Metabolite Safety in Drug Development

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He has coauthored over publications, including Attrition in the Pharmaceutical Industry Wiley, , Reactive Drug Metabolites Wiley, , and three editions of the book Pharmacokinetics and Metabolism in Drug Design Wiley, Request permission to reuse content from this site. Smith and Suzanne L.

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Dear and Angus N. Dear and Andrew McEwen. Scott Obach, Amit S. Kalgutkar, and Deepak K. Gerry Kenna and Richard A. Some Case Studies Deepak K. Dalvie, R. Scott Obach, and Amit S. Dear, Stephanie North, and Graeme Young. This objective is certainly achieved in a lucid, scholarly and engaging manner. I would not hesitate to recommend this book to anyone interested in this subject and also for those who may wish to delve into this area.

Drug formulation, the mixing of API with other chemical ingredients to create the drug product DP , is often a major hurdle in drug development.

Drug Development Process - TOX, ADME, PK/PD, Clinical POC and Drug Approval

At this stage, the route of administration intended for the clinic should be clearly identified. Drugs may be introduced either enterally oral, buccal, and rectal or parenterally not through the alimentary canal including by injectable routes intravenous, intramuscular, and subcutaneous , topically, and by inhalation. Except for imaging diagnostic agents, vaccines, and antibodies, most drugs targeting neurodegenerative diseases and their symptoms will be administered by the enteral or possibly topical routes.

Drugs intended to be administered orally may be formulated as a solution, suspension, capsule, or tablet. Any formulation intended for human use is subject to rigorous quality control manufacturing and safety testing. In addition to the clinical application, the specific physicochemical properties of a DS will influence formulation options. A number of parameters must be considered when creating the DP formulation. The components of any formulation must have physical and chemical compatibility with the DS.

Formulations may incorporate components such as dissociation enhancers that are found to improve bioavailability of the active DS. Solid formulations, particularly tablets, may be coated to improve swallowing, mask an unpleasant taste, protect ingredients during storage, improve appearance, and control drug release over time or target it to specific regions of the gastrointestinal tract.

In most instances, the clinical drug formulation is not fully optimized before submission of the IND and the initial first-in-human FIH clinical studies. Therefore, it is customary to compose a simple formulation to be presented as the DP in the IND and used in phase1 studies to deliver the drug to human subjects. For example, an oral FIH trial design may utilize drug supplied as a powder; an appropriate quantity is weighed out by the pharmacist and placed in a gelatin capsule prior to administration.

For both oral and intravenous FIH trial designs, a specific amount of drug may be supplied in a clinical vial also known as powder in bottle, or PIB to which the appropriate volume of vehicle specific liquid component is added prior to administration. These approaches are most useful for early phase 1 trials involving relatively few human subjects. As the clinical trials become more complex and involve more subjects, oral formulations may be prepared in tablets or capsules containing scaled quantities, or 'strengths,' of the drug for example, 50 mg, mg, and mg so that each patient can take a combination of quantities to target individual body weight.

Once the unit dose is established usually after phase 2 and before phase 3 clinical trials , a formulation is selected as the final DP for later stage clinical trials and product release. As described above for APIs, all formulations intended for human use are prepared under rigorous specifications as outlined in the GMP guidelines.

Starting from the initial drug discovery phase, analytical chemistry applications are found throughout the drug development process. These applications can be categorized into two major subdivisions: pharmaceutical analysis and bioanalysis. Pharmaceutical analysis involves the measurement of an analyte in a neat sample or formulation, whereas bioanalysis is the quantification of an analyte in a biological matrix.

US FDA guidance on safety testing of drug metabolites revised

Reliable analytical methods are required to test and qualify in-coming materials, in-process methods, equipment, formulations, DSs, and DPs. These methods are critical for analyzing the various formulations that may be investigated for a final dosage form and are integral to quality control in GLP and GMP settings. Therefore, analytical methods may need to be developed for a variety of materials and circumstances, each with a different intended purpose. For example, the analytical method required for formulation development may not require the same performance characteristics as those required for a stability-indicating method for DS or DP.

The research and development component includes analytical method development and analytical support for preformulation and formulation. The quality control unit is responsible for the oversight of GMP analytical work. It is essential that the validated methodology used to test the DS be used in clinical manufacturing. The developed method must satisfy two requirements: it must be accurate, requiring high specificity, good precision, and good reproducibility; and it should be practical, with the necessary ruggedness, sensitivity, and linearity.

Assay methods are verified under the ICH guidelines for reproducibility, specificity, selectivity, accuracy, linearity, precision, applicable concentration range, limit of detection, limit of quantification, ruggedness, and robustness. The specifications for DS typically include a physiochemical characterization program that generally requires determination of the composition, physical properties, and primary structure of the desired product.

The suitability of a final compound for pharmaceutical use requires establishment of its identity and purity, as well as knowledge of its chemical and physical properties. Formulation analysis verifies the active and inactive components and dosage, assesses potency, determines shelf-life stability, confirms dissolution properties, and determines whether decomposition has occurred or impurities have been introduced during the formulation process. It is important to ensure that materials of known purity and defined quality are used in all studies and that they conform to applicable FDA regulatory requirements.

Physiologic fluids such as blood, plasma, and urine are analyzed to determine the fate and disposition of a DS administered to a test animal or patient. Aliquots of blood may be sampled over time to determine therapeutic drug concentration ranges. The concentration of the drug in the biological matrix changes with time, typically over a broad range, and, therefore, bioanalytical quantification limits are at concentrations much lower than those required for formulated or bulk drugs. An appropriate bioanalytical method is required to detect drug at these low levels, as well as linearly over an appropriate range.

Matrix effects and stability issues can also make accurate analysis of the analyte difficult; these include, among many others, endogenous materials extracted from the biological matrix that may interfere in the analysis, enzymes in the biological fluid that are capable of metabolizing the analyte, plasma proteins that the analyte can bind to, and concomitant drugs that might interfere in the analysis. All these factors must be considered when planning an analysis.

PK, or the study of the time course of a drug in the body incorporating the processes of ADME, is a key determinant in the selection of a viable drug candidate.

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Since many potential drugs are eliminated from further development because of poor PK properties, drug discovery programs now incorporate early ADME screens for desirable 'drug-like' properties to optimize the selection of successful candidates. These predictive ADME approaches include in silico models, physiochemical parameters, and in vitro assays of permeation and drug metabolism to better evaluate the properties of potential pharmaceuticals and to concentrate additional efforts on only the most promising compounds. After these screening data are evaluated in concert with efficacy results, compounds that are predicted to have favorable PK properties are studied further using in vivo animal models.

PK parameters are extrapolated from measurements of drug concentration in the plasma, blood, or other relevant biological matrix over a selected time period usually several time points concluding at 24 or 48 hours post dose. PK provides information that can guide future animal and clinical studies for the selection of the dose levels and frequency of administration. The IND package requires PK data generated in two species one rodent, one nonrodent , preferably using the same two species used for the safety studies. These studies usually include multiple dose levels so that PK dose dependency can be evaluated.

Oral and intravenous administrations are compared to determine the oral bioavailability of the drug if an oral route is anticipated for the clinic. It is not necessary to delineate all ADME characteristics of a molecule at the time of IND submission, since the first clinical study generally focuses on the pharmacokinetics and metabolism of the drug in humans.

Toxicokinetic TK endpoints are similar to PK except that the samples are collected from animals during the toxicology and safety studies described below and usually do not cover as many time points. They help the investigator understand the drug's behavior at the maximal dose levels used in toxicology studies as well as steady state, accumulation, and trough levels after repeated administration.

The same bioanalytical methods as developed for in vivo PK evaluations are usually suitable for measuring drug concentration in the relevant biological matrix for example, plasma ; however, the method will need to be validated if it is applied to GLP study samples. Metabolism studies are also recommended by the FDA.

These studies can be useful to evaluate the potential for drug-drug interactions and cytochrome P inhibition and to generate drug metabolite profiles for different species, including humans. Metabolism studies are typically conducted using in vitro methods for exposing hepatic microsomes, cytosolic fractions, hepatocyte cultures, or other applicable test systems to the drug. Using a bioanalytical method, any metabolites are described as a fractional percent of parent-drug peak. In vitro metabolism studies are frequently the first glimpse into the effects of human metabolic pathways on a drug and may reveal considerable metabolic differences between humans and preclinical species.

In the event of significant interspecies metabolite profile differences, investigators may compare these with the human metabolite profile to identify which species, if any, most closely matches the humans, and then select this species for the pivotal safety and toxicology studies. Because of the importance of these interspecies results for understanding the potential disposition of the drug in humans, many development plans begin these studies about the same time as the first animal PK studies.

Despite numerous technical advances in the science of toxicology and attempts to develop in silico screening, the primary methods used to assess safety remain single- and repeat-dose toxicology studies conducted in rodent and nonrodent species. Definitive animal studies establish the safety characteristics, including the no observable adverse effect level NOAEL , of the candidate drug.

With very few exceptions, these studies are rigorously documented and conducted under regulatory guidelines — for example, FDA GLP. The highest dose levels tested in the definitive animal studies are almost always based on the maximum tolerated dose determined from the range-finding studies rather than either the expected dose level to be used in the clinical trial or an expected plasma concentration.

By the time a drug reaches definitive animal safety testing, a human trials clinician is included in the drug development team to provide study details on the proposed FIH clinical trial.

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In general, the route and frequency of drug administration, vehicle, and dose formulation if applicable to be used in initial human trials is reflected in the definitive animal studies. To account for differences between humans and laboratory species, a safety margin is established based on the NOAEL in the 'most sensitive' of the tested species. Toxicology studies are commonly conducted in rats and dogs, though other large animal species may be appropriate for specific products or therapeutic applications.

For example, rabbits are frequently the species of choice for safety testing of vaccines. Preliminary toxicity studies are often performed as part of the lead compound selection process. The route of administration in these studies must be the same as the proposed clinical route. If the proposed route is oral, drug is administered by gavage to rats and by gavage or capsule to dogs. The duration of administration and dose regimen must, at a minimum, conform to the proposed clinical protocol.

For example, if 14 days of continuous drug administration is proposed for the phase 1 clinical trial, then animal toxicity studies of at least 14 to 28 days are typically required to support a clinical study of this length. Although usually occurring after phase 1 dosing, longer term animal studies for example, 60 days and longer will be needed to support later stage human clinical trials. The frequency of dosing for example, three times a week for 4 weeks in the animal studies should also mimic the clinical dosing schedule.

Pivotal safety studies are performed with drug manufactured under GMP conditions whenever possible, although the FDA does not state this requirement. In the event that a drug is not manufactured under GMP conditions, the investigator is required to demonstrate that the clinical drug is essentially the same as that used in animal safety studies.

If significant differences for example, different counterion salts are observed between GMP materials scheduled for the clinic and the materials used in a pivotal preclinical safety study, the regulating agency may deem the safety study to be invalid and request that bioequivalency studies be conducted or the pivotal study be repeated using the correct materials. Because most repeat-dose toxicity studies of therapeutics reveal some adverse effects at higher dose levels, group assignment also includes a recovery group to evaluate whether adverse effects are transient or irreversible after repeat dosing.

For dose level selection, allometric body surface area scaling may be used to convert from many preclinical species to human dose levels, with additional multiples added to account for interspecies differences and potential safety factors. In addition to the pivotal safety studies, required ancillary studies, specified in ICH guidelines, complete most regulatory packages.

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FDA Revises Guidance on Safety Testing of Drug Metabolites

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