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First-order Absorption (first-order + absorption)
Selected AbstractsPharmacokinetic,pharmacodynamic study of apomorphine's effect on growth hormone secretion in healthy subjectsFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 4 2003Guy Aymard Abstract Apomorphine (APO) stimulates growth hormone (GH) release via dopamine D2 receptors (DRD2). There is no specific study assessing the relationship between APO pharmacokinetic (PK) and the pharmacodynamic (PD) response e.g. GH release. The objective of the study is the PK,PD modelling of APO in healthy subjects. This is a randomized crossover study with s.c. administration of 5, 10, and 20 ,g/kg of APO in 18 healthy subjects. APO concentrations were modelled according to both a bi-compartmental model with zero-order absorption and a bi-compartmental model with first-order absorption. PK,PD relationship was modelled in accordance with the Emax Hill equation using plasma concentrations of APO calculated according to the bi-compartmental model with zero-order absorption. Modelled parameters were very similar to the experimental parameters. PK of APO was linear and there was no significant difference between the tested doses for AUC0,, and Cmax (normalised to the dose 1 ,g/kg), t1/2, and t1/2,. These parameters expressed as mean (CV%: SD/mean) were: 17.2 (26.9) ng/mL·min, 0.26 (33.3) ng/mL, 17.1 (54.2) and 45.2 (20.6) min, respectively (n = 53). An anticlockwise hysteresis loop (effect function of APO plasma concentration) appeared for each dose and each subject. The predicted and measured GH concentrations for all subjects and times were similar whatever the dose (P > 0.27). Emax values were 246 (121), 180 (107), 205 (139) ng/mL, respectively, and EC50 were 0.98 (48.1), 1.70 (62.3), 3.67 (65.2) ng/mL, respectively at dose 5, 10, and 20 ,g/kg (P < 10,4). APO and GH concentrations were predicted with good accuracy using bi-compartmental with zero-order absorption PK model and sigmoid Emax PD model, respectively. [source] Kinetic analysis of oxytetracycline residues in Chinese mitten crab, Eriocheir sinensis, muscle following intramuscular administrationJOURNAL OF FISH DISEASES, Issue 8 2010Q Feng Abstract Crab culture is a very important economic industry in China. An epidemic of tremor disease of Chinese mitten crabs, Eriocheir sinensis, has become a serious problem in recent years. A spiroplasm has been proved to be the causative agent of this disease. Oxytetracycline (OTC) is used widely in aquaculture and was confirmed to be very effective against this pathogen. In this study, the distribution and depletion patterns of OTC in crab muscle were evaluated following single intramuscular doses of 2, 8 and 40 mg kg,1 body weight. OTC was detected with a validated HPLC method. Concentration,time profiles were well described by a three-compartment model with first-order absorption after a single dose of 8 and 40 mg kg,1. For comparison, a non-compartment model was employed. A withdrawal time of 48.29 and 55.92 days was suggested prior to consumption after receiving 8 and 40 mg kg,1. A recommended therapeutic dose of OTC in theory was calculated to be 36.37 mg kg,1. OTC was distributed well throughout the body. The elimination of OTC in muscle was slower compared with fish and other crustaceans. A dose of 40 mg kg,1 is suggested for practical use. [source] Effect of temperature on pharmacokinetics of enrofloxacin in mud crab, Scylla serrata (Forsskål), following oral administrationJOURNAL OF FISH DISEASES, Issue 3 2008W H Fang Abstract The study was conducted to evaluate the pharmacokinetics of enrofloxacin following a single oral gavage (10 mg kg,1) in mud crab, Scylla serrata, at water temperatures of 19 and 26 °C. Enrofloxacin concentration in haemolymph was determined using high-performance liquid chromatography (HPLC). A multiple and repeated haemolymph sampling from the articular cavity of crab periopods was developed. The haemolymph of an individual crab was successfully sampled up to 11 times from the articular cavity. The profile of haemolymph enrofloxacin concentration of an individual crab versus time was thus achieved. The mean haemolymph enrofloxacin concentration versus time was described by a two-compartment model with first-order absorption at two water temperatures. The peak concentrations of haemolymph enrofloxacin at 19 and 26 °C were 7.26 and 11.03 ,g mL,1, at 6 and 2 h, respectively. The absorption and distribution half-life time ( and t1/2,) at 19 °C were 3.7 and 4.5 h, respectively, which were markedly larger than the corresponding values (1.1 and 1.5 h) at 26 °C; the elimination half-life time (t1/2,) was 79.1 and 56.5 h at 19 and 26 °C, respectively. The area under curve (AUC), total body clearance (Cl) and mean residence time (MRT0,,) at 19 °C were 636.0 mg L,1 h, 0.016 L h,1 kg,1 and 102.5 h, respectively; the corresponding values at 26 °C were 583.4 mg L,1 h, 0.018 L h,1 kg,1and 63.7 h. These results indicate that enrofloxacin is absorbed and eliminated more rapidly in mud crab at 26 °C than at 19 °C. [source] Pharmacokinetics of controlled-release verapamil in healthy volunteers and patients with hypertension or anginaBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 1 2002Suneel Gupta Abstract Aims: To study the dose-ranging population pharmacokinetics of controlled release verapamil in healthy subjects and patients with angina or hypertension. To characterize the pharmacodynamics of controlled-release verapamil in patients with hypertension. Methods: Dose-ranging studies were conducted in healthy volunteers and patients with hypertension and angina. Subjects received doses of 120, 180, 360, or 540 mg racemic verapamil as an osmotic controlled-release formulation. A population pharmacokinetic model involving zero-order release of verapamil into the gastrointestinal tract with first-order absorption and elimination was used to describe the steady-state plasma concentration profile for R - and S -verapamil. A population sigmoid Emax pharmacodynamic model was used to describe the effect of R - and S -verapamil on mean arterial blood pressure. Results:S -verapamil had an approximate 4-fold greater apparent clearance than R -verapamil in both healthy volunteers and patients. The apparent plasma clearance of R - and S -verapamil in healthy volunteers decreased over the dose range of 120,540 mg. A similar dose-dependent decrease in apparent plasma clearance was also noted in patients. None of the patient demographic variables examined (age, total body weight, lean body weight, body mass index, and height) explained the variability in verapamil pharmacokinetics. The pharmacodynamic model describing the relationship between verapamil plasma concentration and mean arterial blood pressure indicated that the S -verapamil had a 3.6-fold lower estimated EC50 compared to R -verapamil. Conclusions: The results from this dose-ranging pharmacokinetic investigation in healthy volunteers and patients are consistent with previous reports in healthy subjects. S -verapamil is cleared more rapidly than R -verapamil and the estimated EC50 for S -verapamil was 3.6-fold lower than for R -verapamil. Estimated EC50 values for R - and S -verapamil decreased with increasing age and decreasing weight. Copyright © 2002 John Wiley & Sons, Ltd. [source] Population pharmacokinetic analysis of cilostazol in healthy subjects with genetic polymorphisms of CYP3A5, CYP2C19 and ABCB1BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2010Hee-Doo Yoo WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , The interindividual variability of the pharmacokinetic parameters of cilostazol is relatively large. , Cilostazol undergoes extensive hepatic metabolism via the P450 enzymes, primarily CYP3A and, to a lesser extent, CYP2C19. , Indeed, <1% of the administered dose of cilostazol is excreted unchanged in the urine. WHAT THIS STUDY ADDS , A population pharmacokinetic analysis of cilostazol was conducted to evaluate the impact of CYP3A, CYP2C19 and ABCB1 polymorphisms on cilostazol disposition in vivo. , Genetic polymorphisms of CYP3A5 and CYP2C19 explain the substantial interindividual variability in the pharmacokinetics of cilostazol. , ABCB1 genotypes do not to appear to be associated with the disposition of cilostazol. AIMS To investigate the influence of genetic polymorphisms in the CYP3A5, CYP2C19 and ABCB1 genes on the population pharmacokinetics of cilostazol in healthy subjects. METHODS Subjects who participated in four separate cilostazol bioequivalence studies with the same protocols were included in this retrospective analysis. One hundred and four healthy Korean volunteers were orally administered a single 50- or 100-mg dose of cilostazol. We estimated the population pharmacokinetics of cilostazol using a nonlinear mixed effects modelling (nonmem) method and explored the possible influence of genetic polymorphisms in CYP3A (CYP3A5*3), CYP2C19 (CYP2C19*2 and CYP2C19*3) and ABCB1 (C1236T, G2677T/A and C3435T) on the population pharmacokinetics of cilostazol. RESULTS A two-compartment model with a first-order absorption and lag time described the cilostazol serum concentrations well. The apparent oral clearance (CL/F) was estimated to be 12.8 l h,1. The volumes of the central and the peripheral compartment were characterized as 20.5 l and 73.1 l, respectively. Intercompartmental clearance was estimated at 5.6 l h,1. Absorption rate constant was estimated at 0.24 h,1 and lag time was predicted at 0.57 h. The genetic polymorphisms of CYP3A5 had a significant (P < 0.001) influence on the CL/F of cilostazol. When CYP2C19 was evaluated, a significant difference (P < 0.01) was observed among the three genotypes (extensive metabolizers, intermediate metabolizers and poor metabolizers) for the CL/F. In addition, a combination of CYP3A5 and CYP2C19 genotypes was found to be associated with a significant difference (P < 0.005) in the CL/F. When including these genotypes, the interindividual variability of the CL/F was reduced from 34.1% in the base model to 27.3% in the final model. However, no significant differences between the ABCB1 genotypes and cilostazol pharmacokinetic parameters were observed. CONCLUSIONS The results of the present study indicate that CYP3A5 and CYP2C19 polymorphisms explain the substantial interindividual variability that occurs in the metabolism of cilostazol. [source] Population pharmacokinetic analysis of varenicline in adult smokersBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 5 2009Patanjali Ravva WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT? , Several clinical pharmacology studies have characterized the pharmacokinetics of varenicline in young adult and elderly smokers and subjects with impaired renal function. , Varenicline pharmacokinetics is linear over the recommended dose range. , Varenicline total clearance is linearly related to its renal clearance. , Both are progressively reduced as renal function declines, which results in a progressive increase in varenicline systemic exposure and prolonged half-life. WHAT THIS STUDY ADDS? , This work provides an integrated model-based analysis of varenicline pharmacokinetics across multiple studies in the target patient population. , The model describes the impact of patient-specific covariates, such as renal function, and provides a rationale for dose adjustment. , The resulting model also provides a means to predict individual-specific drug exposures to clinical responses in subsequent analyses. AIMS To characterize the population pharmacokinetics of varenicline and identify factors leading to its exposure variability in adult smokers. METHODS Data were pooled from nine clinical studies consisting of 1878 subjects. Models were developed to describe concentration,time profiles across individuals. Covariates were assessed using a full model approach; parameters and bootstrap 95% confidence intervals (CI) were estimated using nonlinear mixed effects modelling. RESULTS A two-compartment model with first-order absorption and elimination best described varenicline pharmacokinetics. The final population parameter estimates (95% CI) were: CL/F, 10.4 l h,1 (10.2, 10.6); V2/F, 337 l (309, 364); V3/F, 78.1 l (61.9, 98.9); Q/F, 2.08 l h,1 (1.39, 3.79); Ka, 1.69 h,1 (1.27, 2.00); and Alag, 0.43 h (0.37, 0.46). Random interindividual variances were estimated for Ka[70% coefficient of variation (CV)], CL/F (25% CV), and V2/F (50% CV) using a block covariance matrix. Fixed effect parameters were precisely estimated [most with % relative standard error < 10 and all with % relative standard error < 25], and a visual predictive check indicated adequate model performance. CL/F decreased from 10.4 l h,1 for a typical subject with normal renal function (CLcr = 100 ml min,1) to 4.4 l h,1 for a typical subject with severe renal impairment (CLcr = 20 ml min,1), which corresponds to a 2.4-fold increase in daily steady-state exposure. Bodyweight was the primary predictor of variability in volume of distribution. After accounting for renal function, there was no apparent effect of age, gender or race on varenicline pharmacokinetics. CONCLUSIONS Renal function is the clinically important factor leading to interindividual variability in varenicline exposure. A dose reduction to 1 mg day,1, which is half the recommended dose, is indicated for subjects with severe renal impairment. [source] Population pharmacokinetics of sirolimus in de novo Chinese adult renal transplant patientsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2009Zheng Jiao WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT? , Sirolimus is an immunosuppressive agent used for the prophylaxis of renal allograft rejection. , Several conventional pharmacokinetic and population pharmacokinetic studies have been conducted to assess the pharmacokinetic characteristics of sirolimus in White or African-American recipients. WHAT THIS STUDY ADDS? , The population pharmacokinetics of sirolimus in Chinese adult renal transplant recipients was characterized for the first time. , New drug,drug interactions between herbal medicines and sirolimus were identified as the covariates on sirolimus clearance. AIMS This study was aimed at determining the population pharmacokinetics of sirolimus and identifying factors that explain pharmacokinetic variability in de novo Chinese adult renal transplant patients. METHODS Data were retrospectively extracted from a formal multicentre clinical trial, which was originally designed to evaluate the safety and efficacy of ciclosporin dose reduction and ciclosporin elimination in patients receiving sirolimus. All patients received 12-month treatment, i.e. induction therapy with ciclosporin, sirolimus and corticosteroids during the first 3 months followed by either ciclosporin dose reduction or ciclosporin discontinuation thereafter. Eight-hundred and four sirolimus trough blood concentrations (C0) from 112 patients were used to develop a population pharmacokinetic model using the nonmem program. A one-compartment model with first-order absorption and elimination was selected as the base model. The influence of demographic characteristics, biochemical and haematological indices, ciclosporin daily dose, ciclosporin C0 as well as other commonly used co-medications were explored. RESULTS The typical values with interindividual variability for apparent clearance (CL/F) and apparent volume of distribution (V/F) were 10.1 l h,1 (23.8%) and 3670 l (56.7%), respectively. The residual variability was 29.9%. CL/F decreased significantly with silymarin or glycyrrhizin co-therapy in hepatically impaired patients, and with increasing total cholesterol levels or ciclosporin C0. Moreover, CL/F increased nonlinearly with increasing sirolimus daily dose. The median parameter estimates from a nonparametric bootstrap procedure were comparable and within 5% of the estimates from nonmem. CONCLUSIONS These results provide important information for clinicians to optimize sirolimus regimens in Chinese renal transplant patients. [source] Minimal effect of MDR1 and CYP3A5 genetic polymorphisms on the pharmacokinetics of indinavir in HIV-infected patientsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 3 2007Caroline Solas What is already known about this subject ,,Before this study, few data were available on the potential effect of genetic variants of P-glycoprotein or the CYP3A5 enzyme on the pharmacokinetic variability of protease inhibitors (PI). ,,MDR1 C3435T polymorphism was often linked with the pharmacokinetic variability of nelfinavir. CYP3A5*3 polymorphism was linked with the pharmacokinetic variability of calcineurin inhibitors and was therefore strongly suspected of being one of the key factors in the pharmacokinetic variability of other CYP3A susbtrates. What this study adds ,,Our results showed that both MDR1 C3435T and CYP3A5*3 polymorphisms are involved in the pharmacokinetic variability of the absorption or elimination of indinavir, but probably jointly with other factors. ,,The potent CYP3A inhibitory effect of ritonavir may hide the variability linked to genetic differences in the CYP3A5 gene, thereby reducing the overall pharmacokinetic variability of the boosted protease inhibitor. ,,Genotyping MDR1 and/or CYP3A5 does not appear to be a clinically relevant factor in optimizing protease inhibitor boosted regimens. Aims The protease inhibitor indinavir is characterized by an important interindividual pharmacokinetic variability, which results from the actions of the metabolizing enzymes cytochrome P450 (CYP) 3A and the multidrug efflux pump P-glycoprotein (P-gp), encoded by MDR1. Using a population pharmacokinetic approach, we investigated the effect of several MDR1 and CYP3A5 polymorphisms on the pharmacokinetic parameters of indinavir in HIV-infected patients. Methods Twenty-eight patients receiving indinavir alone or together with ritonavir were included. Indinavir pharmacokinetics were studied over a 12 h interval. Genetic polymorphisms were assessed by real-time PCR assays and direct sequencing for MDR1 and by PCR-SSCP analysis for CYP3A5. Results The pharmacokinetics of indinavir were best described by a one-compartment model with first-order absorption. In the final model, the MDR1 C3435T genotype and ritonavir were identified as statistically significant covariates (P , 0.001) for the absorption rate constant (95% confidence interval on the difference between CC and CT genotype 0.37, 5.53) and for clearance (95% confidence interval on the difference 5.8, 26.2), respectively. Patients with the CYP3A5*3/*3 genotype receiving indinavir alone had a 31% decrease in the indinavir clearance rate compared with patients carrying the CYP3A5*1/*3 genotype. Conclusions The MDR1 C3435T genotype affects the absorption constant of indinavir suggesting that P-gp may be implicated in its pharmacokinetic variability. Through its inhibition of CYP3A and P-gp, ritonavir could attenuate the pharmacokinetic variability linked to genetic differences, reducing significantly the interindividual variability of indinavir. However, genotyping MDR1 and/or CYP3A5 to optimize protease inhibitor boosted regimens does not seem clinically relevant. [source] Population pharmacokinetics of darbepoetin alfa in healthy subjectsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2007Balaji Agoram Aim To develop and evaluate a population pharmacokinetic (PK) model of the long-acting erythropoiesis-stimulating protein, darbepoetin alfa in healthy subjects. Methods PK profiles were obtained from 140 healthy subjects receiving single intravenous and/or single or multiple subcutaneous doses of darbepoetin alfa (0.75,8.0 µg kg,1, or either 80 or 500 µg). Data were analysed by a nonlinear mixed-effects modelling approach using NONMEM software. Influential covariates were identified by covariate analysis emphasizing parameter estimates and their confidence intervals, rather than stepwise hypothesis testing. The model was evaluated by comparing simulated profiles (obtained using the covariate model) to the observed profiles in a test dataset. Results The population PK model, including first-order absorption, two-compartment disposition and first-order elimination, provided a good description of data. Modelling indicated that for a 70-kg human, the observed nearly twofold disproportionate dose,exposure relationship at the 8.0 µg kg,1 -dose relative to the 0.75 µg kg,1 -dose may reflect changing relative bioavailability, which increased from ,,48% at 0.75 µg kg,1 to 78% at 8.0 µg kg,1. The covariate analysis showed that increasing body weight may be related to increasing clearance and central compartment volume, and that the absorption rate constant decreased with increasing age. The full covariate model performed adequately in a fixed-effects prediction test against an external dataset. Conclusion The developed population PK model describes the inter- and intraindividual variability in darbepoetin alfa PK. The model is a suitable tool for predicting the PK response of darbepoetin alfa using clinically untested dosing regimens. [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] Pharmacokinetics and pharmacodynamics of TF-505, a novel nonsteroidal 5,-reductase inhibitor, in normal subjects treated with single or multiple dosesBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 3 2002Tomoe Fujita Aims To assess the tolerability, pharmacokinetics and pharmacodynamics of a novel nonsteroidal,, and,, noncompetitive,, inhibitor,, of,, type,, I,, and,, type,, II,, 5,-reductases, (,)-(S)-4-[1-[4-[1-(4-isobutylphenyl) butoxy]benzoyl]indolizin-3-yl]butyric acid (TF-505), after single and multiple oral doses in healthy volunteers. Methods In the single-dose study, six young adult males in each dose group received 25 mg or 50 mg of TF-505, and six older males (, 40 years) in each dose group received 75 mg or 100 mg of TF-505. The subjects were given the drug in ascending dose and in the fasting state. Six subjects also received 50 mg of TF-505 after breakfast in a two-period crossover manner. In the multiple-dose study, six older males in each dose group received 12.5 mg or 25 mg TF-505 after breakfast daily for 7 days. Plasma concentrations of TF-505, dihydrotestosterone (DHT) and testosterone were measured. The pharmacokinetics of TF-505 were analysed by a compartment model with first-order absorption, first-order elimination and a lag time. Pharmacokinetic and pharmacodynamic relationships were evaluated by indirect response modelling with inhibition of input. Results Maximum plasma concentration (Cmax) and the area under the concentration,time curve (AUC) increased proportionately after the single dose up to 50 mg and with the multiple doses. Linearity was not detected between 75 and 100 mg of TF-505. Dose dependency was also noted for the effect of TF-505 on DHT concentrations following single doses up to 50 mg and multiple doses. Plasma DHT concentrations decreased maximally to 58.2, 49.5, 54.2 and 49.8% of basal values at 8,12 h after single administration of 25, 50, 75 and 100 mg TF-505, respectively, and to 60.5 and 49.4% at the 7th and 5th dose following multiple doses of 12.5 and 25 mg TF-505, respectively. The predicted effect curves matched the observed data when the indirect response model was applied to the time course of the suppressant effect of TF-505 on plasma DHT concentrations after both the single and multiple studies. Fifty percent inhibitory concentrations (IC50) of 0.82, 1.48, 1.31 and 0.88 µ g ml,1, zero-order rate constants for the onset of plasma DHT concentration changes (kin) of 17.8, 17.4, 17.0 and 10.7% h,1 and first-order rate constants,, for,, increase,, in,, plasma,, DHT,, concentrations,, to,, basal,, values,, (kout),, of,, 0.17,,, 0.16,,, 0.17,, and,, 0.10 h,1,, for,, the,, single,, study,, at,, doses,, of,, 25,,, 50,,, 75,, and 100 mg, respectively, were attained. In the multiple-dose study, IC50s were 1.74 and 1.49 µg ml,1 for the 12.5 and 25 mg doses, respectively. No serious adverse events related to TF-505 were observed. Conclusions TF-505 was well tolerated in healthy male volunteers. Accumulation of TF-505 in plasma was not observed during multiple dosing. The indirect response model described the relationships between pharmacokinetics and pharmacodynamics of TF-505. Such modelling is expected to yield an appropriate dosage regimen in subsequent clinical trials. [source] | ||||||||||