Pharmacokinetic data, collection

Often in pharmacokinetics the analyst has data on more than one individual. In a typical Phase 1 clinical trial, there might 12-18 subjects who have pharmacokinetic data collected. Applying a compartmental model to each individual s data generates a vector of parameter estimates, each row of which represents a realization from some probability distribution. For example,... 

Perhaps the area where PopPK has made the largest impact is in drug development. Prior to the introduction of NONMEM as a commercial software package, there was little one could do with pharmacokinetic data collected from Phase 3 clinical studies beyond, perhaps, summary statistics and correlations between some summary measure of the pharmacokinetic data, like the mean or median concentration in a subject, and subject... 

Karlsson and Sheiner (1993) presented an easy method to estimate IOV. In order to estimate IOV serial pharmacokinetic data must be collected on each subject on each occasion. If only a single sample is available on each occasion an estimate of IOV cannot be calculated. Begin by assuming that each subject has pharmacokinetic data collected on O occasions, j = 1, 2,. .. O, and that the model parameter for the ith subject (0 ) is written as... 

In a study designed to gather pharmacokinetic data, two healthy human volunteers were exposed to HFC-134a at 4,000 ppm delivered via a mouthpiece (Vinegar et al. 1997). The exposures were scheduled to last for 30 min. Blood samples were collected throughout the exposures. The exposures were abruptly terminated following an unexpected and uncontrollable rise in pulse rate in one subject and a drop in pulse rate and blood pressure and loss of consciousness in the second. This vasovagal response is sometimes observed... 

Vinegar, A., G.W.Jepson, R.S.Cook, J.D.McCafferty, III, and M.C.Caracco. Human inhalation of Halon 1301, HFC-134a and HFC-227ea for collection of pharmacokinetic data. AL/OE-TR-1997-0116, Occupational and Environmental... 

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. ... 

Hits on individual assays can be analyzed in a couple of different ways. First, drugs can be identified that have similar strength hits and then the ADR profiles of these drugs can be examined to identify ADRs that maybe associated with these hits. Also, contained in BioPrint are extensive collections of ADR associations [2], which have been identified by querying the database for statistically significant correlations between individual assays and individual ADRs. These ADRs are stored in the database and can be accessed by searching assay or the ADR. It is also useful to consult the pharmacokinetic data to confirm that the strength of the in vitro hit is consistent with in vivo exposure levels. 

Gilman JT, Gal P. Pharmacokinetic and pharmacodynamic data collection in children and neonates. Chn Pharmacokinet 1992 23(l) l-9. 

Pharmacokinetic data were collected as well as pharmacodynamic measurements of platelet aggregation support (ristocetin cofactor activity) and cuticle wound blood flow. An important component of these studies was the suitability of the model. These models were chosen because of the biochemical deficiency of the particular factors and the parallel clinical syndromes. Such in vivo data can help in determining activity and dosing when such a product is first used in human trials. The Refacto molecule was also studied in rats and monkeys to determine its no observed adverse effect level, that was more than 10 times normal circulating levels. The major toxicity observed was the development of antibodies to the molecule that blocked activity and resulted in an acquired hemophilia syndrome. Similar findings were demonstrated when plasma-derived material was injected into monkeys [20]. 

Rats weighing 180-240 g are kept on standard diet. Groups of 8 non-fasted animals are treated orally with various doses of the test compounds suspended in 0.4% starch suspension. One control group receives the vehicle only. Blood is withdrawn from the tip of the tail immediately before, and 1,2,3,5, and 24 hours after administration of the candidate compound. Blood glucose is determined in 10 pi blood samples collected from the tip of the tail. If pharmacokinetic data for the candidate compound are already available, when performing this test, additional blood samples (100 pi) should be taken at max by retro orbital bleeding for detection of free fatty acids, triglycerides and insulin. 

For the purposes of simplicity, the description of each study is limited to the collection, handling, and interpretation of pharmacokinetic data although clearly safety (and pharmacodynamic) parameters are also studied. 

While formulation interactions often are subject to in vitro investigations, the section below presents a particular example of an in vivo formulation interaction study (CPMP/EWP/QWP/1401/98 2002) a potential interaction of a drug in medical practice frequently given concomitantly with another drug (i.e. both mixed in a syringe) was subject to a clinical study which is illustrated below. For the purposes of simplicity, the description is limited to the collection, handling, and interpretation of pharmacokinetic data although clearly safety and pharmacodynamic parameters were also studied. 

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