Bioavailability pharmacokinetic modeling

Wright, J. D., Ma, T., Chu, C. K., Boudinot, F. D., Discontinuous oral absorption pharmacokinetic model and bioavailability of l-(2-fluoro-5-methyl-beta-L-arabinofuranosyl)uradl (L-FMAU) in rats, Biopharm. Drug Dispos. 1996, 17, 197-207. 

Of the various methods that may be used to determine bioavailability for ASOs, the best refer to tissue levels as the most relevant metric for calculating an estimate of absolute bioavailability. As mentioned in Chapter 4, ASOs distribute rapidly to the tissues, with an extremely slow transfer rate back into the central circulation. In addition, the elimination of ASOs occurs predominantly by nucleases in the tissue compartment. Thus, bioavailability based on plasma concentrations does not provide an accurate estimate of absolute bioavailability for ASOs if plasma concentrations cannot be quantified at extremely low concentrations for a prolonged period of time to adequately assess systemic exposure. The direct use of tissue levels in combination with physiologic pharmacokinetic modeling, however, may allow the accurate determination of bioavailability for ASOs. 

The three major parameters examined in urinary excretion bioavailability studies are the cumulative amount of drug excreted unmetabolized in the urine ( Xu)-, the maximum urinary excretion rate (ERmax) and the time of maximum excretion rate (Tmax)- In simple pharmacokinetic models, the rate of appearance of drug in the urine is proportional to the concentration of drug in the systemic circulation. Thus, the values for Tmax and ERmax for urine studies are analogous to the Tmax and Cmax values derived from blood level studies. The value of r ax decreases as the absorption rate of the drug increases, and increases as the... 

Integration of in vitro results and pharmacokinetic modeling is also used to assess the bioavailability of nutrients [85] using TNO s gastrointestinal model TIM [www. tno.nl/pharma]. 

Cai, H., Stoner, C., Reddy, A., Freiwald, S., Smith, D., Winters, R., Stankovic, C. and Surendran, N. (2006) Evaluation of an integrated in vitro - in silico PBPK (physiologically-based pharmacokinetic) model to provide estimates of human bioavailability. International Journal of Pharmaceutics, 308, 133-139. 

Kerbusch, T., Wahlby, U., Milligan, P.A., and Karlsson, M.O. Population pharmacokinetic modelling of darifenacin and its hydroxylated metabolite using pooled data, incorporating saturable first-pass metabolism, CYP2D6 genotype and formulation-dependent bioavailability. British Journal of Clinical Pharmacology 2003 56 639-652. 

As the clearance of rhG-CSF is known to decrease with a rise in dose and is known to be saturable, the average clearance after i.v. administration will be lower than that after s.c. administration. Therefore, the apparent absolute bioavailability with subcutaneous administration calculated from the AUC ratio is expected to be a conservative estimate. In a second study by Flayashi et al., the estimation of rhG-CSF absorption kinetics after s.c. administration with a nonlinear elimination pharmacokinetic model using a modified Wagner-Nelson method was studied... 

Both of these approaches allow for assessment of systemic absorption by not conducting complete mass balance studies (e.g., expired air to catch absorbed compound metabolized to COj or HjO expired end products). In vivo dermal absorption studies not taking into account other routes of excretion must be interpreted with caution. One extension of this mass balance excretory analysis is to assess dermal absorption by only monitoring the primary excretory route for the compound studied. Dermal bioavailability has been assessed in exhaled breath using real-time ion trap mass spectrometry to track the uptake and ehmination of compounds (e.g., trichloroethylene) from dermal exposure in humans and rats (Poet et al., 2000). A physiologically based pharmacokinetic model can be used to estimate the total bioavailability of compoimds. The same approach was extended to determine the dermal uptake of volatile chemicals imder non-steady-state conditions using real-time breath analysis in rats, monkeys, and humans (Thrall et al., 2000). 

Etoposide causes multiple DNA double-strand breaks by inhibiting topoisomerase II. The pharmacokinetics of etoposide are described by a two-compartment model, with an a half-life of 0.5 to 1 hour and a (5 half-life of 3.4 to 8.3 hours. Approximately 30% of the dose is excreted unchanged by the kidney.16 Etoposide has shown activity in the treatment of several types of lymphoma, testicular and lung cancer, retinoblastoma, and carcinoma of unknown primary. The intravenous preparation has limited stability, so final concentrations should be 0.4 mg/mL. Intravenous administration needs to be slow to prevent hypotension. Oral bioavailability is approximately 50%, so oral dosages are approximate two times those of intravenous doses however, relatively low oral daily dosages are used for 1 to 2 weeks. Side effects include mucositis, myelosuppression, alopecia, phlebitis, hypersensitivity reactions, and secondary leukemias. 

All piroxicam batches were manufactured in compliance with Good Manufacturing Practices, and three formulations having fast, moderate, and slow dissolution were chosen for comparison to a lot of the innovator s product in a human bioavailability study [100]. The resulting pharmacokinetic data provided still another opportunity to examine the effects of formulation variables. To explore the relationship between the in vitro dissolution of piroxicam from these capsules and in vivo absorption, Polli [ 102] used the following previously described [145] deconvolution-based model ... 

The original proposal of the approach, supported by a Monte Carlo simulation study [36], has been further validated with both pre-clinical [38, 39] and clinical studies [40]. It has been shown to be robust and accurate, and is not highly dependent on the models used to fit the data. The method can give poor estimates of absorption or bioavailability in two sets of circumstances (i) when the compound shows nonlinear pharmacokinetics, which may happen when the plasma protein binding is nonlinear, or when the compound has cardiovascular activity that changes blood flow in a concentration-dependent manner or (ii) when the rate of absorption is slow, and hence flip-flop kinetics are observed, i.e., when the apparent terminal half-life is governed by the rate of drug input. 

In addition to the mechanistic simulation of absorptive and secretive saturable carrier-mediated transport, we have developed a model of saturable metabolism for the gut and liver that simulates nonlinear responses in drug bioavailability and pharmacokinetics [19]. Hepatic extraction is modeled using a modified venous equilibrium model that is applicable under transient and nonlinear conditions. For drugs undergoing gut metabolism by the same enzymes responsible for liver metabolism (e.g., CYPs 3A4 and 2D6), gut metabolism kinetic parameters are scaled from liver metabolism parameters by scaling Vmax by the ratios of the amounts of metabolizing enzymes in each of the intestinal enterocyte compart-... 

Obach et al. [27] proposed a model to predict human bioavailability from a retrospective study of in vitro metabolism and in vivo animal pharmacokinetic (PK) data. While their model yielded acceptable predictions (within a factor of 2) for an expansive group of compounds, it relied extensively on in vivo animal PK data for interspecies scaling in order to estimate human PK parameters. Animal data are more time-consuming and costly to obtain than are permeability and metabolic clearance data hence, this approach may be limited to the later stages of discovery support when the numbers of compounds being evaluated are fewer. 

Since the identification of hydroxamic acids as potent bidentate ZBGs, an enormous range of hydroxamic acid inhibitors based on this model has been developed and is described in numerous reviews and therefore will not be dealt with in depth here [17]. Instead, the focus of this report will be on efforts to improve on these "1st generation" inhibitors, specifically to improve biological and physicochemical characteristics, such as pharmacokinetics and bioavailability and to achieve isoform selectivity. 

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