Browsing by Subject "viranomaisohjeistot"

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.