Pharmacokinetic studies documentation

During the 1990 Washington Conference on Analytical Methods Validation Bioavailability, Bioequivalence and Pharmacokinetic Studies [1], parameters that should be used for method validation were defined. The final report of this conference is considered the most comprehensive document on the validation of bioanalytical methods. Many multinational pharmaceutical companies and contract research organizations contributed to its final draft. This scientific meeting was sponsored by the American Association of Pharmaceutical Scientists (AAPS), the Association of Official Analytical Chemists (AOAC), and the U.S. Food and Drug Administration (FDA). The conference report has been used as a reference by bioanalytical laboratories and regulatory agencies worldwide. 

Human pharmacokinetic studies indicate that methylmercury has a half-life in blood and the whole body of about 50 days (CDC 2005). Hair grows at about 1 cm/month with a delay of around 20 days between current blood concentration and appearance of mercury in hair (Myers et al. 2003). Thus, postnatal maternal hair can be analyzed sequentially to evaluate timing of methylmercury exposure during pregnancy. However, the potential that this affords to document critical periods of prenatal methylmercury exposure has yet to be realized. 

Pharmacokinetic studies must be provided that document the fate of the drug, including absorption, distribution, metabolism, and excretion. In addition, the company must supply information on chemistry, manufacturing, and quality control... 

Acceptance of any test procedure in the documentation of equivalence between two pharmaceutical products by a drug regulatory authority depends on many factors, including the characteristics of the API and the pharmaceutical product. Where an API produces measurable concentrations in an accessible biological fluid such as plasma, comparative pharmacokinetic studies can be performed. Where appropriate, in vitro testing and BCS-based biowaivers for immediate-release pharmaceutical products can assure... 

Metabolism of THC to 11-OH-THC, THCCOOH, and other analytes also contributes to the reduction of THC in the blood. Perez-Reyes et al. compared the pharmacokinetics and pharmacodynamics of tritiated THC and 11-OH-THC in 20 male volunteers (Perez-Reyes et al. 1972). Although equal doses produced equal psychoactive effects, drug effects were perceived more rapidly after 11-OH-THC than after THC. In addition, 11-OH-THC left the intravascular compartment faster than THC. These data suggest that 11-OH-THC diffuses into the brain more readily than THC. Another possible explanation is lower protein binding of 11-OH-THC, as compared to THC, in the blood. Further support for the faster penetration of brain by 11-OH-THC is found in studies documenting a more rapid diffusion of 11-OH-THC than THC into the brains of mice (Perez-Reyes et al. 1972). 

Interferon-o, a 165 amino acid glycoprotein, is effective in the treatment of viral hepatitis C and B, myeloma, melanoma, and renal carcinoma. Little is known about the renal metabolism of interferon-a despite extensive studies in experimental animals. In patients with normal renal function, the serum peak level occurs 8 hours after a subcutaneous injection of 3x10 units of interferon-a. Terminal elimination half-life ranges from 4 to 16 hours and after 24 to 48 hours, the interferon molecule is undetectable in the serum [181]. A-interferon urinary level is undetectable. Some authors have suggested that, despite the lack of urinary excretion, the kidney could play a role in interferon-a metabolism [182]. Indeed, as far as hepatitis C treatment is concerned, dialysis patients often show a better response to therapy than non-dialysis patients. This better efficacy in dialysis patients is associated with an increase of the incidence of adverse effects. This observation raises the question of pharmacokinetic modifications. One study documented that clearance kinetics of interferon-a in patients with chronic renal failure are about half the rate of patients with normal renal function [183]. Indeed interferon is filtered by the glomeruli and largely absorbed and catabolized within tubular cells [184]. 

Data adequacy The key study was well designed and conducted and documented a lack of effects on heart and lung parameters as well as clinical chemistry. Pharmacokinetic data were also collected. The compound was without adverse effects when tested as a component of metered-dose inhalers on patients with COPD. Animal studies covered acute, subchronic, and chronic exposure durations and addressed systemic toxicity as well as neurotoxicity, reproductive and developmental effects, cardiac sensitization, genotoxicity, and carcinogenicity. The values are supported by a study with rats in which no effects were observed during a 4-h exposure to 81,000 ppm. Adjustment of the 81,000 ppm concentration by an interspecies and intraspecies uncertainty factors of 3 each, for a total of 10, results in essentially the same value (8,100 ppm) as that from the human study. ... 

In summary, (oxodioxolyl)methyl esters of carboxylic acid drugs appear to be generally useful as prodrugs. However, more studies are needed to document the structure-metabolism relationships, the relative contribution of enzymatic vs. nonenzymatic reactions in their in vivo activation, the reasons of some failures, their toxic potential, and their pharmacokinetic behavior in humans. 

With respect to pharmaceuticals, the mouse is cited as an alternative species in the ICH S5(R2) guideline for the detection of toxicity to reproduction for medicinal products and toxicity to male fertility (2). Since the ICH guideline is also cited in other guidance documents (3, 4), it is clear that the mouse should be considered for teratology type (see Note 1) studies. In addition, although not specifically mentioned in other guidelines (OECD, FDA, EPA, etc.), the mouse may be an appropriate rodent model for products from the food and chemical industries if the choice is justified based on the available pharmacokinetic or metabolic information etc. (5-8). 

Phase III studies represent the confirmatory phase of drug development, which takes several years and usually involves several thousand patients at multiple trial centers. Large patient numbers are required in these trials to provide convincing documentation of clinical efficacy and safety, a more complete adverse event profile and covariates and estimates of variability in dose response relationship due to individual differences in pharmacokinetics and pharmacodynamics. They are aimed at definitively determining a drug s effectiveness and side-effect profile. Most of these studies are double-blind and placebo-controlled, sometimes with the option of open-label long-term extensions. 

Botanical medications ("herbals") may interact with each other or with conventional drugs. Unfortunately, botanicals are much less well studied than other drugs, so information about their interactions is scanty. Pharmacodynamic interactions are described in Chapter 64. Pharmacokinetic interactions that have been documented (eg, St. John s wort) are listed in Table 66-1. 

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