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Tracking Bioavailability

Tracking Bioavailability
Iain Shaw, Director, 14-C Enabled Drug Development, Quotient Clinical, Fordham, Cambridgeshire, UK

The identification and development of successful drug candidates is an increasingly complex and expensive process and pharmaceutical companies are constantly looking for new technologies to improve compound selection. ivMicrotracer technology from Quotient Clinical, couples tracer intravenous dosing with accelerator mass spectrometry (AMS) to give clinical pharmacologists access to comprehensive human pharmacokinetic data early in drug development.1,2
ivMicrotracer studies allow researchers to evaluate the intravenous (IV) pharmacokinetics of drugs in healthy human volunteers in early clinical studies. This approach provides a powerful way of defining the pharmacokinetic characteristics and absolute bioavailability of lead compounds. Generating this information early in development gives an improved understanding of clinical pharmacokinetic data, potential delivery and formulation options and potentially a reduction in late-stage attrition.

Benefits of Carbon-14 ivMicrotracer Studies
Intravenous pharmacokinetics and absolute bioavailability data may be requested by regulatory authorities to address issues associated with poor and variable bioavailability. Traditionally this meant developing a suitable intravenous formulation and its associated specific preclinical and clinical evaluation prior to conducting an oral/IV crossover study. This approach can take up to one year and cost well over $1.5 million. Carbon-14 ivMicrotracer studies are an alternative approach and can be incorporated into an early clinical development program with minimal impact on overall costs and timings.

ivMicrotracer studies allow development teams to make better informed decisions regarding candidate drugs. The pharmacokinetic data generated can identify issues earlier in development, enabling project activities to be prioritized appropriately and the design of clinical studies to be adjusted as necessary. Because ivMicrotracer studies can be conducted without additional pre-clinical testing to support IV dosing, pharmacokinetic data can be generated in less than five months and for less than $500,000.
hiw-2

click to enlarge

Figure 1: ivMicrotracer PK Data (Source: Quotient Clinical)

ivMicrotracer studies can be performed on drugs intended for any extravascular route of administration. Understanding the pharmacokinetics of drugs intended for oral or other extravascular dose routes is greatly enhanced if the clearance, distribution volumes, and absolute bioavailability are determined by an ivMicrotracer study. An intravenous carbon-14 microdose, usually between a hundredth and a thousandth of the extravascular dose is administered at the time of maximum concentration (Tmax) of the extravascular (or non-IV) dose. Plasma samples for the IV dose are analyzed by LC-AMS and for the oral dose by LC-MS/MS. Administering the IV dose at the Tmax for the extravascular dose ensures that the body handles the tracer IV dose in exactly the same manner as and simultaneously with the extravascular therapeutic dose.3, 4, 5 (Figure 1)
ivMicrotracer studies can be conducted more quickly and cheaply than traditional IV/PK studies. The flexibility of the carbon-14 ivMicrotracer approach allows it to be added directly to an otherwise standard early development clinical protocol. The additional information that is generated can greatly benefit the design of the subsequent clinical program resulting in better study outcomes. Data generated can add considerable value to understanding drug pharmacokinetics, bioavailability, formulation performance and in conjunction with appropriate modelling and simulation tools can support formulation design through to in vitro-in vivo correlation.

At a Glance
Company: Quotient Clinical
Product: ivMicrotracer
Date Introduced: 2008
Product Description: Quotient Clinical ivMicrotracer studies are used in Phase I to obtain lead compound IV PK and absolute bioavailability data. These studies involve concomitant (piggy-back) IV administration of a carbon-14-drug tracer dose at the Tmax of an oral, or other extravascular, therapeutic dose.

About the Author
Iain Shaw is director of 14-C Enabled Drug Development at Quotient Clinical. Prior to this, he was programme manager for Covance Laboratories and has almost 15 years experience in the pharmaceutical industry. Iain has a BSc in Agricultural Chemistry from the University of Glasgow.

References
1. Vogel JS, Turteltaub KW. Accelerator Mass Spectrometry as a bioanalytical tool for nutritional research. Adv Exp Med Biol. 1998 445; 397-410
2. Lappin G, et al. Use of microdosing to predict pharmacokinetics at the therapeutic dose: Experience with 5 drugs. Clin Pharmacol Ther. 2006 80; 203-215
3. Sarapa, et al; J Clin P’col. 2005: 45 p 1198-1205
4. Stevens LA, et al; Microdose and microtracer intravenous pharmacokinetics of RDEA 806 in healthy subjects. Poster presented at the ASCPT meeting March, 2009, National Harbour, MD
5. Stevens LA, et al; A Microdosing study to assess the oral absorption of 14C_EM-1321 in healthy male subjects. Poster presented at the 2006 AAPS Annual Meeting and Exposition.

Toxicology and Hazard Assessment

The Toxicology and Hazard Assessment group is comprised of toxicologists and other health professionals who provide toxicology and risk assessment support to a variety of sponsors, mostly from the federal sector.  Group members have experience in acute, subchronic, and chronic toxicity; developmental and reproductive toxicology; carcinogenicity; genotoxicity; neurotoxicity; developmental neurotoxicology; veterinary toxicology; physiology; pharmacokinetics; clinical pathology; and qualitative and quantitative risk assessment.  The average on the job experience is 15 plus years and several group members are board certified in general toxicology.  Over the past 20 years staff have written over 10,000 toxicological and health risk assessments. Many of our federal sponsors are listed below along with comments on the scope of work performed:

US Department of the Army

    US Army Center for Health Promotion and Preventive Medicine (USACHPPM) – Technical support and analysis for deployed force protection; hazard materials vapor concentrations for future detection/monitoring systems as well as individual and collective protection; Formerly Utilized Defense Sites (FUDS) soil screening levels; Acute Exposure Guideline Levels (AEGLs) for chemical warfare agent munition demilitarization.

US Department of Energy

    Technical support to the Office of Emergency Management to develop chemical specific Protective Action Criteria (PACs) for emergency response planning applications of over 3300 chemicals.

US Department of Homeland Security

    Technical support to the Chemical Restoration Operational Technology Demonstration Project to (1) develop cleanup guidelines for air and surfaces following a chemical terrorist event and (2) regulatory characterization of potential waste streams.

US Environmental Protection Agency

    Office of Pesticide Programs (OPP) – Perform toxicological evaluations and human health risk assessments on pesticides for several OPP Divisions.  Over the past 15 years, hundreds of chemical specific assessments covering all toxicological disciplines have been performed.  A number of assessments evaluating the safety to cats and dogs of a variety of flea and tick products have also been conducted.

    Office of Pollution Prevention and Toxics (OPPT) – Derivation of chemical specific short term inhalation exposure values for the Acute Exposure Guideline Level Program for use in community planning in the event of a chemical release.  Evaluation of industry submitted data for the High Production Volume Chemical Program.

    Office of Research and Development’s National Homeland Security Research Center (ORD/NHSRC) – Derivation of short, intermediate, and longer-term inhalation and drinking water values for the Provisional Advisory Level (PAL) Program and associated related tasks.  These values will be available for use in determining reentry following intentional or natural disasters.

In this effort chemical specific human health exposure values are derived for drinking water and air.  These values assist emergency personnel responding to a manmade or natural disaster in making evacuation and reentry decisions.  As the figure indicates, the values derived fall within three PAL tiers, which increase in severity from PAL 1 to PAL 3.  As data permit, values are derived for four time periods (24 hours, 30 and 90 days, and 2 years) for each PAL tier for both air and drinking water.

    Office of Water (OW) – Preparation of Health Advisory and Support Documents on various chemicals and issues.

US Food and Drug Administration

    Center for Food Safety and Applied Nutrition (CFSAN)– Toxicological review and assessment activities related to direct or indirect food additives.  These include review of chemical specific toxicological data in every toxicology discipline and special projects such as evaluation of data to support a possible Generally Recognized as Safe (GRAS) delisting.

    Center for Veterinary Medicine – Researching issues related to animal feeds.

What We Can Do

Phase I and Phase II Human Clinical Trials / Human Translational Research

Plan and conduct research on bioactives, functional foods, or ingredients to evaluate:

Safety and tolerability

Pharmacokinetics and dose response

Mechanisms of action

Potential health benefits and efficacy

Design and implement human clinical research using:

Large and small multi-center human clinical trials

In-patient and out-patient intervention

Randomized, controlled trials

The secret of Advinus's success

In a way, Rashmi Barbhaiya has pharmaceuticals in his blood. His physician father, Harshad Barbhaiya, worked for the Sarabhais.

After studying at the University of London and University of Florida, Barbhaiya joined Bristol Myers Squibb as a senior research scientist and went on to become vice-president (metabolism and pharmacokinetics).

When he left in 2001, he had a budget of $30 million and led a team of 180 scientists. He then set up his own consultancy outfit called Dynametics Consulting. In 2002, he was picked up by Ranbaxy Laboratories Ltd, India's largest pharmaceutical company by sales, as its head of research and development.

HQK-1001 Clinical Trials

Phase 1 Clinical Trials
Clinical Trials

In January 2008, HemaQuest began a Phase 1 trial of its first drug candidate, HQK-1001, which is initially being developed to treat the hemoglobin disorders, sickle cell disease and beta thalassemia. The first trial administered HQK-1001 to 32 healthy volunteers to evaluate doses that are safe and produce therapeutic drug levels. In the initial trial, normal subjects were treated with increasing single doses of HQK-1001 ranging from 2 to 20 mg/kg. All dose levels were well-tolerated, and there was no difference in the number or severity of side effects between HQK-1001 and placebo.

A multi-dose trial began in March 2008, in which doses of 5, 10 and 15 mg/kg were given once daily for 14 days and tested for safety, pharmacokinetics and potential pharmacodynamic effects in healthy volunteers. In this trial, the drug was also found to be well-tolerated, with no difference in side effects between those receiving placebo and HQK-1001. In addition, the trial demonstrated pharmacodynamic effects documented by increases in reticulocytes, a measure of red blood cell production. Plasma drug concentrations within the therapeutic range (as demonstrated in laboratory studies) were achieved in subjects receiving HQK-1001 at doses of 10 and 15 mg/kg.

Proof of Concept Clinical Trials

HemaQuest is now testing HQK-1001 in two clinical trials, one in beta thalassemia patients in Thailand and Lebanon, and a second in sickle cell disease patients primarily in the United States. HemaQuest expects to have data from these clinical studies in the first half of 2010.

Sickle Cell Trial – Currently Enrolling Patients

Number and Title: HQP-2008-004: A Randomized, Blinded, Placebo-controlled, Dose Escalation Trial to Evaluate the Safety, Tolerability and Pharmacokinetics of HQK 1001 in Subjects with Sickle Cell Disease

Protocol HQP-2008-004 is designed to test HQK-1001 to determine if it is safe in patients with sickle cell disease or sickle beta thalassemia. Additionally, the trial is designed to test different doses of HQK-1001 and to look for certain markers that may indicate if the drug is having an effect in these diseases. This trial is being conducted in medical centers in the United States and Jamaica.

Criteria for participation:

The following criteria (along with other criteria) must be evaluated by the trial physician:

    Male or female patients from ages 12 to 60 years old with sickle cell disease or sickle beta thalassemia
    Patients must have had an average of 1 episode of sickle cell crisis for the last three years OR one episode of acute chest syndrome within the last 5 years
    A fetal hemoglobin (HbF) level greater than or equal to 2%
    Patients may not be eligible if they have the following medical conditions:
        Severe pulmonary hypertension
        Significant electrocardiogram abnormalities
        Transfusions within 3 months
        More than 4 sickle cell events requiring hospitalization with the last 12 months
    Further criteria that may include or exclude patient will be assessed by the physician

For information about this trial email: info@hemaquest.com.
More information can be found at www.clinicaltrials.gov

Thalassemia Clinical Trial – Currently Enrolling Patients

Number and Title: HQ:-2008-003: A Multi-National, Blinded, Placebo-Controlled, Dose Escalation Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of HQK-1001 in Subjects with Beta Thalassemia Intermedia, including Hemoglobin E Beta Thalassemia

Protocol HQP-2008-003 is designed to test HQK-1001 to determine if it is safe in patients with thalassemia intermedia or hemoglobin E beta thalassemia. Additionally, the trial is designed to test different doses of HQK-1001 and to look for certain markers that may indicate if the drug is having an effect in these diseases. This trial is being conducted in medical centers in Bangkok, Thailand, and Beirut, Lebanon.

Criteria for participation:

The following criteria (along with other criteria) must be evaluated by the trial physician:

    Female and male patients from the ages of 12 to 60 years old with thalassemia intermedia or hemoglobin E beta thalassemia
    Baseline hemoglobin levels less than 10 g/dL
    Patients may not be eligible if they have the following medical conditions:
        Greatly enlarged spleen
        Severe pulmonary hypertension
        Significant electrocardiogram abnormalities
        Transfusions within 3 months
        Recent fevers
        Certain medications
        Clinically significant laboratory abnormalities
    Further criteria that may include or exclude patient will be assessed by the physician

PHARMACOKINETIC WORKSHOPS

Workshops presenting the concepts and applications of pharmacokinetics in the pharmaceutical and clinical sciences.
FOR WHOM INTENDED
The Workshops are designed for pharmaceutical scientists, pharmacologists and other scientists, pharmacists, and physicians wishing to apply pharmacokinetics and pharmacodynamics in drug protocol design and drug evaluation. Emphasis is placed on providing a mechanistic, physiologic approach to the subject matter.

Assessing the Immunogenicity of Protein Therapeutics

Immunogenicity poses a risk that should be assessed during drug development, as it possibly compromises drug safety and alters drug characteristics including pharmacokinetics and bioavailability. Immunogenicity assessment strategies combine pre-clinical predictive methods with clinical stage measurement of anti-drug antibodies.

Figure-1: Top view of the HLA Class II DRB1*0101 binding groove, with and chains in respectively blue and green and the bound peptide in orange (PDB-code 1KLU)

Most therapeutic proteins in clinical trials and on the market are to a variable extent immunogenic. Formation of anti-drug antibodies poses a risk that should be assessed during drug development, as it possibly compromises drug safety and alters drug characteristics including pharmacokinetics and bioavailability.

The immunogenicity risk assessment is dependent on the nature of the protein therapeutic, and should be analysed on a case-to-case basis.

Immunogenicity

The immune system has evolved to protect hosts against potentially harmful antigens. Immunogenicity is the immune response a host mounts against an antigen, such as a protein therapeutic. Typically, immunogenicity is characterised by measuring the production of Anti-Drug Antibodies (ADA) against the protein therapeutic.

The fast growing number of therapeutic proteins and related immunogenicity data shows that most of them induce ADA. These ADA can have an impact on drug-characteristics including the pharmacokinetics, bioavailability and drug clearance rate.

While in many cases the ADA are non-neutralising antibodies, there are documented cases where the immunogenicity gives rise to Neutralising Antibodies (NAb). These NAbs have a direct effect on the drugs’ effector-function. Upon development of a protein therapeutic, the likelihood of observing immunogenicity has to be estimated. Moreover, the severity of an observed immunogenicity should also be evaluated. The severity of this response has to be evaluated on a case-to-case basis, as the immune response ranges from a transient appearance of ADA with no clinical effect to severe life-threatening conditions. Both industry and regulatory instances are currently developing immunogenicity risk assessment strategies for protein therapeutics.

Characterising immunogenicity

The measurement and characterisation of antibodies formed against a therapeutic protein by a host is not without technical challenges. A stratified approach (Figure 2) includes several assays to be optimised and validated for each individual drug, in order to

1. screen for circulating antibodies against the protein therapeutic
2. to confirm the positive read-outs with a competitive immunoassay, thereby differentiating false positive read-outs from the actual positive serum samples
3. characterise the type of response and
4. screen for NAbs

Interpretation of immunogenicity percentages’ data for protein therapeutics should be done with care. The measured immunogenicity is to a certain extent dependent on the assays used, and moreover, many of the studies comprise only a small number of patients, sometimes submitted to different treatment schemes based on their individual medical history and disease state.

 An example of the variability of observed immunogenicity is Alemtuzumab, a humanised anti-CD52 antibody. The observed ADA response in the treatment of rheumatoid arthritis varied between 0 to 75 percent throughout six clinical studies published between 1995 and 2005. The combined data resulted in an immunogenicity of 45 percent for 120 patients. On the other hand, in the treatment of patients with B-cell Chronic Lymphocytic Leukemia (B-CLL) only 1.9 percent ADA response was measured for a group of 167 subjects, suggesting a possible influence of the disease state on immunogenicity.

Similarly, Rituximab, a chimeric antibody directed against CD20, does not elicit ADA when used to treat patients suffering from B-CLL. This again may be explained by the antibody causing B-cell depletion, the presence of a B-cell lymphoma and the concomitant use of immunosuppressive drugs, three factors that hamper the overall production of antibodies. Rituximab administered to patients with auto-immune disease like systemic lupus erythomatosus or primary Sjogren’s syndrome showed 65 and 27 percent immunogenicity respectively.

Pre-clinical immunogenicity assessment

For the time being, there are no in vitro methods available to measure the antibody responses raised against protein therapeutics.

The HLA-peptide complex is then transported to the APC surface, where the complex can be recognised by T-cell receptors. This will then cascade the production of cytokines triggering the proliferation and activation of B-cells producing the antibodies against the protein.The HLA-peptide complex is then transported to the APC surface, where the complex can be recognised by T-cell receptors. This will then cascade the production of cytokines triggering the proliferation and activation of B-cells producing the antibodies against the protein.The HLA-peptide complex is then transported to the APC surface, where the complex can be recognised by T-cell receptors. This will then cascade the production of cytokines triggering the proliferation and activation of B-cells producing the antibodies against the protein.The HLA-peptide complex is then transported to the APC surface, where the complex can be recognised by T-cell receptors. This will then cascade the production of cytokines triggering the proliferation and activation of B-cells producing the antibodies against the protein.

Pre-clinical immunogenicity assessment

For the time being, there are no in vitro methods available to measure the antibody responses raised against protein therapeutics.

Therefore, one has to rely on other approaches to estimate the expected immunogenicity of a protein therapeutic. One possibility is to estimate the protein therapeutics’ T-cell epitope content by computer based methods, or by in vitro measuring the level of T-cell activation upon administration of the protein therapeutic to donors or patient material.
Th-epitopes

Being only a part of the host’s immune system, the mechanism to generate antibodies against the protein therapeutic or any other antigen involves at least three cell types:

i) B-cells producing antibodies directed against the antigen
ii) T-helper cells supporting this function by the production of cytokines, and
iii) Antigen Presenting Cells (APC) stimulating the T-helper cells. Typical APCs include dendritic cells, macrophages and B-cells

The APCs take up protein through endocytosis, cleave the protein into peptides in the endosomes, where the peptides can be loaded on membrane-bound Major Histocompatibility Complex (MHC)—in humans these are called Human Leukocyte Antigen (HLA)—class II receptors (Figure 1).

The HLA-peptide complex is then transported to the APC surface, where the complex can be recognised by T-cell receptors. This will then cascade the production of cytokines triggering the proliferation and activation of B-cells producing the antibodies against the protein.

Table-1: Population Frequencies of some highly
prevalent HLA Class II DRB1 Molecules in
different ethnicities HLA polymorphism

As the cascade-process is critically dependent on the presence of peptides that can bind to the HLA Class-II receptors, one could minimise the immunogenicity of a protein therapeutic by selecting protein therapeutics with as little T-cell epitopes as possible.

However, the HLA Class-II system contains many polymorphisms, in order to be able to respond to a broad range of “pathogens”, translating into several HLA receptor allotypes on the cell surface, each with different peptide-specificity.

The diversity is generated:
(i) by the presence of several HLA class-II genes, and
(ii) by a very high degree of polymorphism of most of these genes (Table 1)
Therefore, assessment of the immunogenicity of a therapeutic protein should take into account the prevalence of the different variants within the patient population that is being targeted.

In silico approaches

As peptides bind on HLA in an outstretched fashion (Figure 1), this greatly limits the number of possible binding modes of any peptide to the receptors, as well as the number of interactions between its side-chains. This allows building models that predict the affinity of a peptide for a particular HLA allotype.

The previous generation tools to predict binding peptides to HLA merely focussed on sequence comparison in observed binding peptides. The earliest such models were statistical. Based on a number of experimentally known epitopes, the binding peptides can be aligned to look for amino-acid preferences throughout the sequence positions. Given the final alignment, a statistical profile or matrix is then constructed for the binding groove positions and any new peptide can be aligned to that. The alignment score of the peptide against the matrix is then a measure of its affinity. Rankpep, Propred, Tepitope, and Syphpeiti are examples of such statistical methods. More elaborate models based solely on inference have been constructed as well, using neural networks and classification trees.

Structure-based methods are more recent. These directly model the molecular interactions between a peptide and receptor, using force-fields. This has the advantage that there is less possibility of overfitting the model towards experimental data, which is a serious problem in statistical methods. Structure-based approaches such as Epibase can predict peptide affinities for any HLA allotype, provided that a good model of its structure can be created. For most allotypes this is feasible given careful homology modelling.

The accuracy of predictive methods has evolved strongly over the past 15 years. In Figure 3, the high accuracy of structure-based methodologies is illustrated by comparing three methods, Rankpep, Propred and Epibase, on six of the major HLAII receptors.

In vitro approaches

While in silico methods assist the R&D process in selecting the lowest immunogenic lead-candidates, they can be useful in some applications to measure the actual T-cell activation level on donor or patient material. Indeed, when comparing different formulations of a drug, or when comparing a biosimilar product with the reference product, the T-cell activation and proliferation assays can document the comparability and immunogenicity risk.

A number of assays have been developed to characterise the T-cell responsiveness. Typically Peripheral Blood Mononuclear Cells (PBMC) from patients or naïve community donors are harvested and primed with the protein therapeutic. After a number of days of culture, the cells are restimulated with autologous PBMC and the protein or derived peptides. The T-cell stimulation can then be determined by a suitable proliferation assay. Routinely, Enzyme-linked Immunospot analysis is used to measure the number of cytokine secreting T-cells. By using Fluorescence Activated Cell Sorting (FACS) based systems, the read-outs can characterise the specific T-cell subsets that are being stimulated, thereby refining the interpretation of the type of response triggered. Typically, population wide responses have to be assessed, and therefore the in vitro assays are performed on 50 or more donors.

Conclusions

In silico T-cell epitope characterisation can reliably guide experimental analysis, thereby significantly reducing cost as well as enriching data interpretation of the in vitro T-cell activation data at the HLA allotype level. A combined approach is essential to address important yet poorly understood issues in immunogenicity, such as the immunodominance of T-cell epitopes.

The combined technology allows to estimate the expected immunogenicity of a protein therapeutic. Since the actual measurement of ADA is only possible during clinical trials, the pre-clinical T-cell read-outs allow optimisation of the lead selection of the formulation process and support a comparability analysis. As the animal models for immunogenicity testing are low to non-predictive for the immunogenicity observed in humans, the T-cell work forms an alternative assessment method prior to the first dose in humans.

Fellowships and Training

Clinical Pharmacology Training at the Indiana University School of Medicine involves a rigorous training in clinical research provided by no other specialty, that is designed to prepare fellows for positions as independent investigators in academia, industry and regulatory agencies. The training program is one of a few funded by the National Institutes of Health, certified by the American Board of Clinical Pharmacology, and is the recipient of the Center of Excellence in Clinical Pharmacology grant from the Pharmaceutical Manufacturer's Foundation.

Training in Clinical Pharmacology at the Indiana University School of Medicine involves a series of didactic classes designed to provide basic skills in clinical trial design, pharmacokinetics and pharmacogenetics, and ethical issues in clinical research. These classes take place within a rich research environment that involves the study of drugs in humans at many levels. Fellows have a wide spectrum of research opportunities that are focused around work in an outstanding General Clinical Research Center (GCRC) at the Indiana University School of Medicine and with a vigorous group of well-funded faculty. Areas of particular research strength include the study of drug interactions based on human drug metabolism and its influence on pharmacologic effect, and the influence of pharmacogenetics and pharmacokinetics on inter-individual response to drug therapy for breast cancer, HIV, cardiovascular and psychiatric disease.

The presence of strong groups of investigators in health services research in the Regenstrief Institute means that many of our studies can be carried all the way to real pharmacoeconomic and health care outcomes. Research experience in this area can include the use of large clinical databases to perform epidemiologic studies and the design and conduct of interventional trials in large populations of patients to address issues of cost effectiveness as applied to drugs.

The Indiana University School of Medicine has a strong Center for Bioethics that allows fellows the opportunity to experience excellent training in the ethical issues related to clinical research, and to understand their research in the context of national policy that affects research in clinical therapeutics.

Fellowship salaries are determined by the NIH Post-doctoral training scale. Trainees who qualify for the NIH-funded fellowship i.e. are US citizens or permanent residents, will be eligible for $35,000 of loan reimbursement per year for two years via the NIH Clinical Research Loan Reimbursement program.

Medical Services

The Clinical Pharmacology Service was created in 1972 with the aim of improving the practical use of medicines and channelling clinical research on drugs. It is staffed by specialists in Clinical Pharmacology, a medical specialism recognized by the "Medical Specialism Law".

Clinical Pharmacology is a discipline which permits in-depth knowledge of drugs, their pharmacokinetics, efficacy and role in eliciting side effects in patients to whom they are administered. So clinical pharmacologists can advise other professionals on these matters, as well as doing teaching work.



The Clinical Pharmacology Service takes part in the University Clinic of Navarra’s healthcare and research activities and carries out teaching duties at the University of Navarra.

Healthcare Activites:

In addition to providing therapeutic advice on the use of drugs in humans, the Clinical Pharmacology Service contributes to other clinical areas:

    Hypertension Unit
    Infectious Disease Area

Teaching Activities:

It has an important teaching role at the University of Navarra, both in the Medicine Faculty and in the School of Nursing.

It also contributes to various postgraduate courses, seminars and master-level courses.

It is accredited to teach Clinical Pharmacology as a subject in the MIR programme.

It is also possible for us to offer our experience to students and other professionals working outside of the Clinical Pharmacology Service, and other centres.


Research Activities:

Involvement in the research activities of the University Clinic of Navarra occurs at different levels:

    Clinical Research Unit
    Participation in the commission which advises Medical Directors on issuing the "Approval of the Centre Director", which is needed to conduct clinical trials.
    Participation in the Clinical Research Ethics Committee of Navarra (committee authorized to approve clinical trials)
    Participation in the Clinical Research Ethics Committee and the Research Commission of the University of Navarra (which evaluates research projects which do not constitute clinical trials)

    Phase I-II-III-IV clinical trials

The specific training and experience of its members mean the Clinical Pharmacology Service is exceptionally well informed with regard to research being conducted at the centre. 

    Clinical Pharmacokinetics

Its experience in pharmacokinetics, derived both from clinical care and research projects, mean it can offer an advisory service in this area, in terms of both healthcare and research.

From its beginnings the Clinical Pharmacology Service was conceived as a healthcare service so it has acquired extensive experience in clinical therapeutics, essentially in:

    Hypertension
    Antibiotherapy
    Immunosupression
    Analgesia

clinical pharmacokinetics

Efficiency of your pharmacokinetic (PK) data is vital to your program. As part of a full-service organization, our dedicated Pharmacokinetics group works closely with other operational departments to rapidly generate and report pharmacokinetic data for clinical trials in accordance with ICH E3 guidelines. We offer valuable input into study design, including important preclinical-to-clinical considerations (such as allometric scaling for the selection of the first-time dose in humans) utilizing information from preclinical studies. Employing industry-standard WinNonlin® software, we provide the following services:

    Non-compartmental analysis
    Compartmental pharmacokinetic analysis/simulations
    Assessment of dose proportionality
    Assessment of steady-state kinetics
    Bioavailability
    Drug-drug interaction analysis
    Special population PK analysis
    Pharmacodynamic (PD) and PK/PD modeling
    Deconvolution



You need advice and support for all aspects of clinical pharmacokinetics. We offer consultancy services as part of a complete development program, a full-service single-study package or a stand-alone service.

Our pharmacokineticists work closely with our data management, statistical and analytical staff at all stages of the study to ensure a smooth and effective transition of high-quality PK data.

Research Support for Drug Development

To support drug development research, we conduct studies in various stages, such as in-vitro studies or exploratory pharmacokinetic studies in the exploratory stage, and pharmacokinetic studies, analysis of clinical samples and gene-related studies in the application stage.

Emerging Evidence of the Impact of Kidney Disease on Drug Metabolism and Transport

The clinical pharmacokinetic consequences of kidney disease on drug disposition. CYP, cytochrome P450; MRP, multidrug resistance–associated protein; NAT, N-acetyltransferase; OATP, organic anion-transporting polypeptides; P-gp, P-glycoprotein.

Academy Medal Recipients

Chris is a Pharmacist by education and followed this with a PhD in Pharmaceutical Technology, postdoctoral studies at the University of Toronto, Canada and later an MBA.

He has worked for Glaxo R&D in the UK and Canada, Roche R&D in the UK, Astra R&D UK and now AstraZeneca. His current role involves responsibility for pharmaceutical and analytical R&D activities at the AstraZeneca sites in the UK and the USA.

Chris has been Treasurer and Chairman for the APS and am currently a board member of the EUFEPS Executive Committee and remain a Board member of the APS.

Current position(s): Vice-President, Pharmaceutical & Analytical R&D,AstraZeneca.

Clinical Pharmacokinetics

The Clinical Pharmacokinetics Programme has evolved from close collaboration between the University and Wirral University Teaching Hospital NHS Foundation Trust.

Clinical pharmacokinetics facilitates dose individualisation and ensures patient safety. An advanced understanding of the subject helps the practitioner ensure that patients get the most out of their medicines. If pharmaceutical care aspires to identify and meet the drug-related needs of individual patients, understanding clinical pharmacokinetic methods is essential. The course is relevant to all healthcare professionals who are responsible for direct patient care. It will however be of particular interest to pharmacists working in critical care, renal services, aediatrics/ neonatology, haematology/oncology, gastrointestinal/liver services, elderly care, infectious diseases, medicines information or in undergraduate or post-graduate teaching. The course will give confidence to allow one to tutor others in the subject.

The course is offered as a Certificate in  Professional Development. The aim of the course is to enable students to:

    Demonstrate an understanding of the information conveyed by pharmacokinetic parameters.
    Recognise those drugs for which pharmacokinetic considerations are likely to be of real clinical relevance.
    Calculate initial dosage regimens, based upon individual patient characteristics, including consideration of any relevant pathological or physiological conditions.
    Adjust dosage regimens using clinical endpoints and the results of therapeutic drug monitoring.

Entry Requirements
All entrants will normally be graduates in pharmacy or other healthcare disciplines who will have access to patients in community, primary or secondary healthcare settings. Applicants with other academic backgrounds will be considered.

Clinical Pharmacology Analytical Core

The Clinical Pharmacology Analytical Core (CPAC) is available to assist Indiana University Melvin and Bren Simon Cancer Center (IUSCC) investigators as well as external partners with pre-clinical and clinical pharmacokinetics in support of their research projects and scientific goals.

CPAC has been in existence since September 2004, primarily working with clinical investigators to provide detailed information on drug interactions and pharmacokinetics.

As a result of the identified need for pre-clinical pharmacokinetic and drug metabolism measurements earlier in the drug discovery process (via ITRAC experimental design mapping), CPAC began to expand its capabilities to include discovery pharmacokinetics and preliminary determination of drug metabolism.

The process of rational drug design should be based upon a strong foundation of biology, chemistry, in vivo pharmacology, and pharmacokinetics.  Relevant pharmacokinetic and metabolism studies should be conducted in small animal models or in vitro systems before first drug administration in humans.  This allows for the iterative process of implementing structural changes in the drug molecule to optimize the activity of the drug and its pharmacological and pharmacokinetic properties prior to moving to the more regulated and expensive clinical phase of drug development. For these reasons, CPAC is now interacting closely with another IUSCC-shared resource, the In Vivo Therapeutics (IVT) Core, to coordinate these efforts.

Over the past year, the CPAC and IVT Core have worked together to generate data allowing principal investigators to better evaluate molecules being developed within the IUSCC that show promise as novel cancer drugs.

Pharmacokinetic and metabolism data provide important information to guide drug design and treatment  in pre-clinical drug discovery (bench) as well as in clinical drug development and treatment (bedside). Using state-of-the art technology, CPAC supports the development of safe and more efficacious drug treatment for IUSCC investigators.

The following are some examples of how CPAC has contributed to the development of IUSCC-investigator initiated research - these vignettes are illustrative of how CPAC has helped the IUSCC advance and take the lead in precision prescribing, which refers to the process of matching patients to drugs that will trigger the best response based on an individual’s genetic makeup. CPAC has been of critical importance in some noteworthy findings that are described below.

    Dr. Jamie Renbarger, a clinical pharmacologist and pediatric oncologist,  focuses on the pharmacogenetics of vincristine, the most commonly used anticancer agent in children. Her laboratory work resulted in defining the metabolism of vincristine, identification of the structures of its metabolites, and development, in conjunction with the CPAC, of an extremely sensitive assay for measurement of vincristine and its primary metabolite  This work may explain the observed racial disparities in the outcome of childhood cancer treatment and lead to more effective vincristine dosing schemes. An NIH K23 award supports the work of this young investigator.
    Dr. Christopher J. Sweeney, while working in the Phase I clinic at IUSCC, designed a study to look at the possibility of drug-drug interactions of paclitaxel with PTK 787. Both of these drugs are metabolized by enzymes which have pharmacogenetic polymorphisms. The CPAC developed an assay to quantify paclitaxel and both metabolites in plasma to assist Dr. Sweeney in the identification of the cause of the observed drug-drug interaction which has resulted in PTK787 increasing the clearance of paclitaxel. The results in 18/20 subjects showed a decreased area under the plasma concentration time curve for each compound (on Day 15), illustrating a significant and previously un-indentified drug-drug interaction. This has led to planned studies with the developmental therapeutics/phase 1 group and CPAC to define the mechanisms of this interaction.
    CPAC has also provided preclinical analytical support to several projects identified and supported through the ITRAC mapping process. Karen Pollok and Lindsey Mayo’s projects focused on utilizing the HDM2 inhibitor, nutlin-3, in treatment strategies for chemotherapy-resistant cancers such as melanoma and glioblastoma. CPAC has developed an assay to effectively measure nutlin -3 in vitro and in vivo – generating strong preliminary data in support of the investigator’s hypothesis in their recently submitted R01 application.