Dosage form blood level studies

Those aspects critical to the in vivo bioavailability of the product and routine control tests proposed to ensure that the product has consistent bioavailability from batch to batch. Where a product has low in vivo absorption, the evidence should be discussed and a conclusion reached as to whether this is due to intrinsic properties of the active ingredient(s) or whether it is related to the properties of the dosage form concerned. In the case of products intended to have a nonsystemic effect, the potential for systemic absorption may need to be considered. This may involve specific studies to determine the levels of the active ingredient(s) in the blood, plasma, urine, or feces and a discussion of the clinical significance of those results. 

While in vivo studies assess absorption rates as process-lumped time constants from blood level versus time data, these rate parameters encompass the kinetics of dosage-form release, GI transit, metabolism, and membrane permeation. The use of isolated tissue and cellular preparations to screen for drug absorption potential and to evaluate absorption rate limits at the tissue and cellular levels has been expanded by the pharmaceutical industry over the past several years. For more detail in this regard, the reader is referred to an article by Stewart et al. [68] for references on these preparations and for additional details on the various experimental techniques outlined below. 

Exposure to this compound therapeutically is by the oral route. Since variation in the AUG for oral busulfan results in substantial risk of over- or undertreatment with risk of toxicity or relapse, the use of an intravenous (IV) formulation has been studied. IV formulation reduces this variability by eliminating variability in absorption. Busulfan is a small, highly lipophilic molecule that easily passes the blood-brain barrier. The typical dosage level (tablet form) is 4-8 mg daily. The recommended intravenous dose given prior to bone marrow transplant is 0.8mgkg body weight given as a 2 h infusion every 6 h for 4 days. 

Further studies have shown that decreased intracellular K" concentration was required before ouabain induced arrhythmias in dogs. Increased Na was not necessary. Local anesthetic agents such as quinidine, butidrine and procaine amide reduced K loss through a membrane stabilization effect of red blood cells and not by a direct interaction with ATPase ". Andersen demonstrated that lidocalne was able to alter membrane permeability to Na and at therapeutic dosage. Toxic dosage levels caused a major disruption of membrane integrity which resulted in diffusion of Na and K . The cationic form appeared to be the active species of the drug in human red blood cells. 

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