Current Issue : October - December Volume : 2014 Issue Number : 4 Articles : 5 Articles
Background: Meropenem is a carbapenem antibiotic commonly used in critically ill patients to treat severe\ninfections. The available pharmacokinetic (PK) data has been mostly obtained from healthy volunteers as well as\nfrom clinical studies addressing selected populations, often excluding the elderly and also patients with renal\nfailure. Our aim was to study PK of meropenem in a broader population of septic critically ill patients.\nMethods: We characterized the PK of meropenem in 15 critically ill patients during the first 36 hrs of therapy.\nAditionally, whenever possible, we collected a second set of late plasma samples after 5 days of therapy to evaluate\nPK intra-patient variability and its correlation with clinical course.\nPatients received meropenem (1 g every 8 hrs IV). Drug plasma profiles were determined by high-performance\nliquid chromatography. The PK of meropenem was characterized and compared with clinical parameters.\nResults: Fifteen septic critically ill patients (8 male, median age 73 yrs) were included. The geometric mean of the\nvolume of distribution at the steady state (Vss)/weight was 0.20 (0.15-0.27) L/kg. No correlation of Vss/weight with\nseverity or comorbidity scores was found. However the Sequential Organ Failure Assessment score correlated with\nthe Vss/weight of the peripheral compartment (r2 = 0.55, p = 0.021). The median meropenem clearance (Cl) was 73.3\n(45ââ?¬â??120) mL/min correlated with the creatinine (Cr) Cl (r2 = 0.35, p = 0.033).\nAfter 5 days (N = 7) although Vss remained stable, a decrease in the proportion of the peripheral compartment (Vss2)\nwas found, from 61.3 (42.5-88.5)% to 51.7 (36.6-73.1)%. No drug accumulation was noted.\nConclusions: In this cohort of septic, unselected, critically ill patients, large meropenem PK heterogeneity was\nnoted, although neither underdosing nor accumulation was found. However, Cr Cl correlated to meropenem Cl\nand the Vss2 decreased with patientââ?¬â?¢s improvement....
Purpose: To overcome cytochrome P450 2D6 (CYP2D6) mediated tamoxifen resistance in postmenopausal early\nbreast cancer, CYP2D6 phenotype-adjusted tamoxifen dosing in patients with impaired CYP2D6 metabolism and/or\nthe application of endoxifen, the most potent tamoxifen metabolite, are alternative treatment options. To elucidate\nboth strategies comprehensively we used a physiologically-based pharmacokinetic (PBPK) modeling approach.\nMethods: Firstly simulation of increasing tamoxifen dosages was performed by a virtual clinical trial including\npopulations of CYP2D6 poor (PM), intermediate (IM) and extensive metabolizers (EM) (N = 8,000). Secondly we\nperformed PBPK-simulations under consideration of tamoxifen use plus concomitant increasing dosages of\nendoxifen (N = 7,000).\nResults: Our virtual study demonstrates that dose escalation of tamoxifen in IMs resulted in endoxifen steady-state\nplasma concentrations similar to CYP2D6 EMs whereas PMs did not reach EM endoxifen levels. Steady-state plasma\nconcentrations of tamoxifen, N-desmethyl-tamoxifen, 4-hydroxy-tamoxifen and endoxifen were similar in CYP2D6\nIMs and PMs versus EMs using once daily dosing of 20 mg tamoxifen and concomitant CYP2D6 phenotype-adjusted\nendoxifen dosing in IMs and PMs (1 mg/d and 3 mg/d, respectively).\nConclusion: In conclusion, we suggest that co-administration of endoxifen in tamoxifen treated early breast cancer\nwomen with impaired CYP2D6 metabolism is a promising alternative to reach plasma concentrations comparable\nto CYP2D6 EM patients....
Purpose: Gadofosveset is a Gd-based contrast agent used for magnetic resonance imaging (MRI). Gadolinium kinetic\ndistribution models are implemented in T1-weighted dynamic contrast-enhanced perfusion MRI for characterization\nof lesion sites in the body. Physiology changes in a disease state potentially can influence the pharmacokinetics of\ndrugs and to this respect modify the distribution properties of contrast agents. This work focuses on the in silico\nmodelling of pharmacokinetic properties of gadofosveset in different population groups through the application of\nphysiologically-based pharmacokinetic models (PBPK) embedded in Simcyp�® population pharmacokinetics platform.\nMethods: Physicochemical and pharmacokinetic properties of gadofosveset were introduced into Simcyp�® simulator\nplatform and a min-PBPK model was applied. In silico clinical trials were generated simulating the administration of\nthe recommended dose for the contrast agent (i.v., 30 mg/kg) in population cohorts of healthy volunteers, obese,\nrenal and liver impairment, and in a generated virtual oncology population. Results were evaluated regarding basic\npharmacokinetic parameters of Cmax, AUC and systemic CL and differences were assessed through ANOVA and\nestimation of ratio of geometric mean between healthy volunteers and the other population groups.\nResults: Simcyp�® predicted a mean Cmax = 551.60 mg/l, a mean AUC = 4079.12 mg/L*h and a mean systemic\nCL = 0.56 L/h for the virtual population of healthy volunteers. Obese population showed a modulation in Cmax and\nCL, attributed to increased administered dose. In renal and liver impairment cohorts a significant modulation in\nCmax, AUC and CL of gadofosveset is predicted. Oncology population exhibited statistical significant differences\nregarding AUC when compared with healthy volunteers.\nConclusions: This work employed Simcyp�® population pharmacokinetics platform in order to compute gadofosvesetâ��s\npharmacokinetic profiles through PBPK models and in silico clinical trials and evaluate possible differences between\npopulation groups. The approach showed promising results that could provide new insights regarding administration of\ncontrast agents in special population cohorts. In silico pharmacokinetics could further be used for evaluating of possible\ntoxicity, interpretation of MRI PK image maps and development of novel contrast agents....
Nifedipine-solid-lipid nanoparticles lyophilized with trehalose (NI-SLN-Tre) were prepared by the\nhigh pressure homogenization of a roll mixture consisting of NI and hydrogenated soybean phosphatidylcholine\nand dipalmitoylphosphatidylglycerol, and in vivo pharmacokinetic properties and\ntheir hemocompatibility were determined and compared with those of a NI-SLN suspension. The\nresulting pharmacokinetic data demonstrated that although no significant differences were observed\nbetween the time of peak concentration (Tmax), peak plasma concentration (Cmax), and the\narea under the curve (AUC o??) values of both administrated samples, NI tended to be absorbed to\na much greater extent from the lyophilized NI-SLN-Tre suspensions because of the enhanced solvation\nof NI-SLN in gastrointestinal fluid, derived from formation of hydrogen bonds between the\npolar head groups of the lipids and the O-H groups of trehalose. Furthermore, the results of a hemolysis\nassay revealed that the NI-SLN and NI-SLN-Tre suspensions showed good hemocompatibility\nproperties with hemolysis values of less than 5%. Taken together, the results of this study\ndemonstrate that NI-SLN-Tre exhibits suitable pharmacokinetic properties and good biocompatibility....
Caffeine is a commonly ingested psychoactive substance which affects alertness and cognition. A\nclinical study was conducted to determine the effect of orally ingested caffeine on visual analogue\nscale (VAS) responses in healthy, moderate caffeine-consuming volunteers through the use of\npopulation pharmacokinetic-pharmacodynamic (PK-PD) modeling. Twelve subjects were recruited\nfor a three-period cross-over study which utilized caffeine containing beverages. Each visit\nincluded 8-hour blood plasma and VAS response collection for PK and PD assessment respectively.\nThe VAS used in the study, also called the caffeine analog scale, has been previously validated for\ncaffeine. Population PK-PD modeling was conducted with NONMEM 7.2. Simultaneous and sequential\nmodeling of PK-PD was attempted. Final model selection was based on parameter estimate\nprecision, diagnostic plots, and visual predictive check (VPC) plots. Results showed that a\none-compartment open model with first-order absorption and elimination best described the\npharmacokinetics of caffeine. Sequential PK-PD modeling was successful and an effect compartment\nmodel with linear slope and baseline parameter best described caffeine pharmacodynamics.\nDiagnostic plots showed no major bias and VPC plots showed agreement between observations\nand predictions. The model was able to link VAS responses to caffeine concentration in healthy\nvolunteers and may be useful in clinical trial simulations and design....
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