as mentors for CFAR Developmental Awardees and NIH Career Development (K) awardees. Core personnel also provide mentoring for graduate students working on CFAR projects and offer internships for undergraduates to enhance awareness of clinical pharmacology and analytical chemistry career pathways.

Bioanalytical Services

The CPAC laboratory provides state-of-the-art, customizable services in bioanalytical chemistry to support the HIV research community. A large portfolio of LC-MS/MS methods are available for quantifying drugs, drug metabolites, and other small molecules in plasma and in a variety of uncommon/complex biological matrices such as tissue, dried blood spots (DBS), and hair. Preclinical and clinical samples analyzed with these methods can be divided into 3 categories (or “Tiers”) based on research needs and bioanalytical criteria:

Tier 1 – Discovery (preclinical data, preliminary data, research studies)
Tier 2 – Qualified (preclinical or clinical research purposes suitable for publication, method qualified by 1 day of Precision and Accuracy)
Tier 3 – Validated (clinical studies for FDA submission, TDM, PT, method fully validated according to FDA guidelines)

The CPAC Core recovers costs through a registered recharge center. Service rates are calculated and reviewed at least every two years and are designed to cover costs without profit. Rates for sample analysis and method development are stratified by level of service. Budgets can be prepared on a per sample basis for a streamlined approach to service requests. Contact Lauren Tompkins for service inquiries.

The following tables illustrate the bioanalytical experience of the CPAC laboratory. Drugs and other small molecules (“analytes”) are quantified by LC-MS/MS at each Tier level as described below. Methods developed for a higher Tier level can be used to analyze samples at a lower Tier level, and LC-MS/MS methods can be developed for virtually any compound.

Tier 1 (Discovery) Level
Tier 1 bioanalysis is highly flexible to accommodate early-stage research needs in a cost-effective manner. The CPAC laboratory has quantified the following analytes in a variety of species/matrices by LC-MS/MS at the Tier 1 (Discovery) level.
Antiretrovirals Latency-Reversing/Cure Agents Other Compounds
3TC AZD5582 acyclovir
3TCtp bryostatin-1 ampicillin
ABC ingenol-dibenzoate apixaban
APV panobinostat bedaquiline
ATV prostratin canrenone
BIC romidepsin cefazolin
CAB venetoclax ceftriaxone
CBVtp vorinostat dabigatran
D4T additional proprietary compounds dATP
DOR dCTP
DPV dGTP
DRV dehydronifedipine
DTG ethinylestradiol
EFdA etonogestrel
EFdAtp ganciclovir
EFV levonorgestrel
ETR medroxyprogesterone acetate
EVG meropenem
FTC metronidazole
FTCtp nifedipine
LPV oxacillin
MK-2048 piperacillin
MVC pretomanid
NFV progesterone
NVP pyrazinamide
RAL pyrazinoic acid
RPV remdesivir
RTV rifabutin
SQV rivaroxaban
TAF spironolactone
TFV tazobactam
TFVdp 2,3,5-PTCA (melanin biomarker)
ZDV 7a-thiomethyl spironolactone
ZDVtp

 

Tier 2 (Qualified) Level
Currently available Tier 2 (Qualified) LC-MS/MS methods developed by the CPAC laboratory are listed below. Within each row, any/all of the analytes can be quantified in a single sample of the matrix indicated. Additionally, a single sample can be analyzed with >1 method to quantify a more diverse set of analytes. All Tier 2 methods are Qualified by 1 day of Precision and Accuracy.

*Note: Lower limit of quantification varies by analyte in certain methods.

Species Matrix Analyte Lower Limit of Quantification
Human Breastmilk 3TC, TFV 1 ng/mL
Human Breastmilk ATV 0.5 ng/mL
Human Breastmilk D4T 10 ng/mL
Human Breastmilk ETR, EVG, EFV 25 ng/mL*
Human Breastmilk TAF 0.05ng/mL
Human Cerebrospinal Fluid APV, ATV, DRV, EVG, LPV, RTV, TFV, 3TC, FTC, ABC, ZDV, MVC, RAL, NVP 1 ng/mL*
Human Cerebrospinal Fluid and Plasma EFV, EVG 1 ng/mL
Human Cervicovaginal and Rectal Fluid TFV, FTC 2 ng/mL
Human Cervicovaginal Fluid BIC, DOR 0.25 ng/mL*
Human Cervicovaginal Fluid RPV 1 ng/mL
Human Cervicovaginal Lavage TFV, FTC, RAL, 3TC 5 ng/mL*
Human Rectal Fluid BIC, DOR 0.25 ng/mL*
Human Semen TFV, FTC, RAL 5 ng/mL
Human Seminal Plasma BIC, DOR 0.25 ng/mL*
Human Seminal Plasma TFV, FTC 10 ng/mL
Human Semen CAB, RPV 25 ng/mL (CAB) 0.5 ng/mL (RPV)
Human Serum VOR 1 ng/mL
Human Tissue APV, ATV, EVG, DRV, LPV, RTV 1 ng/mL
Human Tissue BIC 0.1 ng/mL
Human Tissue dATP, dCTP 0.1 ng/mL
Human Tissue DTG, MVC, RPV 1 ng/mL
Human Tissue EFV, RPV 5 ng/mL
Human Tissue RAL 1 ng/mL
Human Tissue RAL, DTG, RPV 0.05 ng/mL
Human Tissue TFV, FTC, 3TC, TFVdp, FTCtp, 3TCtp 0.3 ng/mL
Human Adipose Tissue Cefaziin 0.02 ug extracted
Human Weck Cels EFV, ATV, NVP 0.2 ng/mL
Human Whole Blood DTG, MVC 3 ng/mL*
Human Whole Blood TFVdp, FTCtp, 3TCtp 300 fmol/sample
Human Whole Blood CAB, RPV 25 ng/mL (CAB) 2 ng/mL (RPV)
Dog Plasma EFdA 0.1 ng/mL
Minipig Plasma EFdA 0.1 ng/mL
Mouse Plasma DTV, MVC, RPV 1 ng/mL
Mouse Plasma CAB, RPV 5 ng/mL*
Mouse Plasma progesterone 0.5 ng/mL
Mouse Tissue CAB, RPV 0.1 ng/mL*
Mouse Plasma EFdA 0.1 ng/mL
Multispecies Plasma ATV, RTV 1 ng/mL
Multispecies Plasma EFV 0.25 ng/mL
NHP Plasma EFdA 0.1 ng/mL
NHP Plasma TFV, FTC, 3TC 2 ng/mL
Rabbit Plasma EFdA 0.1 ng/mL
Rabbit Plasma etonogestrel, levonorgestrel 0.5 ng/mL
Rabbit Plasma TAF 0.1 ng/mL
Rabbit Plasma TFV 1 ng/mL
Rabbit Plasma BIC, FTC, EFdA 10 ng/mL (BIC) 1 ng/mL (FTC, EFdA)
Rabbit Plasma RAL 1 ng/mL
Rabbit PBMCs EFdAtp 0.05 ng/mL
Rat Plasma EFdA 0.1 ng/mL
Rat Plasma ENG 0.2 ng/mL
N/A Cell Lysate 3TCtp 300 fmol/mL
N/A PBMC Lysate EFdAtp 0.05 ng/mL
N/A PBMC Lysate TFVdp 0.02 ng/mL
N/A PBMC Lysate TFVdp, FTCtp, 3TCtp, CBVtp, EFdAtp, dATP, dCTP, dGTP 0.1 ng/mL*
Rabbit PBMCs TFVdp 0.02 ng/mL
Human Urine TFV 10 ng/mL
NHP Plasma ENG 0.2 ng/mL
Human ULPC TFVdp, FTCtp 10 ng/mL (TFVdp) 5 ng/mL (FTCtp)
NHP Plasma BIC, FTC, EFdA BIC (10 ng/mL) 1 ng/mL (FTC, EFdA)
Sheep Plasma Progesterone 0.5 ng/mL
NHP Plasma Progesterone 0.05 ng/mL
NHP Plasma MPA 0.05 ng/mL

Tier 3 (Validated) Level
Currently available Tier 3 (Validated) LC-MS/MS methods developed by the CPAC laboratory are listed below. Within each row, any/all of the analytes can be quantified in a single sample of the human matrix indicated. Additionally, a single sample can be analyzed with >1 method to quantify a more diverse set of analytes. All Tier 3 methods are fully Validated according to FDA guidelines.
Matrix Analyte Lower Limit of Quantification
Breast Milk 3TC, LPV, NFV, NVP, RTV, ZDV 10 ng/mL
Cervicovaginal and Rectal Fluid TAF 0.2 ng/mL
Cervicovaginal Fluid DTG 1 ng/mL
Cervicovaginal Fluid TFV, FTC 2 ng/mL
Dried Blood Spots TVFdp, FTCtp, 3TCtp 100 fmol/sample
Hair ATV, RAL 0.1 ng/mL
Hair DRV 0.05 ng/mL
Hair DTG 5 pg/mL
Hair EVG 0.05 ng/mL
Plasma APV, ATV, DRV, LPV, RTV 1 ng/mL
Plasma BIC, DOR, RAL 20 ng/mL (BIC), 3 ng/mL (DOR), 10 ng/mL (RAL)
Plasma DTG, RPV, MVC 1 ng/mL
Plasma EFV 50 ng/mL
Plasma ETR, EVG 25 ng/mL
Plasma MVC, RAL, TFV, FTC 5 ng/mL
Plasma TAF 0.05 ng/mL
Plasma TFV, FTC 0.25 ng/mL
Plasma ÿZDV, 3TC, ABC, TFV, FTC, NVP 1 ng/mL
Rectal Fluid (Swabs) DTG 1 ng/mL
Seminal Plasma DTG 1 ng/mL
Serum vorinostat 1 ng/mL
Tissue TAF 0.02 ng/mL
Tissue TFV, TFVdp 0.02 ng/mL
Vaginal Tissue TFV, FTC, TFVdp, FTCtp 0.3 ng/mL
Vaginal, Cervical, and Rectal Tissue DTG 0.02 ng/mL
PBMC Lysate ÿTFVdp, FTCtp, dATP, dCTP 0.02 ng/mL
PBMC Lysate TFVdp, FTCtp 0.25 pmol/mL (TFVdp), 2.5 pmol/mL (FTCtp)
Upper Layer Packed Cell Lysate TFVdp, FTCtp 10 pmol/mL (TFVdp), 5 pmol/mL (FTCtp)
The UNC CFAR CPAC Core can also provide the following for investigators:

  1. Calibration or validation of routine antiretroviral methods in all biological matrices.
  2. Calibration or validation of routine intracellular antiretroviral methods.
  3. Development of new/customized analytical methodology, in particular HPLC-MS/MS methods, to meet CFAR needs.
  4. Comparison of competing methodologies (new and old) to identify optimal methods.
  5. Interpretive analyses of results.