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Oral Clearance (oral + clearance)
Kinds of Oral Clearance Selected AbstractsPopulation pharmacokinetics of imatinib and the role of ,1 -acid glycoproteinBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2006N. Widmer Aims The aims of this observational study were to assess the variability in imatinib pharmacokinetics and to explore the relationship between its disposition and various biological covariates, especially plasma ,1 -acid glycoprotein concentrations. Methods A population pharmacokinetic analysis was performed using NONMEM based on 321 plasma samples from 59 patients with either chronic myeloid leukaemia or gastrointestinal stromal tumours. The influence of covariates on oral clearance and volume of distribution was examined. Furthermore, the in vivo intracellular pharmacokinetics of imatinib was explored in five patients. Results A one-compartment model with first-order absorption appropriately described the data, giving a mean (± SEM) oral clearance of 14.3 l h,1 (± 1.0) and a volume of distribution of 347 l (± 62). Oral clearance was influenced by body weight, age, sex and disease diagnosis. A large proportion of the interindividual variability (36% of clearance and 63% of volume of distribution) remained unexplained by these demographic covariates. Plasma ,1 -acid glycoprotein concentrations had a marked influence on total imatinib concentrations. Moreover, we observed an intra/extracellular ratio of 8, suggesting substantial uptake of the drug into the target cells. Conclusion Because of the high pharmacokinetic variability of imatinib and the reported relationships between its plasma concentration and efficacy and toxicity, the usefulness of therapeutic drug monitoring as an aid to optimizing therapy should be further investigated. Ideally, such an approach should take account of either circulating ,1 -acid glycoprotein concentrations or free imatinib concentrations. [source] Pharmacokinetics of carisbamate (RWJ-333369) in healthy Japanese and Western subjectsEPILEPSIA, Issue 8 2009Peter Zannikos Summary Purpose:, To compare the pharmacokinetics of carisbamate (RWJ-333369) in healthy Japanese and Western adults, and to comparatively assess carisbamate safety and tolerability between the two populations. Methods:, An open-label study was conducted in 24 Japanese and 24 Caucasian healthy subjects. Subjects received a single oral dose of 250 mg carisbamate on day 1 followed by a 3-day washout period; twice-daily dosing of 250 mg carisbamate on days 5,8; subsequently, 500 mg on days 9,12 and a single dose of 500 mg on day 13. Plasma samples were collected for a pharmacokinetic analysis on days 1, 8, and 13. Plasma and urine samples were analyzed for carisbamate and its urinary metabolites by liquid-chromatography-mass-spectrometry. Results:, Following a single dose, carisbamate Cmax and area under the curve (AUC) geometric mean ratios were 16.4% and 28.8% higher in Japanese than in Caucasians, respectively; these differences were statistically significant and their 90% confidence intervals (CIs) fell outside of the 80,125% limits, which are considered not to be of clinical significance. With dose,body weight normalization, Cmax and AUC were similar in Japanese and Caucasian subjects and the 90% CIs were within the 80,125% boundaries. Carisbamate was well tolerated, and its mean oral clearance and half-life were similar in both groups, ranging from 35.1,41.4 ml/h/kg and 11.5,12.8 h. Discussion:, Carisbamate plasma exposure (AUC) and Cmax in Japanese subjects is ,20,25% higher than in Caucasians due to a higher mg/kg dose. After body weight normalization, carisbamate pharmacokinetics was similar between Japanese and Caucasian subjects following single and multiple dosing, and showed the same dose proportionality. [source] Rufinamide: Clinical pharmacokinetics and concentration,response relationships in patients with epilepsyEPILEPSIA, Issue 7 2008Emilio Perucca Summary Rufinamide is a new, orally active antiepileptic drug (AED), which has been found to be effective in the treatment of partial seizures and drop attacks associated with the Lennox-Gastaut syndrome. When taken with food, rufinamide is relatively well absorbed in the lower dose range, with approximately dose-proportional plasma concentrations up to 1,600 mg/day, but less than dose-proportional plasma concentrations at higher doses due to reduced oral bioavailability. Rufinamide is not extensively bound to plasma proteins. During repeated dosing, steady state is reached within 2 days, consistent with its elimination half-life of 6,10 h. The apparent volume of distribution (Vd/F) and apparent oral clearance (CL/F) are related to body size, the best predictor being body surface area. Rufinamide is not a substrate of cytochrome P450 (CYP450) enzymes and is extensively metabolized via hydrolysis by carboxylesterases to a pharmacologically inactive carboxylic acid derivative, which is excreted in the urine. Rufinamide pharmacokinetics are not affected by impaired renal function. Potential differences in rufinamide pharmacokinetics between children and adults have not been investigated systematically in formal studies. Although population pharmacokinetic modeling suggests that in the absence of interacting comedication rufinamide CL/F may be higher in children than in adults, a meaningful comparison of data across age groups is complicated by age-related differences in doses and in proportion of patients receiving drugs known to increase or to decrease rufinamide CL/F. A study investigating the effect of rufinamide on the pharmacokinetics of the CYP3A4 substrate triazolam and an oral contraceptive interaction study showed that rufinamide has some enzyme-inducing potential in man. Findings from population pharmacokinetic modeling indicate that rufinamide does not modify the CL/F of topiramate or valproic acid, but may slightly increase the CL/F of carbamazepine and lamotrigine and slightly decrease the CL/F of phenobarbital and phenytoin (all predicted changes were <20%). These changes in the pharmacokinetics of associated AEDs are unlikely to make it necessary to change the dosages of these AEDs given concomitantly with rufinamide, with the exception that consideration should be given to reducing the dose of phenytoin. Based on population pharmacokinetic modeling, lamotrigine, topiramate, or benzodiazepines do not affect the pharmacokinetics of rufinamide, but valproic acid may increase plasma rufinamide concentrations, especially in children in whom plasma rufinamide concentrations could be increased substantially. Conversely, comedication with carbamazepine, vigabatrin, phenytoin, phenobarbital, and primidone was associated with a slight-to-moderate decrease in plasma rufinamide concentrations, ranging from a minimum of ,13.7% in female children comedicated with vigabatrin to a maximum of ,46.3% in female adults comedicated with phenytoin, phenobarbital, or primidone. In population modeling using data from placebo-controlled trials, a positive correlation has been identified between reduction in seizure frequency and steady-state plasma rufinamide concentrations. The probability of adverse effects also appears to be concentration-related. [source] Influence of CYP2C9 and CYP2C19 genetic polymorphisms on pharmacokinetics and pharmacodynamics of gliclazide in healthy Chinese Han volunteersJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 3 2010H. Shao PhD Summary Background and objective:,CYP2C9 is the major contributor to gliclazide metabolic clearance in vitro, while the pharmacokinetics of gliclazide modified release are affected mainly by CYP2C19 genetic polymorphisms in vivo. This study aims to investigate the influence of CYP2C9 and CYP2C19 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of gliclazide in healthy Chinese Han volunteers. Methods:, Eighteen healthy Han subjects with various combinations of CYP2C9 and CYP2C19 genotypes received 80 mg gliclazide. Plasma gliclazide concentrations were measured by a liquid chromatography,tandem mass spectrometry method for 84 h and plasma glucose and insulin levels were measured up to 15 h post-dose. Results and discussion:, There was no difference in either pharmacokinetic and or pharmacodynamic parameters of gliclazide when group A (CYP2C9*1/*1, CYP2C19 extensive metabolizers) was compared with group B (CYP2C9*1/*3, CYP2C19 *1/*1). When group C (CYP2C9*1/*1 and CYP2C19 poor metabolizers) was compared with group A, the AUC0,, and Cmax in group C were significantly higher [83·94 ± 40·41 vs. 16·39 ± 5·10 ,g·h/mL (P = 0·000) and 1·50 ± 0·85 vs. 0·45 ± 0·18 ,g/mL (P = 0·000)], and the oral clearance was significantly lower [1·17 ± 0·63 vs. 5·38 ± 1·86 L/h (P = 0·000)]. The half-life of gliclazide was also significantly prolonged in group C subjects when compared with that of group A (33·47 ± 12·39 vs. 19·34 ± 10·45 h), but the difference was not significant (P = 0·052). The increase in serum glucose level at 11 h after dosing (,Cglu11) in group C was significantly higher than that of group A (,1·08 ± 0·42 vs. 0·22 ± 1·01 mmol/L, P = 0·022). The corresponding insulin levels showed no difference between the two groups. Conclusion:,CYP2C9*3 was not associated with any change in the disposition of gliclazide. CYP2C19 polymorphisms appear to exert the dominant influence on the pharmacokinetics of gliclazide in healthy Chinese Han subjects, and may also affect the observed pharmacodynamics of the drug as a result. [source] Scintigraphic study to investigate the effect of food on a HPMC modified release formulation of UK-294,315JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 4 2009J. Davis Abstract The objective of the study was to use the combined approach of gamma scintigraphy and pharmacokinetics, in order to understand the mechanisms explaining the pharmacokinetic differences observed for a modified release (MR) formulation, when administered either in the fed or fasted state. Ten healthy subjects were recruited into a randomized three period single dose study, each subject receiving UK-294,315 40 mg IR (fasted), 100 mg MR (fasted) or 100 mg MR (after a high fat meal). Cmax values were markedly higher for the MR tablet in the fed state versus fasted and mean residence time was about 3 h longer for fasted versus fed; there was little difference in apparent oral clearance. In the fasted state, average gastric emptying of the intact tablet occurred at 1.2 h postdose, with gastric emptying of intact tablet observed in all subjects. In the fed state, rapid disintegration of the MR tablet was observed by scintigraphy, with 7/9 subjects showing complete disintegration in the stomach. Complete disintegration occurred 10.1 h postdose in the fasted state versus 5.9 h after a high fat meal. The study showed that in the fed state, the MR tablet eroded more rapidly than in the fasted state, leading to an overall increase in the rate of absorption. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:1568,1576, 2009 [source] A global examination of allometric scaling for predicting human drug clearance and the prediction of large vertical allometry,JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 8 2006Huadong Tang Abstract Allometrically scaled data sets (138 compounds) used for predicting human clearance were obtained from the literature. Our analyses of these data have led to four observations. (1) The current data do not provide strong evidence that systemic clearance (CLs; n,=,102) is more predictable than apparent oral clearance (CLpo; n,=,24), but caution needs to be applied because of potential CLpo prediction error caused by differences in bioavailability across species. (2) CLs of proteins (n,=,10) can be more accurately predicted than that of non-protein chemicals (n,=,102). (3) CLs is more predictable for compounds eliminated by renal or biliary excretion (n,=,33) than by metabolism (n,=,57). (4) CLs predictability for hepatically eliminated compounds followed the order: high CL (n,=,11),>,intermediate CL (n,=,17),>,low CL (n,=,29). All examples of large vertical allometry (% error of prediction greater than 1000%) occurred only when predicting human CLs of drugs having very low CLs. A qualitative analysis revealed the application of two potential rules for predicting the occurrence of large vertical allometry: (1) ratio of unbound fraction of drug in plasma (fu) between rats and humans greater than 5; (2) C logP greater than 2. Metabolic elimination could also serve as an additional indicator for expecting large vertical allometry. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 95: 1783,1799, 2006 [source] Pharmacokinetics of valerenic acid after single and multiple doses of valerian in older womenPHYTOTHERAPY RESEARCH, Issue 10 2010Gail D. Anderson Abstract Insomnia is a commonly reported clinical problem with as many as 50% of older adults reporting difficulty in falling and/or remaining asleep. Valerian (Valeriana officinalis) is a commonly used herb that has been advocated for promoting sleep. Valerenic acid is used as a marker for quantitative analysis of valerian products with evidence of pharmacological activity relevant to the hypnotic effects of valerian. The objective of this study was to determine the pharmacokinetics of valerenic acid in a group of elderly women after receiving a single nightly valerian dose and after 2 weeks of valerian dosing. There was not a statistically significant difference in the average peak concentration (Cmax), time to maximum concentration (Tmax) area under the time curve (AUC), elimination half-life (T1/2) and oral clearance after a single dose compared with multiple dosing. There was considerable inter- and intra-subject variability in the pharmacokinetic parameters. Cmax and AUC deceased and T1/2 increased with increased body weight. The variability between the capsules was extremely low: 2.2%, 1.4% and 1.4%, for hydroxyvalerenic acid, acetoxyvalerenic acid and valerenic acid, respectively. In conclusion, large variability in the pharmacokinetics of valerenic acid may contribute to the inconsistencies in the effect of valerian as a sleep aid. Copyright © 2010 John Wiley & Sons, Ltd. [source] Impact of pharmacokinetics and pharmacogenetics on the efficacy of pranlukast in Japanese asthmaticsRESPIROLOGY, Issue 6 2009Koichiro ASANO ABSTRACT Background and objective: Wide inter-individual variability in therapeutic effects limits the efficacy of leukotriene (LT) receptor antagonists in the treatment of asthma. We have reported that genetic variability in the expression of LTC4 synthase is associated with responsiveness to pranlukast in Japanese asthmatic patients. However, the effects of pharmacokinetic variability are less well known. This was an analysis of the pharmacokinetics of pranlukast in a population of adult asthmatics, and its effect on clinical responses. Other factors that may be related to the therapeutic effects of pranlukast, including LTC4 synthase gene polymorphisms, were also investigated. Methods: The population pharmacokinetics of pranlukast was analysed in a one-compartment model, using data collected in 50 Japanese adults with moderate to severe asthma, who were treated with pranlukast, 225 mg bd for 4 days. In 32 of these patients, in whom the clinical response to pranlukast (increase in FEV1 after 4 weeks of treatment) was measured in a previous study, a combined pharmacokinetic and pharmacogenetic analysis was performed. Results: Using the population pharmacokinetic model, the estimated the mean oral clearance (CL/F) of pranlukast was 16.4 L/h, and the inter-individual variability was 30.1%. Univariate and multivariate analyses showed that LTC4 synthase polymorphisms, but not the CL/F of the drug, predicted an improvement in pulmonary function with pranlukast treatment (P < 0.05). Conclusions: There was marked inter-individual variability in the pharmacokinetics of pranlukast among adult asthmatics, but this had little impact on the clinical effectiveness of the drug. [source] A Randomized, Double-Blind, Pharmacokinetic Study of Oral Maribavir with Tacrolimus in Stable Renal Transplant RecipientsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 10 2009M. D. Pescovitz Maribavir is being developed as a novel agent for the prevention or treatment of cytomegalovirus infections after stem cell and organ transplantation. This was a randomized, double-blind, placebo-controlled study designed to evaluate the potential pharmacokinetic interaction of concomitant administration of maribavir and tacrolimus. Twenty-five adult renal transplant recipients with stable renal function and stable dosing regimens of tacrolimus were randomized (20 maribavir 400 mg p.o. q12 h: 5 placebo). Tacrolimus whole blood concentration profiles were determined before and after 7 days of co-administration with maribavir. When co-administered with maribavir, tacrolimus mean Cmax increased 38%, tacrolimus trough concentrations (12 h post-dose) increased 57% and tacrolimus AUC(0-,) increased 51%. Apparent oral clearance of tacrolimus decreased 34% and Tmax was delayed by 0.5 h. There were no serious adverse events and no subject prematurely discontinued treatment. Because of the limited 7-day dosing course, the adverse event profile could not be adequately assessed. However, as seen with other maribavir studies, dysgeusia was common (90% of maribavir subjects and 20% of placebo subjects). In conclusion, co-administration of maribavir 400 mg twice daily increases exposure to tacrolimus. Routine therapeutic drug monitoring of tacrolimus blood concentrations should be included both at initiation and completion of maribavir treatment. [source] The utility of mixed-effects covariate analysis in rapid selection of doses in pediatric subjects: A case study with fexofenadine hydrochlorideBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 9 2004Rajesh Krishna Abstract Fexofenadine hydrochloride is a non-sedating antihistamine that is used in the treatment of symptoms associated with seasonal allergic rhinitis and chronic idiopathic urticaria. A pooled analysis of pharmacokinetic data from children 6 months to 12 years of age and adults was conducted to identify the dose(s) in children that produce exposures comparable to those in adults for the treatment of seasonal allergic rhinitis. The pharmacokinetic parameter database included peak and overall exposure data from 269 treatment exposures from 136 adult subjects, and 90 treatment exposures from 77 pediatric allergic rhinitis patients. The data were pooled and analysed using NONMEM software, version 5.0. A covariate model based on body weight and age and a power function model based on body weight were identified as appropriate models to describe the variability in fexofenadine oral clearance and peak concentration, respectively. Individual oral clearance estimates were on average 44%, 36% and 61% lower in children 6 to 12 years (n = 14), 2 to 5 years (n = 21), and 6 months to 2 years (n = 42), respectively, compared with adults. Trial simulations (n = 100) were carried out based on the final pharmacostatistical models and parameter estimates to identify the appropriate dose(s) in children relative to the marketed dose of 60 mg fexofenadine hydrochloride in adults. The trials were designed as crossover studies in 18 subjects comprising various potential dosing regimens with and without weight stratification. Pharmacokinetic parameter variability was assumed to have a log-normal distribution. Individual weights and ages were simulated using mean (SD) estimates derived from the studies used in this analysis and proportional measurement/model mis-specification errors derived from the analysis were incorporated into the simulation. The results indicated that a 30 mg dose of fexofenadine hydrochloride administered to children 1 to 12 years of age and weighing >10.5 kg and a 15 mg dose administered to children 6 months and older and weighing ,10.5 kg produces exposures similar to those seen with the 60 mg dose in adults. Copyright © 2004 John Wiley & Sons, Ltd. [source] CYP3A inductive potential of the rifamycins, rifabutin and rifampin, in the rabbitBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 4 2001Allan Weber Abstract Rifabutin is effective in the treatment and prevention of Mycobacterium avium infection in people with HIV infection. Rifabutin is structurally related to another rifamycin, rifampin, a well-known inducer of the human P-450 isoform 3A. The rabbit isoform CYP3A6 and the human isoform CYP3A4 have similar P-450 predominance and substrate specificity and are both induced by rifampin. Our goal was to predict the CYP3A induction capacity of rifabutin and to determine if ex vivo CYP3A induction potential of rifamycins is predictive of that obtained in vivo. We determined the in vivo and ex vivo CYP3A6 induction by 4 days of treatment with rifabutin (100 mg/kg), rifampin (100 mg/kg), or vehicle (DMSO) in the rabbit. The ex vivo measures were CYP3A6 activity (N-demethylation of erythromycin and hydroxylation of triazolam) and CYP3A content in rabbit hepatic microsomes preparations. The in vivo measures were oral clearance of triazolam and its formation clearance to its hydroxylated metabolites, , -hydroxytriazolam and 4-hydroxytriazolam. Rifampin increased CYP3A6 activity by 2- to 3-fold in hepatic microsomes compared to vehicle. Rifabutin increased CYP3A content 1.7-fold, but did not significantly increase microsomal CYP3A6 activity. Oral triazolam clearance and formation clearances to the two hydroxylated metabolites were 2- to 3-fold greater in rabbits treated with rifampin. These clearances were unaffected by rifabutin administration. Ex vivo enzyme activities correlated with in vivo changes in clearance of triazolam and the formation clearance to its hydroxylated metabolites. Rifabutin is a weaker inducer of CYP3A6 than rifampin. These data suggest that ex vivo enzyme activity is a viable approach to predict in vivo inductive potential of CYP3A inducers. Copyright © 2001 John Wiley & Sons, Ltd. [source] Gefitinib,phenytoin interaction is not correlated with the 14C-erythromycin breath test in healthy male volunteersBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 2 2009Stephanie Chhun WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , The response to gefitinib is variable and could be explained partly by the interindividual variability in gefitinib exposure. , Gefitinib is mainly metabolized by CYP3A4 and CYP2D6, and is to a lesser extent a P-glycoprotein (P-gp) substrate. , Patients with cancer are at high risk of drug,drug interactions, such as with phenytoin, a potent CYP3A4 inducer. WHAT THIS STUDY ADDS , The reduced systemic exposure of gefitinib with multiple-dose phenytoin treatment. , An effect attributed to the possible induction of intestinal CYP3A4 because of the lack of correlation between changes in gefitinib disposition and the erythromycin breath test and the lack of association between allelic variant in the ABCB1 gene and baseline and induced oral gefitinib clearance. , The CYP2D6 extensive metabolizer seems to be less sensitive to the interaction with phenytoin, as the magnitude of induction of gefitinib clearance was greater in CYP2D6 poor metabolizers than in CYP2D6 extensive metabolizers. AIMS We aimed to describe the pharmacokinetic interaction between phenytoin, a potent CYP3A4 and P-glycoprotein (P-gp) (ABCB1) inducer, and gefitinib, a CYP3A4, CYP2D6 and P-gp substrate. METHODS An open-label, randomized, two-phase crossover study was conducted. Eighteen healthy male volunteers (nine homozygous CC and nine homozygous TT as determined by their ABCB1 C3435T polymorphism in exon 26) received a single oral dose of 250 mg gefitinib alone or after 5 days treatment with phenytoin (5 mg kg,1 daily). Gefitinib plasma concentrations were determined by high-performance liquid chromatography. Hepatic CYP3A4 activity was evaluated by the 14C-erythromycin breath test (ERMBT) and the ABCB1 and CYP2D6 genetic polymorphisms were determined by the TaqMan allelic discrimination assay and long polymerase chain reaction, respectively. RESULTS Following treatment with phenytoin, mean gefitinib Cmax and AUC0,, decreased by 26 ± 44% [95% confidence interval (CI) for the difference 5,48%, P= 0.005] and 47 ± 26% (95% CI for the difference 34,60%, P= 0.001), respectively, and apparent oral clearance increased by 126 ± 93% (95% CI for the difference 80,172%, P= 0.004). Concomitantly, phenytoin increased the mean ERMBT by 91 ± 44% (95% CI 75,105%, P < 0.001) from baseline, but the extent of liver CYP3A4 induction was not correlated to the extent of interaction. Furthermore, this interaction was independent of ABCB1 genetic polymorphism. The CYP2D6 genotype was slightly but significantly related to gefitinib clearance (P= 0.04) during the control phase. CONCLUSIONS The significant interaction between gefitinib and phenytoin was not correlated with the erythromycin breath test and was independent of ABCB1 polymorphism, but may involve presystemic CYP3A-mediated intestinal first-pass. [source] Lack of tacrolimus circadian pharmacokinetics and CYP3A5 pharmacogenetics in the early and maintenance stages in Japanese renal transplant recipientsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 2 2008Shigeru Satoh WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Circadian variations of tacrolimus pharmacokinetics are controversial. , Also, the pharmacokinetics has time-dependent variability, such as a decrease in oral clearance and increase in the dose-adjusted AUC after transplantation. , Although the CYP3A5 polymorphism is associated with tacrolimus pharmacokinetics, differences in the influence of this gene on the pharmacokinetics between the early and maintenance stages have not yet been clarified. WHAT THIS STUDY ADDS , Tacrolimus pharmacokinetics did not show circadian variation in either the early or maintenance stage with our designated-time administration strategy. , Based on previous results and our own findings, the interval between food consumption and tacrolimus administration might influence the interindividual and interinstitutional variability of tacrolimus chronopharmacokinetics. , The CYP3A5 polymorphism may be associated with the time-dependent changes in tacrolimus oral clearance. AIMS We investigated whether tacrolimus pharmacokinetics shows circadian variation and the influence of the CYP3A5 A6986G polymorphism on the pharmacokinetics in both the early and maintenance stages after renal transplantation. METHODS Tacrolimus was administered twice daily at specified times (09.00 and 21.00 h) throughout the pre- and post-transplant period according to the trough-targeting strategy. Fifty recipients with stable graft function were studied on day 28 and beyond 1-year post transplantation. Whole blood samples were collected prior to and 1, 2, 3, 4, 6, 9 and 12 h after both the morning and evening doses during hospitalization. RESULTS Tacrolimus pharmacokinetics did not show circadian variation in either the early or maintenance stage [AUC0,12 197.1 (95% confidence interval 182.9, 212.3) in daytime vs. 203.6 ng h ml,1 (189.8, 217.4) in the night-time at day 28, 102.0 (92.1, 111.9) vs. 107.7 (97.9, 117.5) at 1 year, respectively]. In CYP3A5 *1 allele carriers (CYP3A5 expressers), body weight-adjusted oral clearance was markedly decreased from the early stage to the maintenance stage [0.622 (0.534, 0.709) to 0.369 l h,1 kg,1 (0.314, 0425)] compared with a smaller decrease [0.368 (0.305, 0.430) to 0.305 (0.217, 0.393)] in CYP3A5 non-expressers; however, the CYP3A5 genetic variation did not influence tacrolimus chronopharmacokinetics. CONCLUSION Equivalent daytime and night-time tacrolimus pharmacokinetics were achieved during both the early and maintenance stages with our specified-time administration strategy. The CYP3A5 polymorphism may be associated with the time-dependent changes in the oral clearance of tacrolimus, suggesting that genotyping of this polymorphism is useful for determining the appropriate dose of tacrolimus in both the early and maintenance stages after renal transplantation. [source] Effect of multiple doses of montelukast on the pharmacokinetics of rosiglitazone, a CYP2C8 substrate, in humansBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 3 2007Kyoung-Ah Kim Aims To investigate the effect of multiple dosing with montelukast, a selective leukotriene-receptor antagonist, on the pharmacokinetics of rosiglitazone, a CYP2C8 substrate, in humans. Methods A two-period, randomized crossover study was conducted in 10 healthy subjects. After administration of oral doses of placebo or 10 mg montelukast daily for 6 days, 4 mg rosiglitazone was administered and plasma samples were obtained for 24 h and analyzed for rosiglitazone and N-desmethylrosiglitazone using high-performance liquid chromatography with fluorescence detection. Results During the montelukast phase, the total area under the time-concentration curve (AUC) and peak plasma concentration of rosiglitazone were 102% (90% CI 98, 107%) and 98% (90% CI 92, 103%) of the corresponding values during the placebo phase, respectively. Multiple dosing with montelukast did not affect the oral clearance of rosiglitazone significantly (90% CI 94, 105%; P = 0.50). The AUC ratio and plasma concentration ratios of N-desmethylrosiglitazone : rosiglitazone were not changed by multiple dosing with montelukast (90% CI 90, 103%; P = 0.14). Conclusions Multiple doses of montelukast do not inhibit CYP2C8-mediated rosiglitazone metabolism in vivo despite in vitro findings indicating that montelukast is a selective CYP2C8 inhibitor. [source] Population pharmacokinetics of imatinib and the role of ,1 -acid glycoproteinBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2006N. Widmer Aims The aims of this observational study were to assess the variability in imatinib pharmacokinetics and to explore the relationship between its disposition and various biological covariates, especially plasma ,1 -acid glycoprotein concentrations. Methods A population pharmacokinetic analysis was performed using NONMEM based on 321 plasma samples from 59 patients with either chronic myeloid leukaemia or gastrointestinal stromal tumours. The influence of covariates on oral clearance and volume of distribution was examined. Furthermore, the in vivo intracellular pharmacokinetics of imatinib was explored in five patients. Results A one-compartment model with first-order absorption appropriately described the data, giving a mean (± SEM) oral clearance of 14.3 l h,1 (± 1.0) and a volume of distribution of 347 l (± 62). Oral clearance was influenced by body weight, age, sex and disease diagnosis. A large proportion of the interindividual variability (36% of clearance and 63% of volume of distribution) remained unexplained by these demographic covariates. Plasma ,1 -acid glycoprotein concentrations had a marked influence on total imatinib concentrations. Moreover, we observed an intra/extracellular ratio of 8, suggesting substantial uptake of the drug into the target cells. Conclusion Because of the high pharmacokinetic variability of imatinib and the reported relationships between its plasma concentration and efficacy and toxicity, the usefulness of therapeutic drug monitoring as an aid to optimizing therapy should be further investigated. Ideally, such an approach should take account of either circulating ,1 -acid glycoprotein concentrations or free imatinib concentrations. [source] Effect of severe renal impairment on the pharmacokinetics of azimilide following single dose oral administrationBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 5 2002Alfred E. Corey Aims To assess the influence of severe renal impairment on azimilide pharmacokinetics. Methods A single oral dose of 125 mg azimilide dihydrochloride was administered to subjects with normal and severely impaired renal function. Blood and urine samples were collected for 22,28 and 10 days, respectively. Results Azimilide renal clearance decreased in subjects with renal impairment (mean 14 vs 4.8 ml h,1 kg,1, 95% confidence interval on the ratio 0.23, 0.50). However, no change in any other pharmacokinetic parameter including oral clearance (mean 109 vs 104 ml h,1 kg,1, 95% confidence interval on the ratio 0.67, 1.36) was observed. Conclusions Since azimilide blood concentrations are essentially unaffected by renal function, an a priori dosage regimen adjustment is not required in patients with renal impairment. [source] Pharmacokinetics of tibolone in early and late postmenopausal womenBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 2 2002C. J. Timmer Aims, Tibolone is a tissue-specific compound with favourable effects on bone, vagina, climacteric symptoms, mood and sexual well being in postmenopausal women, without stimulating the endometrium or breast. Since tibolone is used for the treatment of both young and elderly postmenopausal women, its pharmacokinetics were studied to investigate potential differences with age. In addition, the bioequivalence of the 1.25 and 2.5 mg tablets was evaluated. Methods, Single doses of 1.25 or 2.5 mg of tibolone were given in a double-blind, randomized, two-way cross-over study to women aged between 45 and 55 years or between 65 and 75 years of age. Results, Age did not have a significant effect on Cmax, tmax, and t½ of tibolone and its metabolites and on the body weight standardized oral clearance (CL/F kg,1) of the 3,- and 3,-hydroxy tibolones. In early postmenopausal women, significantly lower values were found for the AUC(0,16 h), and AUC(0,,) of 3,-hydroxy tibolone 24.6±6.6 vs 29.2±4.9 and 27.1±6.9 vs 32.3±6.5 ng ml,1 h for the 1.25 mg tablet, respectively, and 45.4±13.9 vs 55.7±14.1 and 49.6±14.6 vs 62.6±17.3 ng ml,1 h for the 2.5 mg tablet, respectively. When these values were adjusted for the significantly higher body weight of the early postmenopausal women, the differences disappeared. No significant differences between early and late postmenopausal women were found for the AUC(0,8 h), and AUC(0,,) of 3,-hydroxy tibolone. The rate of absorption of tibolone and the rates of absorption or formation of the 3,- and 3,-hydroxy tibolones were significantly higher after the 1.25 mg dose than after the 2.5 mg tablet, resulting in increases of 32%, 27% and 17% for the dose normalized- Cmax of tibolone and the 3,- and 3,-hydroxy tibolones, respectively. tmax for tibolone and its metabolites was 12,27% less after 1.25 mg compared to 2.5 mg, which was statistically significant. The two formulations were bioequivalent with respect to the dose-normalized AUC(0,,) and the AUC(0,tfix) values for the 3,-hydroxy tibolone (ratio point estimate [90%, confidence limits]: 1.08 [1.04, 1.14] and 1.08 [1.03, 1.13], respectively) and for the 3,-hydroxy tibolone (1.07 [1.01, 1.14] and 1.04 [0.96, 1.12], respectively). Both formulations were also bioequivalent with respect to CL/F kg,1 and t½. Conclusions, The pharmacokinetics of tibolone are similar in early (age 45,55 years) and late (65,75 years) postmenopausal women. The 2.5 and 1.25 mg tablets are bioequivalent with respect to the extent of absorption. The rate of absorption or formation of the metabolites of tibolone were not bioequivalent, but these differences are considered to have no clinical relevance in view of the chronic administration of tibolone. [source] | ||||||||||