Author: Veeda_admin

A Contract Research Organization (CRO) plays a vital role as a service provider to the pharmaceutical industry.

The market size of the global contract research organization (CRO) services was estimated at USD 38,396.4 million in 2018. By the end of 2026, it is expected to hit USD 90,926.3 million.

It should be noted that in terms of the number of generic drugs, 20% of global exports are from India.

This makes India the biggest global supplier of generic medicines.

It is very much obvious that to get marketing approval for generic drugs on foreign soil, manufacturers from India have to clear all the regulatory parameters.

Thus, BA/BE studies are of great importance, and conducting them requires due planning and experience.

Generic companies have the R&D for product development, manufacturing, and quality testing.

Many of the bigger pharmaceutical firms have their own clinical and bioanalytical units.

They are capable of carrying out Phase 1 and BA/BE studies.

However, because of the desire to produce more compounds in shorter time periods, there comes a point when the internal resources become saturated.

Often, several smaller firms, virtual companies, and generic companies do not have the privilege of performing BA/BE trials with their own dedicated clinical unit or full in-house capability.

They may not have the clinical and bio-analytical capability.

Thus, the role of CRO or outsourcing of BA/BE studies comes into the picture.

They reduce the cost of BA/BE study, help pharmaceutical companies to file ANDA applications, and bring new medicines to market quickly.

The typical services outsourced for BA/ BE studies from a pharmaceutical company to a CRO may include Bioanalytical Analysis, Bioanalytical Site Selection and Qualification, Clinical Study Design, Clinical Protocol Development, Clinical Site Selection and Qualification, Clinical Conduct, Clinical Monitoring, Data Management, Pharmacokinetic Analyses, Statistical Analyses, Pharmacokinetic Report Writing, Integrated ICH Report Writing, Project Management, and FDA/Regulatory Consultation.

How to Select a CRO?

The first step before outsourcing a study to a CRO is to develop a list of potential CROs that are involved in conducting BA/BE studies.

CROs that have good experience in conducting BA/BE studies and can meet the sponsor’s timeline should be given first preference.

The list should include both CROs that provide all services and those that provide only clinical or analytical services.

CROs that have a proven record of carrying out BA/BE studies with appropriate clinical conduct, laboratory analysis, data management, biostatistics, pharmacokinetics, and medical writing should be given priority.

They should comply with Good Clinical Practices (GCP), Good Laboratory Practices (GLP), and other applicable regulatory practices and guidelines.

How to Assess the Qualification of a CRO?

The sponsor company should assess a CRO on different parameters before finalizing to outsource the project.

The parameters include Clinical Capabilities, Bioanalytical Capabilities, Pharmacokinetic capabilities, and quality deliverables on time.

The sponsor should obtain copies of past FDA inspection reports (483s and Establishment Inspection Reports [EIRs]) through the Freedom of Information (FOI).

The client should also request any FDA warning letters that have been issued against the CRO, if any.

The ability to recruit volunteers for both small and large sample studies is a major assessment criterion for the qualification of any CRO.

The CRO should be able to recruit the entire study population at a single center, preferably as a single group.

The client should ensure that the Bioanalytical team is well-experienced in analyzing the analyte or metabolite of the drug, as appropriate.

The client should also verify that the facility adheres to cGLPs and has a clean inspection history from regulatory bodies.

The Bioanalytical team of the CRO should be able to provide a written validation report.

The CRO should have validated pharmacokinetic and statistical programs in place and should be compliant with 21 CFR Part 11 (especially concerning change control).

The CRO should also provide performance metrics used for monitoring the timelines and financial metrics.

The client should request ‘‘references’’ that include those companies that outsourced studies and, in return, had successful ANDA or NDA approvals.

After evaluating the credentials and performance metrics of each CRO, the sponsor should physically visit the site and audit the clinical, bioanalytical, and pharmacokinetic capabilities of the CRO.

The audit should include the evaluation of the:

• Procedure for the CRO to handle an unexpected and serious adverse event (AE) investigation.
• Training records for the clinical team
• CRO’s capability to synchronize plasma and urine deliveries to different bioanalytical facilities
• CRO’s ability to coordinate functional handoffs
• CRO’s clinical project management capabilities
• Validation of the data collection system
• SOPs, CRF, and database correction, change control
• Deliverables like CRFs (CRO or sponsor format), transport procedures to the bioanalytical unit, and content of the written clinical report

The client should also asses the capability of the laboratory project management with regard to their coordination with the clinic, pharmacokineticist, and the sponsor during the study.

Finally, to support the BA/BE study, the CRO should provide written documentation of the final analytical report that should contain supplementary project-specific validation data.

Thus, in a nutshell, it can be said that factors like the number of years in the business, qualified team of scientific, medical, and statistical experts, the ability of CRO to recruit volunteers, a sufficient number of beds for in-housing, calibrated laboratory equipment with suitable SOPs, location of the CRO, duration of getting IEC/IRB approval, employee training on SOPs, adherence to GCP and GLP, correct volunteer database, appropriate ambulatory service, clean kitchen facilities with maintained hygiene, recreation rooms for volunteers, working QAU system, facility management, and accurately designed scientific organization charts assess the qualification of a CRO to conduct BA/BE studies.

Conclusion

A generic manufacturer outsources a BA/BE study so that their product can be proved bioequivalent to that of a Reference Listed Drug (RLD).

The key elements for the success of the BA/BE study between the client and the CRO are transparent Communication at all levels, Sensitivity to the project’s requirements, timelines, and flexibility to recognize and adjust to unexpected events throughout the project timeline.

Work culture compatibility between a sponsor and CRO is also a substantial merit, as it leads to a more aligned relationship in the future.

REFERENCE

1. Outsourcing Bioavailability and Bioequivalence Studies to Contract Research Organizations, Patrick K. Noonan. Generic Drug Product Development Solid Oral Dosage Forms Chapter 13, Pg. No. 299-321.

When it comes to developing nations, there is a greater preference among the populace for generic pharmaceutical drugs as opposed to branded ones.

In India, generic drugs comprise 71% of the pharmaceutical market.

The reason for this is not hard to guess – a large proportion of the population having a low income level means the market is bound to be highly price sensitive.

Generic Drugs & Healthy Human Volunteers

Generic drugs may not have to go through the full gamut of clinical trials from Phase 1 to Phase 3, but they do have to pass the Bio-Availability and Bio-Equivalence (BA/BE) tests in order to earn the marketing license.

Healthy volunteers have an important role to play in enabling the BA/BE testing of such drugs.

Through BA/BE testing, a pharmaceutical company can determine if the molecule that they have developed has a similar response to the branded drug that it seeks to compete with.

Another reason BA/BE testing is important is to identify if there is a possibility of any side effects occurring as a result of being exposed to the generic drug molecule.

How Healthy Volunteers Contribute to BA/Be Testing of Generic Drugs

Because the drug is only being tested for bioavailability and bioequivalence with a previously known drug, the testing can be performed on healthy volunteers and need not necessarily involve patient volunteers.

Pharmaceutical companies would find it easier to recruit healthy volunteers as the number of patient volunteers would be comparatively smaller, and not all of them would be willing to subject themselves to a clinical test.

Thus, healthy volunteers play an important role in enabling the market introduction of generic drugs, which have a key role to play in making healthcare affordable in India and other developing countries.

Reviewing the Role of Healthy Volunteers in Testing of Investigational Drugs

In addition to this, First-In-Human (FIH) Phase 1 clinical studies for investigational drugs are also preferably performed on healthy volunteers.

The key goal that is sought to be achieved through healthy volunteer studies is to determine the pharmacokinetics and pharmacodynamics of a novel drug that is sought to be introduced, as well as to determine the right level of dosage and its safety and tolerability.

Typically, this involves a total of 20-80 healthy volunteers divided into groups of 3-6 each, who are administered escalating doses of the investigational drug.

Through these studies, a pharmaceutical company attempts to identify the bodily mechanisms involved in absorption, metabolism, and excretion of the drug, its pharmacokinetic profile, and the safety and tolerability of the drug at different dosage levels.

By conducting trials on healthy volunteers, a pharmaceutical company gets to understand the body’s response to a drug as well as its safety profile in the absence of any pre-existing pathological conditions influencing the response.

Thus, healthy volunteers play a key role in the journey of pharmaceutical drugs, both branded and generic, from the laboratory to the market.

Not only do pharmaceutical companies benefit by being able to reduce the time taken between the drug research and commercialization, but the fact that the drug can be introduced early also means it can be sold at lower prices, thus benefiting the patients who would depend on the drug for treatment.

Every new drug or molecule that is developed in the laboratory needs to undergo extensive trials before it could be marketed.

And with a growing number of innovative molecules and drugs that are being developed by pharmaceutical companies, the role of Contract Research Organizations (CROs) in aiding clinical trials is set to grow in prominence.

According to a report by Frost & Sullivan, the global CRO market, which was valued at $45.8 billion in 2018, is set to grow at a CAGR of 7.9% and reach a total size of $71.7 billion by 2024.

The key driver behind this growth is the increasing requirement for novel therapies to meet precision medicine needs.

While a pharmaceutical company could certainly develop in-house capabilities to conduct those trials, better sense would dictate outsourcing the conduct of clinical trials to a Contract Research Organization (CRO) for the following reasons:

The Core Competency

A pharmaceutical company has its energies dedicated to developing new drugs and managing commercially viable mass production of drugs.

However, between the two aspects, there is a crucial step of conducting clinical trials and obtaining regulatory clearances.

And that requires specialized expertise of its own.

CROs have professional teams working, with their core competency concentrated in the area of conducting clinical trials.

CRO generally work with multiple pharmaceutical companies, and as a result which they attain vast experience and expertise in conducting clinical trials.

CROs guarantee the technical expertise required in clinical studies and corroborate the quality of the research and results.

Expertise of Working With Different Regulatory Bodies

Working with multiple national and international Pharmaceutical companies has enabled CROs to obtain clearances from various regulatory bodies.

Having a vast experience of working with regulatory bodies such as DCGI (India), FDA (United States), ANVISA (Brazil), MHRA (United Kingdom), AGES (European Union), MCC (South Africa), NPRA (Malaysia), as well as WHO, is an added on.

Because of such experiences, a CRO is capable of guiding a pharmaceutical company with regard to the right ways of filing for regulatory clearances in different countries, thus making the process of new market entry smoother.

Comprehensive Portfolio of Clinical Research Services

Setting up an entirely new testing facility and procuring the necessary special-purpose equipment to conduct a certain type of drug testing might be unviable for a pharmaceutical company from a cost-effectiveness perspective.

This is because such capabilities that would be built to serve specific purposes would be sub-optimally utilized.

However, because a CRO helps multiple pharma clients with conducting clinical research, it is commercially more viable for a CRO to create facilities for conducting diverse clinical studies.

Effective Project Management and Quality Assurance

By employing a CRO, a pharmaceutical company would be able to obtain the services of dedicated project managers who can support the company throughout the lifecycle of clinical studies.

Also, a competent CRO would have a robust quality assurance policy in place.

Because of this, a pharmaceutical company can comfortably rely on the CRO when it comes to ensuring that clinical trials are executed in the best possible way.

Time and Cost Savings

By focusing only on its own areas of domain expertise and outsourcing clinical trials and regulatory filings to a CRO, a pharmaceutical company could achieve major cost savings due to the following reasons:

• Elimination of the need to spend capital on procuring equipment for clinical trials.
• Elimination of the need to recruit human resources with the required set of special skills, who would also have to be paid high salaries.

Based on the above-mentioned factors, it is easy to see why, for a pharmaceutical company, it makes great sense to recruit the services of a CRO.

Also, read our article on how to select a CRO.

Disclaimer:

The information contained in this article is intended solely to provide general guidance on matters of interest for the personal use of the reader, who accepts full responsibility for its use.

Accordingly, the information in this article is provided with the understanding that the author(s) and publisher(s) are not herein engaged in rendering professional advice or services.

As such, it should not be used as a substitute for consultation with a competent adviser. Before making any decision or taking any action, the reader should always consult a professional adviser relating to the relevant article posting.

While every attempt has been made to ensure that the information contained in this article has been obtained from reliable sources, Veeda Lifesciences is not responsible for any errors or omissions or for the results obtained from the use of this information.

All information on this article is provided “as is”, with no guarantee of completeness, accuracy, timeliness or of the results obtained from the use of this information, and without warranty of any kind, express or implied, including, but not limited to warranties of performance, merchantability and fitness for a particular purpose.

Nothing herein shall to any extent substitute for the independent investigations and the sound technical and business judgment of the reader.

In no event will Veeda Lifesciences, or its partners, employees, or agents, be liable to the reader or anyone else for any decision made or action taken in reliance on the information in this article or for any consequential, special, or similar damages, even if advised of the possibility of such damages.

No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, mechanical, electronic, photocopying, recording, or otherwise, without the prior written permission of the publisher.

As per Global Data, around 69.9% of global clinical trials since April 2020 suffered disruption due to the suspension of enrolment, whereas 12.8% are due to delayed initiation, and 17.3% are due to slow enrolment.

Moreover, among the trials affected by slow enrolment, around 15.4% (of the 17.3%) have been due to reduced availability of sites and investigators.

Given the situation that the pharmaceuticals sector finds itself in, there are bound to be significant changes in clinical research practices.

Some of these trends have been listed below:

1. Virtual Tour of Facility for Audit Purposes

With in-person visits to a CRO office for inspection of facility infrastructure no longer possible due to the pandemic, there is a growing demand for virtual tours of the facility for conducting audits.

Once CROs create these virtual tours, even in the post-COVID era, most pharma companies will prefer having virtual tours, as they help reduce travel costs and time.

2. Pharmaceutical Companies to Have Greater Reliance on CROs

There are a couple of factors due to which pharmaceutical companies are bound to have a much greater reliance on CROs in the future: – The complexity of clinical development requirements is constantly increasing, and consequently, the need is increasingly being felt for specialized expertise to take care of the requirements.

This is on account of pharma companies having to address multiple therapeutic areas, such as in-orphan diseases, oncology, CNS, diabetes, cardiovascular diseases, and internal medicine.

Often, biopharmaceutical companies, especially smaller ones, lack the internal infrastructure to conduct their own studies.

The fully loaded costs for every successful molecule have now grown to over $2 billion on average, and therefore, the importance of therapeutic expertise and scalability in reducing costs and time-to-market for new drugs is being acknowledged across the pharmaceutical industry.

One aspect where data-driven approaches can prove immensely beneficial is in conducting Real World Evidence (RWE) studies, where the economic value of a new drug or therapy can be ascertained.

RWE studies are occupying a place of increasing importance in the pharmaceutical industry because developmental and regulatory costs are increasing, and therefore, it is necessary to be reasonably assured of the commercial success of a new drug that is sought to be introduced in the market.

As such, CROs would strive to develop in-house data analytics capabilities, and pharmaceutical companies would come to rely on CROs to a great extent for commercial advice.

‘Necessity is the mother of invention,’ goes an old proverb.

The necessity to innovate upon the way clinical research has been traditionally conducted might bring about a complete transformation with regard to trial processes and efficiency.

We can confidently say that in the post-COVID era, clinical research is poised to witness exciting times.

Disclaimer:

The information contained in this article is intended solely to provide general guidance on matters of interest for the personal use of the reader, who accepts full responsibility for its use.

Accordingly, the information in this article is provided with the understanding that the author(s) and publisher(s) are not herein engaged in rendering professional advice or services.

As such, it should not be used as a substitute for consultation with a competent adviser. Before making any decision or taking any action, the reader should always consult a professional adviser relating to the relevant article posting.

While every attempt has been made to ensure that the information contained in this article has been obtained from reliable sources, Veeda Lifesciences is not responsible for any errors or omissions or for the results obtained from the use of this information.

All information on this article is provided “as is”, with no guarantee of completeness, accuracy, timeliness or of the results obtained from the use of this information, and without warranty of any kind, express or implied, including, but not limited to warranties of performance, merchantability and fitness for a particular purpose.

Nothing herein shall to any extent substitute for the independent investigations and the sound technical and business judgment of the reader.

In no event will Veeda Lifesciences, or its partners, employees, or agents, be liable to the reader or anyone else for any decision made or action taken in reliance on the information in this article or for any consequential, special, or similar damages, even if advised of the possibility of such damages.

No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, mechanical, electronic, photocopying, recording, or otherwise, without the prior written permission of the publisher.

Shift in Focus

The clinical research industry has come a long way from viewing patients as mere “subjects” to playing an integral part in the success of clinical trials.

Pharmaceutical and biotechnology industries are consciously making changes in the conduct of clinical trials by designing patient-centric trials.

With access to technology, many of the patients are well-informed, making it important for sponsor companies to encourage quality patient-physician interactions even before enrollment into a trial.

This approach is a win-win situation for the Sponsor and patient, with the patient made aware of the trial design and expected outcomes, while the Sponsor finds cost-effective solutions even before patient enrollment.

Multi-dimensional Approach to Transparent Communication

Sponsor companies are seen engaging in innovative ways of gathering patient feedback, such as contests or competitions, to gauge patients’ views on varied aspects of the trials, be it design, perceived effectiveness, patient needs, or even on different regulatory documents.

For instance, patient feedback on informed consent forms (ICFs) can help simplify language so that the form easily conveys trial rules, procedures involved, and/or the expected/unexpected risks of participation.

By promoting open communication between companies, doctors, and patients using technology and social media platforms, the chances of patient retention and satisfaction are higher, thereby leading to improved clinical outcomes.

Encouraging hospitals and clinics to maintain centralized electronic medical records can also contribute to accurate, timely, and seamless storage of patient data.

This, in turn, reduces errors in data handling with easier access to full patient history while conducting clinical trials.

In addition, publishing clinical trial documents such as protocols and study reports on a centralized repository that is accessible to professionals and non-professionals implies the Sponsor’s efforts in promoting transparency and building trust with the public.

Patient Engagement Initiatives

Pharmaceutical industries, stakeholders, regulatory bodies, and healthcare providers understand the need to have a patient engagement model built on mutual trust, transparency, accountability, inclusiveness, and effective communication and partnership.

Research studies are being carried out to examine the implementation of patient-centric activities in contract research organizations and in pharmaceutical/biotechnology companies.

These studies suggest that each company has its own way of implementing patient centricity, with many factors influencing their decision, such as organizational hierarchy, investment, and availability of resources.

Although patient engagement initiatives have gained momentum in the past decade, there is an urgent need to standardize these initiatives across pharmaceutical/biotechnological sectors and regulatory bodies to maintain ethical clinical practices as well as to measure performance using operational metrics.

Conclusion

Patient centricity is gaining prominence as access to healthcare increases.

This inevitably puts the clinical research industry in the spotlight to adapt and adopt technologies to build a mutually beneficial partnership.

This helps in keeping a check on the quality and ethical aspects of the clinical trial with better research outcomes and healthcare, as well as improved return on investments.

Sources

• Sharma NS. Patient-centric approach for clinical trials: Current trend and new opportunities. Prespect Clin Res. 2015;6(3):134-138.
• Pushparajah DS. Making Patient Engagement a Reality. The Patient – Patient-Centered Outcomes Research. 2018 Feb;11(1):1-8.
• Yeoman G, Furlong P, Seres M et al. Defining patient centricity with patients for patients and caregivers: a collaborative endeavor. BMJ Innov. 2017 Apr;3(2):76-83.
• Lamberti MJ and Awatin J. Mapping the Landscape of Patient-centric Activities Within Clinical Research. Clinical Therapeutics. 2017 Nov;39(11):2196-2202

The last two decades have witnessed many businesses capitalize on technological solutions to improve their processes and profitability, and the healthcare industry is no different.

Technological solutions have added a great deal of value to the healthcare industry.

Their application in clinical trials has not only boosted the operational efficacies but also aided in patient centricity.

Patient centricity ensures factoring patients’ point of view and puts them at the center of the trial.

Patient experience is very crucial for better clinical trials and drug outcomes.

However, factors such as patients’ data confidentiality, regulations and compliance issues, and inaccessibility of patients at the required time have posed a challenge to this novel approach.

IoT-driven technology has come to offer a solution and is helping more and more researchers adopt the approach and improve their processes.

Information Sharing

Patient recruitment is a tasking process and researchers have to put in lot of efforts in order to provide important information about the trial.

Lack of clarity in this communication can make it leave the patients in ambiguity and make the recruitment process more challenging.

Patients need to be provided with information that is simple, to the point, and easy to understand.

Here, using the digital medium eases things out for them.

A short audio-visual presentation on the matter with necessary details would certainly improve the patient experience; it enables them to comprehend every aspect of the trial and facilitates their decision-making process.

Onboarding Patients with Technology

Use of technology in clinical trials for onboarding certainly alleviates the experience for patients.

Onboarding requires patients to sign a consent form.

In the past, these were required at multiple stages, and considering everything was manual, a lot of paperwork was involved, making it quite taxing.

Technology has taken the entire consent process digital.

The advanced Electronic Content Systems (ECS) for clinical trials are patient-friendly and regulatory compliant, enabling patients to fill out their consent forms online, automating the process of patient enrollment and making it faster and efficient.

Such systems lessen the administrative workload via improved consent tracking management and reduce informed consent errors.

Eliminating Distance Issues

Technology has eliminated the distance issues and is aiding clinical researchers in finding and reaching out to patients worldwide.

For a successful patient-centric clinical trial, finding the right quality and number of patients is a must.

With mobile technology and IOT, the location of the patient is becoming immaterial.

Technology has made it possible to connect with global patients in eloquent ways and collect larger volumes and better-quality data through virtual trials.

While more advanced technological applications are still needed, technology has certainly aided patient centricity in clinical trials, enabling better quality studies and results.

It has had a positive and encouraging impact on the patients’ experience.

Introduced in the 1970s by Ralph A De Fronzo, Jordan Tobin, and Reubin Andres to quantify insulin secretion and resistance, glucose clamp studies are now considered the “gold standard” for studying pharmacodynamic and pharmacokinetic effects of different formulations of insulin.

There are many variants of the glucose clamps, such as hyperinsulinemic-euglycemic, hypoglycemic, and hyperglycemic glucose clamps.

Hyperglycemic glucose clamps are used for quantifying the sensitivity of beta cells to glucose by maintaining a steady hyperglycemic state through the infusion of variable concentrations of glucose.

Hypoglycemic clamps have been used to study iatrogenic hypoglycemia and the effect of hypoglycemic agents on hepatic glucose production, while hyperinsulinemic-euglycemic clamps are used for their ability to detect subtle differences in insulin preparations.

For hyperinsulinemic-euglycemic pumps, the plasma insulin concentration is raised to a pre-determined level by priming and continuous infusion of insulin.

In addition, the plasma glucose concentration is maintained by exogenous glucose infusion to induce a steady state of hyperglycemia.

This helps in measuring the whole-body sensitivity to insulin, wherein the concentration of infused exogenous glucose must be equal to the amount of glucose used by the body in response to the induced hyperglycemic state.

Similarly, hyperglycemic pumps function by keeping a constant plasma glucose concentration with the desired hyperglycemic plateau and are helpful in assessing an individual’s insulin secretion capacity.

In hypoglycemic clamp studies, a pre-defined blood glucose concentration is maintained for a specified period by separate intravenous infusion of insulin and glucose.

Blood samples are then collected at the glucose plateau phase for further biochemical study of counter-regulatory hormonal responses.

This may help in identifying any glycemic threshold that can be correlated to the onset of hypoglycemic symptoms.

Advantages of Glucose Clamps

• Reproducible results with accurate measurement of insulin action
• Hyperinsulinemic-euglycemic pumps are safe for use in elderly patients as well as in special populations such as individuals with renal or hepatic disorders.
• Hypoglycemic clamp is the best method to understand and study counter-reactions to hypoglycemic conditions.
• The perfect apparatus for assessing preparations of insulin or insulin analogs
• Clamp studies do not interfere with the results of other test techniques and can be used in combination with them. For example, the determination of hepatic function.

To validate the outcome of glucose clamp studies, it is necessary to ensure the good quality of glucose clamps along with improved computer algorithms to obtain optimal glucose infusion rates and sound blood glucose data.

Eventually, such standardized results will be beneficial in research studies on diabetes and its management.

Pharmacokinetics deals with the change in concentration of a drug over time within the human body.

Absorption, distribution, metabolism, and excretion are the four main phases of a pharmacokinetic study.

Pharmacokinetic studies of drug molecules provide insight into how to minimize the need for clinical studies.

They also reduce the costs of generic product development by simplifying bioequivalence testing.

Topical medication is defined as pharmaceutical products that are applied to a particular place on or in the body, like the skin or mucous membranes.

Local Anaesthetics, Corticosteroids, Retinoids, NSAIDs, Antivirals, Vitamin D3 derivatives, and Immunomodulators are some classes of topical drugs.

Topical drugs are also available in various formulations, including creams, foams, gels, lotions, and ointments.

The ability to enhance cutaneous drug distribution of both lipophilic and hydrophilic products has been demonstrated by new vesicular formulations, including microemulsions, liposomes, and nanoparticles.

The evaluation of pharmacokinetic studies for topical drugs is carried out according to the stratum corneum (SC) concentration-time curve.

This curve was generated after assessing the concentration of the drug in the outermost layers of the skin (SC) with respect to time.

The curves provide information on drug absorption, steady-state, and drug elimination.

For assessing the bioequivalence of a topical drug product, the following parameters are considered to be the major criteria:

1. The maximum concentration of active drug molecules in the SC (Cmax)
2. The time to achieve the maximum concentration (Tmax)
3. The area under the curve in the SC versus the time curve (AUC)

Absorption and Distribution

After administration of a topical drug, the first layer to be absorbed is the drug, and then it is distributed throughout the tissue.

The concentration of a drug that reaches the target site from a topically administered medicine is highly dependent on these three characteristics:

1. Drug
2. Its formulation
3. Properties of the skin to which it is applied.

The stratum corneum plays a significant role in the permeation of topical drug products.

It acts as an effective barrier by allowing only a few percent of a topically applied dose to be absorbed.

The absorption of topical drugs into the skin depends on various factors, including molecular size, lipophilicity, pH of the formulation, penetrant concentration, chemical enhancers, skin hydration, skin enzymes, temperature, and formulation composition.

To provide a reasonable approximation of the concentration of drugs in the skin as a function of time and to derive the dermatokinetic parameters (Cmax, Tmax, and AUC), which are of definite importance, frequent measurement of drug levels in the skin is vital.

Therefore, the FDA’s draft guidelines for DPK state that, at a minimum, eight separate locations must be evaluated for drug levels: four of the sites are examined during uptake (e.g., 0.25, 0.5, 1, and 3 hours post-application), and four sites during clearance (e.g., 4, 6, 8, and 24 hours post-application).

Also, the FDA has proposed that all skin samples be taken on a single day to prevent inter-day variability, which is of considerable concern because of the restricted supply of skin in a given subject.

The success of the skin kinetic analysis depends similarly on the development of sensitive analytical methods to measure the drug quantity.

Tape Stripping, Micro dialysis, and in vitro percutaneous tests, such as Flux assessment and concentration of skin tissue, are feasible approaches for pharmacokinetic examination of topical formulations.

These pharmacokinetic skin sampling experiments are used mainly to assess topical product bioequivalence.

Another important instrument for evaluating dermatokinetic parameters is confocal laser scanning microscopy.

For fluorescent drugs or probes, confocal images are feasible and do not require the skin to prepare optical sections.

This method helps an investigator produce a concentration profile after topical application of the drug product.

Clearance and Metabolism

Most of the dermatokinetics studies revolve around the absorption phase of a topical drug.

However, clearance of a topical drug is equally important in assessing the bioavailability of the topical formulations. Following skin permeation, the key process involved in post-absorption is clearance.

Continuous, fenestrated, and discontinuous are the three types of capillaries found in the human body.

The capillaries are closely related to clearance, as they are the first permeable sections of circulation encountered by a permeate that has been added topically.

Parameters that alter the drug clearance of topical products include the thickness of the blood vessel, the area, the distance between blood vessels, and the blood flow rate.

It is very interesting to know that the skin contains all the major enzymes responsible for metabolism, which are found in the liver and other tissues.

These enzymes possess the ability to catalyze several metabolic reactions.

Evaluating the metabolism of topical formulations through in vivo experiments is difficult since biological specimens can often contain metabolites from other tissues.

In-vitro permeation studies and measuring the metabolite in skin homogenate or the receptor fluid are the methods through which the metabolism of topical drugs is assessed.

Conclusion

Evaluating the dermatokinetic parameters is of paramount importance to assess the safety and efficacy of topical formulations.

Numerous approaches are used to determine the real-time measurement of molecules in the skin layers.

Regulatory bodies, such as the US Food and Drug Administration (FDA), are investing time and money in developing various techniques for characterizing the pharmacokinetics of topical drugs.

The maximal concentration of the active drug molecule in the SC (Cmax), the time to achieve the maximum concentration (Tmax), and the area under the curve (AUC) are the most commonly assessed parameters in dermatokinetic studies.

Different methods are reported for assessing the pharmacokinetic profile of topically applied drug molecules, as discussed above.

Clearance and Metabolism of topical drugs are also essential to consider the pharmacokinetics of topical formulations.

Finally, one should know that most of the topical drug molecules entering the dermis are quickly cleared by the microvascular system.

However, few drug molecules get retained in the skin, leading to the depot effect.

REFERENCE

1. Nair, S. Jacob, B. Al-Dhubiab, M. Attimarad, S. Harsha. Basic considerations in the dermatokinetics of topical formulations. Brazilian Journal of Pharmaceutical Sciences vol. 49, n. 3, jul./sep., 2013.
2. WJ McAuley, L Kravitz. Pharmacokinetics of topical products. Dermatological Nursing, 2012, Vol 11, No 2.