Guide Bioequivalence Studies in Drug Development: Methods and Applications (Statistics in Practice)

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We use them to give you the best experience. If you continue using our website, we'll assume that you are happy to receive all cookies on this website. Notrox Research is a contract research organisation CRO that conducts clinical trials for pharmaceutical companies. Specialising in bioequivalence studies comparing approved drugs against generic formulations, the company provides high-quality data from trials conducted by highly trained staff in state-of-the-art facilities. All studies are performed in accordance to good clinical practices GCP. It provides high-quality, cost-effective clinical pathology laboratory services, which support pre-clinical studies or clinical trials.

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The experienced research team has extensive knowledge of human haematology, urinalysis, coagulation, and clinical biochemistry, as well as therapeutics, international regulation, and operations optimisation. Clinical study services also help ensure timely enrolment of patients and successful trial conduct. The company assesses proposed studies to optimise various aspects, including regulatory issues and approval, enrolment limitations, logistics, timelines, trial materials, and epidemiology.

Notrox provides specialised, custom laboratory services for assays, bio-markers, or drug safety studies. Performed in good laboratory practice GLP compliant laboratories, the company has an extensive list of bioanalytical services for all stages of drug development and commercialisation, including the transfer, validation, and analysis of samples for multiple biological species and matrices; state-of-the-art assay development; and metabolite identification. The bioanalytical methods available for measuring compounds include liquid chromatography-mass spectrometry LC-MS , mass spectrometry MS , and high-performance liquid chromatography HPLC.

The laboratories provide accurate, high-quality results and are staffed by scientific experts. A noteworthy example for agriculture is plant phosphorus deficiency induced by precipitation with iron and aluminum phosphates at low soil pH and precipitation with calcium phosphates at high soil pH. Absolute bioavailability compares the bioavailability of the active drug in systemic circulation following non- intravenous administration i. It is the fraction of the drug absorbed through non-intravenous administration compared with the corresponding intravenous administration of the same drug.

The comparison must be dose normalized e. In pharmacology, in order to determine absolute bioavailability of a drug, a pharmacokinetic study must be done to obtain a plasma drug concentration vs time plot for the drug after both intravenous iv and extravascular non-intravenous, i. The formula for calculating the absolute bioavailability, F , of a drug administered orally po is given below where D is dose administered. If we compare the two different dosage forms having same active ingredients and compare the two drug bioavailability is called comparative bioavailability.

Although knowing the true extent of systemic absorption referred to as absolute bioavailability is clearly useful, in practice it is not determined as frequently as one may think. The reason for this is that its assessment requires an intravenous reference ; that is, a route of administration that guarantees all of the administered drug reaches systemic circulation. Such studies come at considerable cost, not least of which is the necessity to conduct preclinical toxicity tests to ensure adequate safety, as well as potential problems due to solubility limitations.

These limitations may be overcome, however, by administering a very low dose typically a few micrograms of an isotopically labelled drug concomitantly with a therapeutic non-isotopically labelled oral dose the isotopically-labelled intravenous dose is sufficiently low so as not to perturb the systemic drug concentrations achieved from the non-labelled oral dose.

The intravenous and oral concentrations can then be deconvoluted by virtue of their different isotopic constitution, and can thus be used to determine the oral and intravenous pharmacokinetics from the same dose administration. This technique eliminates pharmacokinetic issues with non-equivalent clearance as well as enabling the intravenous dose to be administered with a minimum of toxicology and formulation.

The technique was first applied using stable-isotopes such as 13 C and mass-spectrometry to distinguish the isotopes by mass difference. More recently, 14 C labelled drugs are administered intravenously and accelerator mass spectrometry AMS used to measure the isotopically labelled drug along with mass spectrometry for the unlabelled drug. There is no regulatory requirement to define the intravenous pharmacokinetics or absolute bioavailability however regulatory authorities do sometimes ask for absolute bioavailability information of the extravascular route in cases in which the bioavailability is apparently low or variable and there is a proven relationship between the pharmacodynamics and the pharmacokinetics at therapeutic doses.

In all such cases, to conduct an absolute bioavailability study requires that the drug be given intravenously. Intravenous administration of a developmental drug can provide valuable information on the fundamental pharmacokinetic parameters of volume of distribution V and clearance CL. In pharmacology, relative bioavailability measures the bioavailability estimated as the AUC of a formulation A of a certain drug when compared with another formulation B of the same drug, usually an established standard, or through administration via a different route.

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When the standard consists of intravenously administered drug, this is known as absolute bioavailability see above. Relative bioavailability is one of the measures used to assess bioequivalence BE between two drug products. When T max is given, it refers to the time it takes for a drug to reach C max. While the mechanisms by which a formulation affects bioavailability and bioequivalence have been extensively studied in drugs, formulation factors that influence bioavailability and bioequivalence in nutritional supplements are largely unknown.

The absolute bioavailability of a drug, when administered by an extravascular route, is usually less than one i. Various physiological factors reduce the availability of drugs prior to their entry into the systemic circulation. Whether a drug is taken with or without food will also affect absorption, other drugs taken concurrently may alter absorption and first-pass metabolism, intestinal motility alters the dissolution of the drug and may affect the degree of chemical degradation of the drug by intestinal microflora.

Disease states affecting liver metabolism or gastrointestinal function will also have an effect.

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Each of these factors may vary from patient to patient inter-individual variation , and indeed in the same patient over time intra-individual variation. Biologic activity of digoxin tablets. J Am Med Ass. Anderson S, Hauck WW. Consideration of individual bioequivalence. J Pharmacokinet Biopharm. Schall R.

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    Guidance for Industry. Gould AL. A practical approach for evaluating population and individual bioequivalence. Stat Med.

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    J Clin Pharmacol. Patterson S. A review of the development of statistical design and analysis techniques for assessing in vivo bioequivalence: Part two. Ind J Pharm Sc. Rheinstein PH. Therapeutic inequivalence. Drug Safety.

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    A pharmacokinetic and clinical review of the potential clinical impact of using different formulations of cyclosporine A. Clin Ther. Evaluation of bioequivalence for highly variable drugs with scaled average bioequivalence. Clin Pharmacokinet. Bioequivalence approaches for highly variable drugs and drug products. Pharm Res.

    Sheiner LB. Bioequivalence revisited.