Bioavailability/Bioequivalence (BA/BE) Studies

Introduction

Under Philippine laws, generic medicines are being promoted to improve access to safe, effective, and quality medicines at the lowest possible cost. As mandated in AO 67 s.1989: Revised Rules and Regulations on Registration of Pharmaceutical Products and Bureau Circular No. 01 s. 1997: Enforcement of the Requirement for Bioavailability Studies for Registration of Products Included in List B (Prime) under AO 67 s. 1989,  the concept of Bioavailability/Bioequivalence was introduced to all stakeholders to highlight the importance of interchangeability between generic and innovator drugs (or brand-name). Generic drugs are drugs not covered by patent protection and are labeled solely by their international non-proprietary or generic name. When an innovative drug product has gone off-patent, pharmaceutical or generic companies may file an abbreviated new drug application (ANDA) for generic approval. For the approval of generic drug products, the Food and Drug Administration (FDA) requires that evidence of bioequivalence be provided through the conduct of bioavailability and bioequivalence studies. The list of products requiring bioequivalence studies for marketing authorization is found in FDA Circular No. 2013-014.

Bioavailability refers to the extent and rate to which a drug, from a specified dosage, reaches the bloodstream in an active, or free-drug form (in contrast to the amount of drug entering the non-circulating part of a tissue). In bioavailability studies, the concentration of the drug in the plasma or blood is measured after the drug is administered and its bioavailability is measured over time. On the other hand, bioequivalence means the absence of a significant difference in the rate and extent to which the active ingredient of drug products being compared becomes available in the circulation when administered at the same dose under similar conditions.

Under the Fundamental Bioequivalence Assumption, if two drug products are shown to be bioequivalent, it is assumed that they will generally reach the same therapeutic effect or they are therapeutically equivalent. In some cases, bioequivalence may not necessarily imply therapeutic equivalence and therapeutic equivalence does not guarantee bioequivalence either. This should be further evaluated with additional studies.

Approved drug products are considered to be therapeutic equivalents if bioequivalence is demonstrated in products containing identical amounts of the active ingredient, dosage forms, and routes of administration. They are also expected to have the same therapeutic effect and safety profile when administered to participants for their intended use specified in the labeling.

Design and conduct of BA/BE studies

A common design to compare two formulations is a randomized, two-period, two-sequence single-dose crossover design. A sufficient length of washout period of at least five half-lives (the time it takes for the drug to be eliminated from the body) between dosing periods is necessary to prevent a possible carry-over effect of the previous dose to the next dosing period. Sometimes, a higher-order crossover design (Balaam’s design, two-sequence three-period dual design, four-period design with two sequences, four-period design with four sequences) may be needed to estimate intra-subject variability between formulations.

For the renewal or extension of product registrations of generic medicines, the test product used in bioequivalence studies should be compared with a corresponding dosage form of the comparator or innovator product. The test product should be representative of the actual marketed product.

An appropriate sample size calculation should be done to determine the number of participants included in the study. It is also imperative to control factors that may result in variations unrelated to the differences between drug products. For this reason, studies are normally performed on healthy volunteers. The suitability of volunteers should be based on clinical laboratory tests, a medical history, and a physical examination. Participants are preferably nonsmokers and without a history of alcohol or drug abuse. Additional medical investigations and precautions may have to be carried out before, during, and after the completion of the study depending on the drug’s therapeutic class and safety profile.

Other than the characteristics of participants, diet, fluid intake, and physical activity are also standardized. There may be certain food and drinks that should be abstained from which may interact with circulatory, gastrointestinal, hepatic, or renal function (e.g. alcoholic drinks, caffeine, grapefruit, citrus fruits, or other food and beverages containing xanthines) during a suitable period before and during the study. Participants should also not take any other concomitant medication (including herbal remedies) for an appropriate interval before as well as during the study. In case unavoidable, such as in the instances of treatment of adverse events, the use of concomitant medication should be reported indicating its purpose and dose and time of administration.

Administration of drug products or formulations to the participants should be based on the randomization plan. Generally, a single dose study should be conducted after fasting for a specified number of hours as stated in the study protocol, and subsequent fasting usually four hours after administration dosing. A standardized volume of fluid intake should be administered with the test and comparator products as fluid intake may influence gastric passage for oral administration forms. After the administration, blood samples are withdrawn from the participants at specified time intervals. Each collected sample is analyzed to determine drug concentration at a specific time point. Drug concentrations are analyzed over time to determine the rate and extent of absorption of the drug products under study.

Criteria for bioequivalence

Bioequivalence studies should be performed in accordance with Good Clinical Practice (GCP) and Good Laboratory Practice (GLP) principles. The assessment of bioequivalence is based upon 90% confidence intervals for the ratio of the population geometric means (test/reference) for the parameters under consideration. Bioequivalence is concluded if the average bioavailability of the test formulation is within that of the reference formulation.

Comparative bioavailability studies

The design and conduct of bioequivalence studies may also be applied to comparative bioavailability studies evaluating different formulations used during the development of a new medicinal product containing a new chemical entity to determine human safety and efficacy. Comparative bioavailability studies may also be done to compare different pharmaceutical formulations such as tablets and capsules which may or may not exhibit very similar bioavailability.

Biowaivers

For immediate-release, solid oral dosage forms with active pharmaceutical ingredients (APIs) belonging to Class I and III according to the Biopharmaceutics Classification System (BCS), the World Health Organization (WHO) recognizes the possibility to waive in vivo bioequivalence studies using in vitro dissolution tests. For a waiver to be granted, the drug substance should be highly soluble, highly permeable, and rapidly dissolving. The approach is based on the differences in the solubility of drug compounds related to dose and intestinal permeability in combination with the dissolution properties of the dosage form, which may account for differences in bioavailability.

As an FDA-accredited BA/BE testing facility, our institution is compliant with the standards of Good Clinical Practice (GCP) and Good Laboratory Practice (GLP) to ensure the proper conduct of bioequivalence studies. We are one with the government in our aim to deliver accessible cheaper and quality medicines for the Filipino people.

List of Validated Methods

Bioavailability and bioequivalence are important aspects of drug regulation and manufacturing to ensure that drugs reach the consumers in a high-quality form. Pharmalytics Corporation, since its establishment in 2014, has conducted over a hundred bioavailability/bioequivalence studies and biowaivers. Below are some of our listed compounds we are capable of testing:

  • Abacavir + Dolutegravir + Lamivudine
  • Abacavir + Lamivudine
  • Abiraterone
  • Aceclofenac
  • Aceclofenac + 4-Hydroxy Aceclofenac
  • Acenocoumarol
  • Acetylsalicylic Acid + Salicylic Acid
  • Acyclovir
  • Adefovir
  • Afatinib
  • AKP-119
  • Albendazole + Albendazole sulfoxide
  • Albuterol
  • Alendronate
  • Alfuzosin
  • Aliskiren
  • Almotriptan
  • Alogliptin + Pioglitazone + Hydroxy Pioglitazone (M-IV)
  • Alprazolam
  • Aminocaproic Acid
  • Amiodarone + Desethylamiodarone
  • Amisulpride
  • Amitriptyline + Nortriptyline + E-10-OH Nortriptyline
  • Amlodipine
  • Amlodipine + Atenolol
  • Amoxicillin
  • Amoxicillin + Clavulanic Acid
  • Ampicillin
  • Anastrozole
  • Apixaban
  • Apomorphine
  • Apomorphine Sulfate
  • Apremilast
  • Aprepitant
  • Aripiprazole
  • Armodafinil
  • Artemether & Dihydroartemisinin
  • Asenapine + N-Desmethyl Asenapine
  • Atazanavir
  • Atazanavir + Ritonavir
  • Atenolol
  • Atorvastatin
  • Atorvastatin + O-Hydroxy Atorvastatin + P-Hydroxy Atorvastatin + Ezetimibe
  • Atorvastatin + o-OH Atorvastatin + p-OH Atorvastatin
  • Azilsartan
  • Azilsartan + Azilsartan M-I + Azilsartan M-II
  • Azilsartan + Chlorthalidone
  • Azithromycin
  • Balsalazide + 5-Aminosalicylic Acid
  • Baricitinib
  • Beclomethasone Dipropionate + Beclomethasone Monopropionate
  • Benazepril + Benazeprilat
  • Benzbromarone
  • Bicalutamide
  • Bisoprolol
  • Bisoprolol + Hydrochlorothiazide
  • Bosentan
  • Brivaracetam
  • Budesonide
  • Bupropion + Hydroxybupropion + Threo-Hydroxy Bupropion + Erythro-Hydroxy Bupropion
  • Butyl Hyoscine (Butylscopolamine)
  • Cabergoline
  • Calanolide A
  • Calcitriol
  • Canagliflozin
  • Candesartan + Amlodipine + Atorvastatin
  • Candesartan + Hydrochlorothiazide
  • Canrenone
  • Capecitabine
  • Captopril
  • Carbamazepine
  • Cariprazine
  • Carisoprodol
  • Carvedilol +4-Hydroxyphenyl Carvedilol
  • Cefixime
  • Cefprozil
  • Ceftriaxone
  • Cefuroxime
  • Celecoxib
  • Cephalexin
  • Cetirizine
  • Chlorpheniramine
  • Chlorpromazine
  • Chlorthalidone
  • Chlorzoxazone
  • Cholecalciferol
  • Cilostazol
  • Cimetidine
  • Cinacalcet
  • Cinnarizine
  • Ciprofibrate
  • Ciprofloxacin
  • Citalopram
  • Citric acid
  • Clarithromycin
  • Clarithromycin + 14-Hydroxy Clarithromycin
  • Clavulanic Acid
  • Clevidipine + Clevidipine metabolite H 152/81
  • Clindamycin
  • Clonazepam
  • Clopidogrel
  • Clopidogrel + Clopidogrel acid
  • Clopidogrel Acid
  • Cloxacillin
  • Clozapine
  • Codeine
  • Colchicine
  • Crisaborole
  • Cyclobenzaprine
  • Cyproterone Acetate
  • Dalfampridine
  • Dapagliflozin
  • Dapagliflozin + Metformin
  • Dapsone
  • Darifenacin
  • Darunavir
  • Deferasirox
  • Descarboethoxyloratadine
  • Desloratadine
  • Desmethyl Sibutramine
  • Deutetrabenazine + Dihydrodeutetrabenazine
  • Dexchlorpheniramine
  • Diazepam
  • Diclofenac
  • Dicycloverine
  • Didanosine
  • Didesmethyl Sibutramine
  • Dihydrocodeine
  • Dihydrodeutetrabenazine
  • Diindolylmethane
  • Diphenhydramine + Ibuprofen
  • Dipyridamole
  • Dofetilide
  • Domperidone
  • Donepezil
  • Doxazosin
  • Doxepin + Nordoxepin
  • Doxycycline
  • Dronedarone + Desbutyl Dronedarone
  • Drospirenone
  • Drotaverine
  • Duloxetine
  • Dutasteride
  • Dutasteride + Tamsulosin
  • Efavirenz
  • Efavirenz + Emtricitabine + Tenofovir
  • Elagolix
  • Eletriptan
  • Eluxadoline
  • Empagliflozin + Linagliptin
  • Emtricitabine
  • Emtricitabine + Efavirenz
  • Emtricitabine + Tenofovir Alafenamide + Dolutegravir
  • Enalapril
  • Enalapril + Enalaprilat
  • Enalaprilat
  • Encapsulated Amphotericin B
  • Encapsulated Doxorubicin
  • Entacapone
  • Entecavir
  • Enzalutamide
  • Erythromycin
  • Erythromycin ethylsuccinate
  • Escitalopram
  • Eslicarbazepine
  • Eslicarbazepine + Eslicarbazepine acetate
  • Esomeprazole
  • Esomeprazole + Naproxen
  • Estradiol
  • Estrone Sulfate + Equilin Sulfate
  • Eszopiclone
  • Ethinylestradiol
  • Ethionamide + Ethionamide Sulfoxide
  • Ethosuximide
  • Etoricoxib
  • Everolimus
  • Exemestane
  • Ezetimibe
  • Ezetimibe + Simvastatin + Simvastatin Acid
  • Famotidine
  • Febuxostat
  • Felodipine
  • Fenofibric Acid
  • Fesoterodine + 5-Hydroxymethyl Tolterodine
  • Fexofenadine
  • Fexofenadine + Pseudoephedrine
  • Finasteride
  • Fingolimod + Fingolimod Phosphate
  • Flecainide
  • Flucloxacillin
  • Fluconazole
  • Fluoxetine
  • Fluoxetine + Norfluoxetine
  • Fluphenazine
  • Fluticasone Propionate
  • Fluticasone Propionate + Salmeterol
  • Fluvoxamine
  • Fosinoprilat
  • Free Amphotericin B
  • Free Dabigatran
  • Free Doxorubicin
  • Free Estradiol + Estrone
  • Free Estrone + Equilin
  • Furosemide
  • Gabapentin
  • Galantamine
  • Gemfibrozil
  • Gestodene
  • Glibenclamide
  • Gliclazide
  • Glimepiride
  • Glyburide
  • Griseofulvin
  • Guaifenesin + Dextromethorphan
  • Guaifenesin + Pseudoephedrine
  • Hydrochlorothiazide
  • Ibuprofen
  • Indomethacin
  • Irbesartan
  • Isoniazid
  • Isosorbide 5-Mononitrate
  • Isosorbide Dinitrate
  • Isoxsuprine
  • Ketoconazole
  • Labetalol
  • Lamivudine
  • Levetiracetam
  • Levonorgestrel
  • Lisinopril
  • Loperamide
  • Loratadine
  • Lorazepam
  • Losartan
  • Losartan Carboxylic Acid
  • Lovastatin
  • Lovastatin Hydroxy Acid
  • Mefenamic Acid
  • Meloxicam
  • Memantine
  • Metformin
  • Methadone
  • Metoclopramide
  • Metoprolol
  • Metronidazole
  • Montelukast
  • Naproxen
  • Nevirapine
  • Nitrendipine
  • Nitrofurantoin
  • Nor Apomorphine
  • Norelgestromin
  • Norethindrone
  • Norfloxacin
  • Olanzapine
  • Olmesartan
  • Olmesartan + Azelnidipine
  • Olmesartan + Hydrochlorothiazide
  • Omeprazole
  • Ondansetron
  • Ornidazole + Ciprofloxacin
  • Orphenadrine
  • Oseltamivir
  • Oseltamivir + Oseltamivir Carboxylate
  • Oseltamivir acid
  • Oxcarbazepine + MHD
  • Oxybutynin + N-Desethyl Oxybutynin
  • Palbociclib
  • Paliperidone
  • Pantoprazole
  • Paracetamol (Acetaminophen)
  • Paroxetine
  • Pazopanib
  • Penbutolol +4-Hydroxy Penbutolol
  • Penciclovir
  • Pentoxifylline
  • Perindopril
  • Perindopril +Perindoprilat
  • Perindoprilat
  • Perphenazine
  • Phenoxybenzamine
  • Phentermine
  • Phenytoin
  • Phloroglucinol
  • Pimavanserin
  • Pioglitazone + Hydroxy Pioglitazone
  • Piracetam
  • Pirfenidone
  • Pitavastatin
  • Pomalidomide
  • Posaconazole
  • Potassium
  • Pramipexole
  • Prasugrel
  • Pravastatin
  • Pregabalin
  • Progesterone
  • Propafenone + 5-OH Propafenone
  • Propranolol
  • Pseudoephedrine
  • Pyrazinamide
  • Quetiapine
  • Quinapril + Quinaprilat + Hydrochlorothiazide
  • Quinine
  • Rabeprazole
  • Raloxifene + Raloxifene-4-Glucuronide + Raloxifene-6-Glucuronide
  • Raltegravir
  • Ramipril
  • Ranitidine
  • Ranolazine
  • Rasagiline
  • Ravidasvir
  • Rebamipide
  • Repaglinide
  • Ribavirin
  • Rifampicin
  • Rifampicin & 25-desacetyl rifampicin
  • Rifaximin
  • Rilpivirine
  • Risedronic
  • Risperidone
  • Ritonavir
  • Rivaroxaban
  • Rivastigmine
  • Rizatriptan
  • Ropinirole
  • Rosuvastatin
  • Rosuvastatin + Total Ezetimibe
  • Rotigotine
  • S (-) Amlodipine
  • Safinamide
  • Salbutamol
  • Saxagliptin + 5- Hydroxy Saxagliptin
  • Selexipag
  • Sertraline
  • Sibutramine
  • Sildenafil
  • Sildenafil + N-Desmethyl Sildenafil
  • Silodosin + Silodosin Beta D Glucuronide
  • Simvastatin
  • Simvastatin + Simvastatin Acid
  • Siponimod
  • Sildenafil
  • Sodium
  • Sofosbuvir
  • Solifenacin
  • Sorafenib
  • Sotalol
  • Spironolactone
  • Stavudine
  • Stavudine + Lamivudine + Nevirapine
  • Sulfamethoxazole
  • Sulfamethoxazole + Trimethoprim
  • Sumatriptan
  • Sunitinib
  • Tacrolimus
  • Tadalafil
  • Tamoxifen
  • Tamsulosin
  • Tapentadol
  • Telmisartan
  • Telmisartan + Hydrochlorothiazide
  • Tenofovir
  • Tenofovir + Alafenamide +Emtricitabine
  • Tenofovir Lamivudine + Efavirenz
  • Terbinafine
  • Terbutaline
  • Teriflunomide
  • Testosterone
  • Tetracycline
  • Tezacaftor
  • Tiaprofenic
  • Ticagrelor
  • Ticlopidine
  • Tiopronin
  • Tiotropium
  • Tizanidine
  • Tizoxanide
  • Tofacitinib
  • Tolterodine + 5-Hydroxymethyl
  • Topiramate
  • Total Apomorphine
  • Total Dabigatran
  • Total Doxorubicin
  • Total Estrone
  • Total Ezetimibe
  • Total Iron (Ferric Carboxymaltose/Ferric Citrate/Ferric Sulfate/Ferumoxytol/Iron Sucrose)
  • Total Norapomorphine
  • Total Propranolol + Total 4-Hydroxy Propanolol
  • Tramadol
  • Tramadol + O-Desmethyl Tramadol
  • Trandolapril + Trandolaprilat
  • Transferrin Bound Iron (Ferric Carboxymaltose/Ferumoxytol/Iron Sucrose)
  • Transferrin Iron (Ferric Citrate/Ferrous Sulfate)
  • trans-Phytonadione + cis-Phytonadione
  • Trazodone
  • Triamcinolone
  • Triazolam
  • Triflusal + Desacetyl Triflusal
  • Trimetazidine
  • Trimethoprim
  • Triprolidine
  • Ursodiol + Tauroursodeoxycholic Acid + Glycoursodeoxycholic Acid
  • Valacyclovir
  • Valganciclovir
  • Valproic acid
  • Valsartan
  • Varenicline
  • Venlafaxine + O-Desmethyl Venlafaxine
  • Vigabatrin
  • Vildagliptin
  • Voriconazole
  • Zidovudine
  • Zidovudine + Lamivudine + Nevirapine
  • Zileuton
  • Ziprasidone
  • Zolmitriptan + N-Desmethyl Zolmitriptan
  • Zolpidem
  • Zopiclone
  • 9 Hydroxy Risperidone
  • (R)-Ibuprofen +(S)-Ibuprofen
  • 2-Pyridyl Acetic Acid
  • 21-desDFZ (21-desacetylDeflazacort)
  • 3-Keto-Desogestrel
References:

Asean guideline for the conduct of bioequivalence studies. (2015). Asean.Org. https://asean.org/wp-content/uploads/2012/10/BE_Guideline_FinalMarch2015_endorsed_22PPWG.pdf

Center for Drug Evaluation and Research. (2014). Guidance for Industry: Bioavailability and Bioequivalence Studies Submitted in NDAs or INDs — General Considerations. U.S. Food and Drug Administration.  https://www.fda.gov/files/drugs/published/Bioavailability-and-Bioequivalence-Studies-Submitted-in-NDAs-or-INDs-—-General-Considerations.pdf

Center for Drug Evaluation and Research. (2022). Preface to the Orange Book. U.S. Food and Drug Administration. https://www.fda.gov/drugs/development-approval-process-drugs/orange-book-preface

Chow S. C. (2014). Bioavailability and Bioequivalence in Drug Development. Wiley interdisciplinary reviews. Computational statistics, 6(4), 304–312. https://doi.org/10.1002/wics.1310

Mishra, V., Gupta, U., & Jain, N. K. (2010). Biowaiver: an alternative to in vivo pharmacokinetic bioequivalence studies. Die Pharmazie-An International Journal of Pharmaceutical Sciences, 65(3), 155-161.

Nagadurga, D. H.  (2019). Bioavailability and Bioequivalence Studies. In U. Ahmad, & J. Akhtar (Eds.), Pharmaceutical Formulation Design – Recent Practices. IntechOpen. https://doi.org/10.5772/intechopen.85145

Norms, & Standards for Pharmaceuticals. (2021). TRS 1033 – 55th report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations. Who. Int; World Health Organization. https://www.who.int/publications/i/item/55th-report-of-the-who-expert-committee-on-specifications-for-pharmaceutical-preparations

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