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Human Pharmacokinetics (human + pharmacokinetic)
Selected AbstractsAccelerating drug development: methodology to support first-in-man pharmacokinetic studies by the use of drug candidate microdosingDRUG DEVELOPMENT RESEARCH, Issue 1 2007Matthew A. McLean Abstract Microdosing of experimental therapeutics in humans offers a number of benefits to the drug development process. Microdosing, conducted under an exploratory Investigational New Drug (IND) application, entails administration of a sub-pharmacological dose of a new chemical entity (NCE) that allows for early evaluation of human pharmacokinetics. Such information can be pivotal for: (1) selecting a compound for full drug development from a small group of candidates; (2) defining the amount of material needed for early development; and (3) setting the initial Phase I dose regimen in humans. Appropriate safety studies must be conducted to support microdosing in humans, but the requirements are generally less extensive than those needed to support a traditional IND. To date, microdosing has not been broadly applied by the pharmaceutical industry due to concerns about analytical sensitivity and the possibility of non-linear pharmacokinetics at extremely low doses. The primary method for detecting analytes following microdosing until now has been accelerator mass spectrometry, which is expensive, not generally available, and requires test agents to be radiolabeled. Presented in this report is an example of pharmacokinetics analysis using LC/MS/MS following microdosing of an experimental agent in cynomolgus monkeys. The results show good linearity in plasma pharmacokinetics for oral doses of 10,mg/kg (therapeutic dose) and 0.0005,mg/kg (microdose) of the test agent. The results also demonstrate the feasibility of applying standard laboratory analytics to support microdosing in humans and raise the possibility of establishing an animal model to screen for compounds having non-linear pharmacokinetics at low dose levels. Drug Dev. Res. 68:14,22, 2007. © 2007 Wiley-Liss, Inc. [source] Physiologically based predictions of the impact of inhibition of intestinal and hepatic metabolism on human pharmacokinetics of CYP3A substratesJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 1 2010Frederique Fenneteau Abstract The first objective of the present study was to predict the pharmacokinetics of selected CYP3A substrates administered at a single oral dose to human. The second objective was to predict pharmacokinetics of the selected drugs in presence of inhibitors of the intestinal and/or hepatic CYP3A activity. We developed a whole-body physiologically based pharmacokinetics (WB-PBPK) model accounting for presystemic elimination of midazolam (MDZ), alprazolam (APZ), triazolam (TRZ), and simvastatin (SMV). The model also accounted for concomitant administration of the above-mentioned drugs with CYP3A inhibitors, namely ketoconazole (KTZ), itraconazole (ITZ), diltiazem (DTZ), saquinavir (SQV), and a furanocoumarin contained in grape-fruit juice (GFJ), namely 6,,7,-dihydroxybergamottin (DHB). Model predictions were compared to published clinical data. An uncertainty analysis was performed to account for the variability and uncertainty of model parameters when predicting the model outcomes. We also briefly report on the results of our efforts to develop a global sensitivity analysis and its application to the current WB-PBPK model. Considering the current criterion for a successful prediction, judged satisfied once the clinical data are captured within the 5th and 95th percentiles of the predicted concentration,time profiles, a successful prediction has been obtained for a single oral administration of MDZ and SMV. For APZ and TRZ, however, a slight deviation toward the 95th percentile was observed especially for Cmax but, overall, the in vivo profiles were well captured by the PBPK model. Moreover, the impact of DHB-mediated inhibition on the extent of intestinal pre-systemic elimination of MDZ and SMV has been accurately predicted by the proposed PBPK model. For concomitant administrations of MDZ and ITZ, APZ and KTZ, as well as SMV and DTZ, the in vivo concentration,time profiles were accurately captured by the model. A slight deviation was observed for SMV when coadministered with ITZ, whereas more important deviations have been obtained between the model predictions and in vivo concentration,time profiles of MDZ coadministered with SQV. The same observation was made for TRZ when administered with KTZ. Most of the pharmacokinetic parameters predicted by the PBPK model were successfully predicted within a two-fold error range either in the absence or presence of metabolism-based inhibition. Overall, the present study demonstrated the ability of the PBPK model to predict DDI of CYP3A substrates with promising accuracy. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:486,514, 2010 [source] Prediction of human pharmacokinetics , renal metabolic and excretion clearanceJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 11 2007Urban Fagerholm The kidneys have the capability to both excrete and metabolise drugs. An understanding of mechanisms that determine these processes is required for the prediction of pharmacokinetics, exposures, doses and interactions of candidate drugs. This is particularly important for compounds predicted to have low or negligible non-renal clearance (CL). Clinically significant interactions in drug transport occur mostly in the kidneys. The main objective was to evaluate methods for prediction of excretion and metabolic renal CL (CLR) in humans. CLR is difficult to predict because of the involvement of bi-directional passive and active tubular transport, differences in uptake capacity, pH and residence time on luminal and blood sides of tubular cells, and limited knowledge about regional tubular residence time, permeability (Pe) and metabolic capacity. Allometry provides poor predictions of excretion CLR because of species differences in unbound fraction, urine pH and active transport. The correlation between fraction excreted unchanged in urine (fe) in humans and animals is also poor, except for compounds with high passive Pe (extensive/complete tubular reabsorption; zero/negligible fe) and/or high non-renal CL. Physiologically based in-vitro/in-vivo methods could potentially be useful for predicting CLR. Filtration could easily be predicted. Prediction of tubular secretion CL requires an in-vitro transport model and establishment of an in-vitro/in-vivo relationship, and does not appear to have been attempted. The relationship between passive Pe and tubular fraction reabsorbed (freabs) for compounds with and without apparent secretion has recently been established and useful equations and limits for prediction were developed. The suggestion that reabsorption has a lipophilicity cut-off does not seem to hold. Instead, compounds with passive Pe that is less than or equal to that of atenolol are expected to have negligible passive freabs. Compounds with passive Pe that is equal to or higher than that of carbamazepine are expected to have complete freabs. For compounds with intermediate Pe the relationship is irregular and freabs is difficult to predict. Tubular cells are comparably impermeable (for passive diffusion), and show regional differences in enzymatic and transporter activities. This limits the usefulness of microsome data and makes microsome-based predictions of metabolic CLR questionable. Renal concentrations and activities of CYP450s are comparably low, suggesting that CYP450 substrates have negligible metabolic CLR. The metabolic CLR of high-Pe UDP-glucuronyltransferase substrates could contribute to the total CL. [source] Prediction of human pharmacokinetics,gut-wall metabolismJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 10 2007Urban Fagerholm Intestinal mucosal cells operate with different metabolic and transport activity, and not all of them are involved in drug absorption and metabolism. The fraction of these cells involved is dependent on the absorption characteristics of compounds and is difficult to predict (it is probably small). The cells also appear comparably impermeable. This shows a limited applicability of microsome intrinsic clearance (CLint)-data for prediction of gut-wall metabolism, and the difficulty to predict the gut-wall CL (CLGW) and extraction ratio (EGW). The objectives of this review were to evaluate determinants and methods for prediction of first-pass and systemic EGW and CLGW in man, and if required and possible, develop new simple prediction methodology. Animal gut-wall metabolism data do not appear reliable for scaling to man. In general, the systemic CLGW is low compared with the hepatic CL. For a moderately extracted CYP3A4-substrate with high permeability, midazolam, the gut-wall/hepatic CL-ratio is only 1/35. This suggests (as a general rule) that systemic CLGW can be neglected when predicting the total CL. First-pass EGW could be of importance, especially for substrates of CYP3A4 and conjugating enzymes. For several reasons, including those presented above and that blood flow based models are not applicable in the absorptive direction, it seems poorly predicted with available methodology. Prediction errors are large (several-fold on average; maximum-15-fold). A new simple first-pass EGW -prediction method that compensates for regional and local differences in absorption and metabolic activity has been developed. It has been based on human cell in-vitro CLint and fractional absorption from the small intestine for reference (including verapamil) and test substances, and in-vivo first-pass EGW -data for reference substances. First-pass EGW -values for CYP3A4-substrates with various degrees of gastrointestinal uptake and CLint and a CYP2D6-substrate were well-predicted (negligible errors). More high quality in-vitro CLint - and in-vivo EGW -data are required for further validation of the method. [source] Prediction of human pharmacokinetics , improving microsome-based predictions of hepatic metabolic clearanceJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 10 2007Urban Fagerholm Physiologically based methods generally perform poorly in predicting in-vivo hepatic CL (CLH) from intrinsic clearance (CLint) in microsomes in-vitro and unbound fraction in blood (fu,bl). Various strategies to improve the predictability have been developed, and inclusion of an empirical scaling factor (SF) seems to give the best results. This investigation was undertaken to evaluate this methodology and to find ways to improve it further. The work was based on a diverse data set taken from Ito and Houston (2005). Another objective was to evaluate whether rationalization of CLH predictions can be made by replacing blood/plasma-concentration ratio (Cbl/Cpl) measurements with SFs. There were apparently no or weak correlations between prediction errors and lipophilicity, permeability (compounds with low permeability missing in the data set) and main metabolizing CYP450s. The use of CLint class (high/low) and drug class (acid/base/neutral) SFs (the CD-SF method) gives improved and reasonable predictions: 1.3-fold median error (an accurate prediction has a 1-fold error), 76% within 2-fold-error, and a median absolute rank ordering error of 2 for CLH (n = 29). This approach is better than the method with a single SF. Mean (P < 0.05) and median errors, fraction within certain error ranges, higher percentage with most accurate predictions, and ranking were all better, and 76% of predictions were more accurate with this new method. Results are particularly good for bases, which generally have higher CLH and the potential to be incorrectly selected/rejected as candidate drugs. Reasonable predictions of fu,bl can be made from plasma fu (fu,pl) and empirical blood cell binding SFs (B-SFs; 1 for low fu,pl acids; 0.62 for other substances). Mean and median fu,bl prediction errors are negligible. The use of the CD-SF method with predicted fu,bl (the BCD-SF method) also gives improved and reasonable results (1.4-fold median error; 66% within 2-fold-error; median absolute rank ordering error = 1). This new empirical approach seems sufficiently good for use during the early screening; it gives reasonable estimates of CLH and good ranking, which allows replacement of Cbl/Cpl measurements by a simple equation. [source] Identification and human pharmacokinetics of dihydroergotoxine metabolites in man: preliminary resultsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 1 2008Beatriz Bicalho Abstract Dihydroergotoxine is a mixture of semi-synthetic ergot alkaloids mainly used for age-related cognitive impairment. In this study, dihydroergotoxine (30,µM) was added to incubates of rat and bovine liver microsomes, and the resulting major metabolites were identified as hydroxy-dihydroergocornine, hydroxy-dihydroergocryptine and hydroxy-dihydroergocristine on the basis of molecular mass measurements, determined with a time-of-flight mass spectrometer. The relevance of these to humans was then investigated by simultaneously monitoring dihydroergotoxine and its hydroxy-metabolites in human plasma by LC-MS/MS after oral dosing of dihydroergotoxine mesylate (27,mg) to a healthy volunteer (male, age 45, height 1.93,m, weight 103,kg). In this preliminary approach, the peaks (Cmax) of dihydroergocornine, dihydroergocryptine and dihydroergocristine were about 0.04,µg/l. The peaks (Cmax) of their hydroxy-metabolites were 0.98, 0.53 and 0.30,µg/l, respectively. In conclusion, in this preliminary approach it was found that hydroxy-dihydroergocornine, hydroxy-dihydroergocryptine and hydroxy-dihydroergocristine were one order of magnitude higher in concentration than their parents in human plasma. Copyright © 2007 John Wiley & Sons, Ltd. [source] | ||||||||||