Single-dose bioavailability studies

JM Neal, WN Howald, KL Kunze, RF Lawrence, WF Trager. Application of negative-ion chemical ionization isotope dilution gas chromatography-mass spectrometry to single dose bioavailability studies of mefloquine. J Chromatogr B Biomed Appl 661 263-269,1994. 

Pharmacokinetic studies demonstrated good oral bioavailability of maraviroc and a terminal half-life of 16-23 h following multiple dosing (Abel et al. 2003 Walker et al. 2005). Single doses of up to 900 mg and multiple doses of up to 300 mg BID for 28 days were well tolerated (Abel et al. 2003 Russell et al. 2003 Walker et al. 2005). In Phase 2a studies, treatment-naive HIV-1 patients with R5 virus who received maraviroc monotherapy at doses ranging from 25 mg QD to 300 mg BID for 10 days experienced a median viral load reduction of 1.64 log jg copies/mL and... 

Under linear concentration conditions (for a P-C concentration range of 0.12-6pM) at 16h incubation and under cell culture conditions mimicking the in vivo postprandial state, the extent of absorption of all-trans P-C through Caco-2 cell monolayers was 11% a value similar to that reported from different human studies. In humans, the bioavailability of a single dose of P-C... 

PYA copolymer Bioavailability enhancer Single-dose toxicity (in rat and dog) and maximum tolerated dose/short-term (2wks—oral) (in rat and dog) toxicity as well as 2 in vitro and 1 in vivo genotoxicity studies. ADME studies with 14C-labelled material are underway and a 3-6 mo toxicity study in the rat is planned No adverse effects seen to date 41... 

There is an extensive amount of literature on the in vitro activities of resveratrol. Bertelli et al. [1996] were the first to study the bioavailability of resveratrol in rats. They assessed analysis of plasma and tissues from rats that were administered red wine in a single dose or a regular dose for 15 day. Results indicated that resveratrol is quickly absorbed with a maximum peak at 1 h in plasma as well as in liver and kidney, although in the heart it peak at 2 h. Values obtained after regular consumption of red wine were higher than without the regular consumption in the different organs studies, in particular in the liver. The kidney seemed to be the main route of excretion (Table 13.2) [Bertelli et al., 1996]. 

It is reasonable to question whether the distribution of the estimates of a drug concentration in a blood specimen might be approximated by the normal distribution. Table 1 presents the results of repeated analyses of a specimen of interference-free plasma spiked to contain a known amount of drug. These data are taken from a comparative bioavailability study in which single doses of an unmarketed generic product and the marketed brand product of a drug were administered on separate occasions to healthy males. The values presented are the first of duplicate determinations of a quality control (QC) specimen that was included with each batch of subject specimens. This was done to verify that the in-process accuracy and precision of the assay method were consistent with the values observed during the assay validation. 

In bioavailability studies, the shape of and the area under the plasma concentration versus time curves are mostly used to assess rate t and extent (AUC) of absorption. Sampling points or periods should be chosen such that the concentration versus time profile is adequately defined to allow calculation of relevant parameters. For single-dose studies, the following parameters should be measured or calculated ... 

If pharmacokinetics are dependent on dose or time, or a slow-release formulation is being studied, it is necessary to examine bioequivalence at steady state. For controlled-release formulations which are intended to produce relatively flat concentration-time profiles, an index of fluctuation is required, for example - Cn,jj])/C. A study at steady state may also be needed if the assay is not sensitive enough to quantify plasma concentrations of drug up to four half-lives after a single dose. Sometimes it is not technically feasible to assay a drug in plasma and it may then the justifiable to compare bioavailability by the total amount of drug excreted in urine, or pharmacodynamic data may be used, but these cases are exceptions. 

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