Current Issue : October - December Volume : 2012 Issue Number : 4 Articles : 7 Articles
Background: Consistent with its effect on gastric emptying, exenatide, an injectable treatment for type 2 diabetes,\r\nmay slow the absorption rate of concomitantly administered oral drugs resulting in a decrease in maximum\r\nconcentration (Cmax). This study evaluated the drug interaction potential of exenatide when administered\r\nadjunctively with oral contraceptives, given their potential concomitant use.\r\nMethods: This trial evaluated the effect of exenatide co-administration on single- and multiple-dose\r\npharmacokinetics of a combination oral contraceptive (ethinyl estradiol [EE] 30 �µg, levonorgestrel [LV] 150 �µg\r\n[Microgynon 30�®]). Thirty-two healthy female subjects participated in an open-label, randomised, crossover trial\r\nwith 3 treatment periods (oral contraceptive alone, 1 hour before exenatide, 30 minutes after exenatide). Subjects\r\nreceived a single dose of oral contraceptive on Day 8 of each period and QD doses on Days 10 through 28.\r\nDuring treatment periods of concomitant usage, exenatide was administered subcutaneously prior to morning and\r\nevening meals at 5 �µg BID from Days 1 through 4 and at 10 �µg BID from Days 5 through 22. Single- (Day 8) and\r\nmultiple-dose (Day 22) pharmacokinetic profiles were assessed for each treatment period.\r\nResults: Exenatide did not alter the bioavailability nor decrease daily trough concentrations for either oral\r\ncontraceptive component. No substantive changes in oral contraceptive pharmacokinetics occurred when oral\r\ncontraceptive was administered 1 hour before exenatide. Single-dose oral contraceptive administration 30 minutes\r\nafter exenatide resulted in mean (90% CI) Cmax reductions of 46% (42-51%) and 41% (35-47%) for EE and LV,\r\nrespectively. Repeated daily oral contraceptive administration 30 minutes after exenatide resulted in Cmax\r\nreductions of 45% (40-50%) and 27% (21-33%) for EE and LV, respectively. Peak oral contraceptive concentrations\r\nwere delayed approximately 3 to 4 hours. Mild-to-moderate nausea and vomiting were the most common adverse\r\nevents observed during the trial.\r\nConclusions: The observed reduction in Cmax is likely of limited importance given the unaltered oral contraceptive\r\nbioavailability and trough concentrations; however, for oral medications that are dependent on threshold\r\nconcentrations for efficacy, such as contraceptives and antibiotics, patients should be advised to take those drugs\r\nat least 1 hour before exenatide injection....
We conducted a performance assessment study for a new sustained-release\r\ncapsule including starch-sponge matrix (SSM). The SSM, which is a support\r\nmedium for drug release, was made from 2.5% cornstarch glue by means of\r\nfreezing dry method. The SSM capsule was applied for nifedipine (NFP), a\r\ncalcium channel blocker, and evaluated pharmacokinetic and\r\npharmacodynamic (PK/PD) profiles of NFP after intraduodenal\r\nadministration of SSM capsules including 2.5 or 5.0 mg of NFP per capsule\r\nto rats. Plasma NFP concentrations from the SSM capsules showed dosedependent\r\nincreases with a Michaelis-Menten like behavior over 360 minutes\r\nafter intraduodenal administration. The values of area under the\r\nconcentration vs. time curve from time zero to 360 min (AUC0-360) of NFP\r\ndeclined in making SSM capsules as compared to control capsules due to a\r\nsimple physical mixture of NFP and cornstarch, but the values of mean\r\nresidence time (MRT0-360) extended and abidingness of SSM capsules were\r\nadmitted with dose-dependent manner. As for a PD parameter, the mean\r\narterial blood pressure (mABP) derived from the SSM capsules showed\r\n15~20% decrease of baseline within 120min after intraduodenal\r\nadministration, and thereafter the mABP in 2.5 mg SSM capsule was\r\ngradually recovered, while a relatively smooth and even change was found in\r\nthe mABP at 5.0 mg SSM capsule. The relationships between plasma NFP\r\nconcentration and sampling-time corresponding mABP after intraduodenal\r\nadministration of SSM capsules showed no rapid change in the mABP,\r\nindicating that a sustained-release mechanism due to the SSM functions\r\nsufficiently to avoid a fluctuating blood pressure accompanied by going up\r\nand down of plasma levels of NFP. The SSM capsules exhibited a sustainedrelease\r\npharmacokinetics of NFP, and made the fluctuation range with blood\r\npressure small compared to the physical mixture preparations. Thus, it was\r\nevidenced that the SSM capsule is useful device to provide a sustainedrelease\r\nsystems and optimal therapeutic efficacy of drugs....
Objectives. Evaluation of pharmacokinetics and pharmacodynamics of darunavir and etravirine among HIV-1ââ?¬â??infected, treatmentexperienced\r\nadults from GRACE, by sex and race.Methods. Patients received darunavir/ritonavir 600/100mg twice daily plus other\r\nantiretrovirals, which could include etravirine 200mg twice daily. Population pharmacokinetics for darunavir and etravirine were\r\ndetermined over 48 weeks and relationships assessed with virologic response and safety. Rich sampling for darunavir, etravirine,\r\nand ritonavir was collected in a substudy at weeks 4, 24, and 48. Results. Pharmacokinetics were estimated in 376 patients for\r\ndarunavir and 190 patients for etravirine. Median darunavir AUC12h and C0h were 60,642ngÃ?·h/mL and 3624ng/mL, respectively;\r\nand for etravirine were 4183ng Ã?· h/mL and 280ng/mL, respectively. There were no differences in darunavir or etravirine AUC12h or\r\nC0h by sex or race. Age, body weight, or use of etravirine did not affect darunavir exposure. No relationships were seen between\r\ndarunavir pharmacokinetics and efficacy or safety. Patients with etravirine exposure in the lowest quartile generally had lower\r\nresponse rates. Rich sampling showed no time-dependent relationship for darunavir, etravirine, or ritonavir exposure over 48\r\nweeks. Conclusions. Population pharmacokinetics showed no relevant differences in darunavir or etravirine exposure by assessed\r\ncovariates. Lower etravirine exposures were associated with lower response rates....
Background: Vascular endothelial growth factor (VEGF) is a potent regulator of angiogenesis, and its role in cancer\r\nbiology has been widely studied. Many cancer therapies target angiogenesis, with a focus being on VEGF-mediated\r\nsignaling such as antibodies to VEGF. However, it is difficult to predict the effects of VEGF-neutralizing agents. We\r\nhave developed a whole-body model of VEGF kinetics and transport under pathological conditions (in the\r\npresence of breast tumor). The model includes two major VEGF isoforms VEGF121 and VEGF165, receptors VEGFR1,\r\nVEGFR2 and co-receptors Neuropilin-1 and Neuropilin-2. We have added receptors on parenchymal cells (muscle\r\nfibers and tumor cells), and incorporated experimental data for the cell surface density of receptors on the\r\nendothelial cells, myocytes, and tumor cells. The model is applied to investigate the action of VEGF-neutralizing\r\nagents (called ââ?¬Å?anti-VEGFââ?¬Â) in the treatment of cancer.\r\nResults: Through a sensitivity study, we examine how model parameters influence the level of free VEGF in the\r\ntumor, a measure of the response to VEGF-neutralizing drugs. We investigate the effects of systemic properties\r\nsuch as microvascular permeability and lymphatic flow, and of drug characteristics such as the clearance rate and\r\nbinding affinity. We predict that increasing microvascular permeability in the tumor above 10-5 cm/s elicits the\r\nundesired effect of increasing tumor interstitial VEGF concentration beyond even the baseline level. We also\r\nexamine the impact of the tumor microenvironment, including receptor expression and internalization, as well as\r\nVEGF secretion. We find that following anti-VEGF treatment, the concentration of free VEGF in the tumor can vary\r\nbetween 7 and 233 pM, with a dependence on both the density of VEGF receptors and co-receptors and the rate\r\nof neuropilin internalization on tumor cells. Finally, we predict that free VEGF in the tumor is reduced following\r\nanti-VEGF treatment when VEGF121 comprises at least 25% of the VEGF secreted by tumor cells.\r\nConclusions: This study explores the optimal drug characteristics required for an anti-VEGF agent to have a\r\ntherapeutic effect and the tumor-specific properties that influence the response to therapy. Our model provides a\r\nframework for investigating the use of VEGF-neutralizing drugs for personalized medicine treatment strategies....
Background: Nephropathic cystinosis is an autosomal recessive disorder resulting in an impaired transport of\r\ncystine trough the lysosomal membrane causing an accumulation of free cystine in lysosomes. The only specific\r\ntreatment for nephropathic cystinosis is cysteamine bitartrate. This study was aimed to describe the relationship\r\nbetween cysteamine plasma concentrations and white blood cell cystine levels, and to simulate an optimized\r\nadministration scheme to improve the management of patients with cystinosis.\r\nMethods: Cysteamine and cystine concentrations were measured in 69 nephropathic cystinosis patients. A total of\r\n250 cysteamine plasma concentrations and 243 intracellular cystine concentrations were used to perform a\r\npopulation pharmacokinetic and pharmacodynamic analysis. An optimized administration scheme was simulated in\r\norder to maintain cystine levels below 1 nmol half-cystine/mg of protein and to investigate the possibility of\r\nadministrating the treatment less than 4 times a day (QID, recommended). The current dosing recommendations\r\nare 1.3 g/m2/day for less than 50 kg BW and 2 g/day thereafter; the maximum dose should not exceed 1.95 g/m2/\r\nday.\r\nResults: Cysteamine concentrations were satisfactorily described by a one-compartment model. Parameter\r\nestimates were standardized for a mean standard bodyweight using an allometric model. WBC cystine levels were\r\nadequately described by an indirect response model where the first-order removal rate constant is stimulated by\r\nthe cysteamine concentrations.\r\nConclusions: According to simulations, in order to increase the percentage of patient with cystine levels below 1\r\nnmol half-cystine/mg of protein, the current dosages could be changed as follows: 80 mg/kg/day (QID) from 10 to\r\n17 kg, 70 mg/kg/day (QID) from 17 to 25 kg, 60 mg/kg/day (QID) from 25 to 40 kg and 50 mg/kg/day (QID) from\r\n40 to 70 kg (these dosages remain under the maximum recommended dose). However an 8-hourly daily treatment\r\n(TID) did not provide acceptable cystine levels and should not be proposed...
Pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulation can be an invaluable tool for use in making crucial decisions in drug development and clinical settings, including those pertaining to compound selection, dose selection, study design, and patient population, all of which can impact the cost of development and treatment. Clinical PK-PD modeling and simulation of antimicrobial agents are possible because minimum inhibitory concentration (MIC) values can be easily measured in the hospital laboratory. However, no such easily measured clinical markers are available for many other types of drugs. In this point of view, we thought that the proteomics approach may be available for find the direct PD parameter such as drug specific biomarker. Many reports also suggest that proteomics is a promising tool in the search for drug-specific biomarker proteins that could be used in PK-PD modeling and simulation. Thus, by enabling examination of drug-induced changes in the expression of specific biomarker proteins, proteomic data could be used in PD analyses in much the same way that MICs are used in PD evaluations of antimicrobial agents....
Pharmacokinetics is a first, but essential step to improve population-tailored postoperative analgesia, also after Caesarean delivery.\r\nWe therefore aimed to quantify the impact of caesarean delivery on the pharmacokinetics of intravenous (iv) paracetamol (2 g,\r\nsingle dose) and iv ketorolac tromethamine (30 mg, single dose) in 2 cohorts eachof 8 women at caesarean delivery and to\r\ncompare these findings with postpartum to quantify intrapatient changes.We documented a higher median paracetamol clearance\r\nat delivery when compared to 10ââ?¬â??15 weeks postpartum (11.7 to 6.4 L/hÃ?·m2, P < 0.01), even after correction for weight-related\r\nchanges. Similar conclusions were drawn for ketorolac: median clearance was higher at delivery with a subsequent decrease (2.03\r\nto 1.43 L/hÃ?·m2, P < 0.05) in postpartum (17ââ?¬â??23 weeks). These differences likely reflect pregnancy- and caesarean-delivery-related\r\nchanges in drug disposition. Moreover, postpartum paracetamol clearance was significantly lower when compared to estimates\r\npublished in healthy young volunteers (6.4 versus 9.6 L/hÃ?·m2), while this was not the case for ketorolac (1.43 versus 1.48 L/hÃ?·m2).\r\nThis suggests that postpartum is another specific status in young women that merits focused, compound-specific pharmacokinetic\r\nevaluation....
Loading....