Article

Biowaiver monographs for immediate release solid oral dosage forms: Acetaminophen (Paracetamol) - Commentary

Leiden University, Leyden, South Holland, Netherlands
Journal of Pharmaceutical Sciences (Impact Factor: 3.01). 01/2006; 95(1):4-14. DOI: 10.1002/jps.20477
Source: PubMed

ABSTRACT Literature data are reviewed on the properties of acetaminophen (paracetamol) related to the biopharmaceutics classification system (BCS). According to the current BCS criteria, acetaminophen is BCS Class III compound. Differences in composition seldom, if ever, have an effect on the extent of absorption. However, some studies show differences in rate of absorption between brands and formulations. In particular, sodium bicarbonate, present in some drug products, was reported to give an increase in the rate of absorption, probably caused by an effect on gastric emptying. In view of Marketing Authorizations (MAs) given in a number of countries to acetaminophen drug products with rapid onset of action, it is concluded that differences in rate of absorption were considered therapeutically not relevant by the Health Authorities. Moreover, in view of its therapeutic use, its wide therapeutic index and its uncomplicated pharmacokinetic properties, in vitro dissolution data collected according to the relevant Guidances can be safely used for declaring bioequivalence (BE) of two acetaminophen formulations. Therefore, accepting a biowaiver for immediate release (IR) acetaminophen solid oral drug products is considered scientifically justified, if the test product contains only those excipients reported in this paper in their usual amounts and the test product is rapidly dissolving, as well as the test product fulfils the criterion of similarity of dissolution profiles to the reference product.

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Useimmiten eroja esiintyi aihepiireissä liittyen kirjallisuudessa kuvattuihin BE:n määrityksen yleisiin kiistanalaisuuksiin ja ongelmakohtiin, joista osan on havaittu vaikeuttavan BE:n määritystä lääkevalmisteiden välillä (mm. moniannostutkimukset, BE-tutkimukset ruuan kanssa, lääkeaineen vs. metaboliitin määritys, kapean terapeuttisen leveyden lääkeaineet, runsaasti varioivat lääkeaineet). Tulevaisuudessa olisi hyvä saada ko. ongelmakohdat ratkaistuksi viranomaisten BE-ohjeistojen harmonisoimiseksi. Harmonisointi selkeyttäisi lääkemarkkinoita, vähentäisi viranomaisten ja lääkeyritysten työtaakkaa ja turhia in vivo BE-tutkimuksia (tehdään yleensä terveillä vapaaehtoisilla koehenkilöillä). Turhia in vivo tutkimuksia halutaan vähentää, koska koehenkilöitä ei haluta altistaa lääkkeille turhaan. Lisäksi ne ovat kalliita ja aikaavieviä. Erikoistyössä tutkittiin, miten fysiologiaan perustuvasta imeytymis- ja kulkeutumismallista (CAT, compartmental absorption and transit model) muokattua famakokineettistä simulaatiomallia voitaisiin hyödyntää lääkevalmisteiden in vivo BE-tutkimuksiin liittyvän riskin arvioinnissa. Työssä tarkasteltiin, millaisille lääkeaineille malli ennustaa BE-tutkimuksen tulosta hyvin ja millaisille heikommin/huonosti. Samalla arvioitiin malliin sisältyviä virhelähteitä. Mallissa huomioitiin mahasuolikanavan fysiologisia tekijöitä, lääkeaineen fysikaaliskemiallisia ja farmakokineettisia ominaisuuksia, sekä lääkevalmistekohtaisia tekijöitä, eli liukenemisen nopeusvakio (Kd) ja valmistetyypistä riippuva mahan tyhjeneminen. Farmakokineettiseen tilamalliin yhdistettynä simulaatioista saatiin valmistekohtaiset lääkeaineen pitoisuuskuvaajat, joista arvioitiin valmisteille biologista hyötyosuutta kuvaavien parametrien suhde ja edelleen niiden biologisen samanarvoisuuden toteutumista. Arvioinnit pohjautuivat viranomaisohjeistoissa esitettyihin kriteereihin. Havaittiin, että, jotta simulaatiotulokset olisivat luotettavia, formulaatioiden eroa kuvaavien Kd-arvojen on oltava päteviä. Lisäksi formulaatioista on oltava riittävästi tietoa (valmistetyyppi, hajoamistapa ja formulaation apuaineet). Ihannetapauksessa valmisteissa on samankaltainen koostumus hyvin tunnettuja apuaineita. Kun mainitut tekijät täyttyvät, malli ennustaa BE-riskiä luotettavimmin biofarmaseuttisen luokittelujärjestelmän (BCS) I, ja III lääkeaineille, sekä luokan II lääkeaineille, kun saturaatioliukoisuus fysiologisella pH välillä ei rajoita imeytymistä. Muussa tapauksessa tulosten tarkastelussa on kriittisesti arvioitava, onko tekijöillä vaikutusta riskiarvion luotettavuuteen. Simulaatiomallinnuksen heikkoutena ovat oletukset, siksi tulosten tarkastelussa on arvioitava tapauskohtaisesti myös niiden vaikutus mallin erotuskykyyn. Simulaatiomalli on käyttökelpoinen lääkkeiden tutkimus- ja tuotekehitystyössä. Methods for the assessment of the bioequivalence (BE) of drug products are generally well-documented and the approaches for such studies are described in guidances issued by regulatory authorities throughout the world. While in general, the BE requirements of most regulatory bodies have much in common, in various instances specific issues and approaches may differ. In the literature part of the master's thesis these differences in the selected regulatory BE guidelines (Europe, United States and World Health Organization) was examined and also the scientific reasons behind these differences were considered. It was found that the prime differences were in the BE related issues in which the scientific community are not in agreement (multiple dosing, highly variable drugs, moieties to be measured (parent/metabolite), food effect studies etc.). The differences were also related to drug products that have biopharmaceutical, bioavailability (BA), pharmacokinetic, and pharmacodynamic properties that preclude the use of standard approaches that are outlined in regulatory guidelines. In the future the push for international harmonization of regulatory standards is hopefully leading to worldwide discussions and changes regarding BE and other components of the drug approval process (both new and generic drugs). Expensive in vivo BE studies are usually needed for generic drug products or if a formulation is significantly altered during clinical trials. In this master´s thesis a pharmacokinetic model (based on a compartmental absorption and transit model, CAT) was constructed and tested to predict relative BA, to assess the risk of bioinequivalency and to probe properties of drugs suitable for the use of the model. Also the errors and uncertainties related to the model were discussed. GI tract physiology, formulation type and drug solubility, dissolution, absorption and elimination rates were taken into account in this pharmacokinetic simulation model. In the model formulation differences were described by dissolution rate constant (Kd) (calculated from experimental dissolution data) and gastric emptying rate (GE) (varies for different formulations). Hence, when integrated with a pharmacokinetic compartment model it was possible to get predictions of concentration-time profiles of different formulations. Generalised rules in BE assessment were used to estimate the risk of bioinequivalency. The resolution power of the model and the errors related to the model was evaluated by theoretical pharmacokinetic simulations. Generally, the simulations suggested that the model predicts the risk in the BE study most accurately when the drug belongs to the class I/III in the biopharmaceutical classification system (BCS) or to the class II when saturation solubility is not the limiting step in the absorption. Used Kd value is valid if dissolution data is accurate (method discriminative). Also, there has to be enough information about the formulation (type, disintegration, excipients). Otherwise it has to be considered if these factors effect on the resolution power. The weaknesses of the simulation models are assumptions. Hence, when exploring the results it has to be estimated case by case, if they affect on model´s ability to separate formulations (reliability of the risk assessment and the ability to predict relative BA). This model is useful tool in formulation development and regulatory applications.