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Saturday, August 14, 2010
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.
Iain Shaw, Director, 14-C Enabled Drug Development, Quotient Clinical, Fordham, Cambridgeshire, UK
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
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
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
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
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.
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