Current Issue : October - December Volume : 2015 Issue Number : 4 Articles : 6 Articles
Controlled release (CR) formulations are usually designed to achieve similar exposure (AUC) levels as the\nmarketed immediate release (IR) formulation. However, the AUC is often lower following CR compared to\nIR formulations. There are a few exceptions when the CR formulations have shown higher AUC. This study\ninvestigated the impact of CR formulations on oral drug absorption and CYP3A4-mediated gut wall metabolism.\nA review of the current literature on relative bioavailability (Frel) between CR and IR formulations of\nCYP3A substrates was conducted. This was followed by a systematic analysis to assess the impact of the\nrelease characteristics and the drug-specific factors (including metabolism and permeability) on oral bioavailability\nemploying a physiologically-based pharmacokinetic (PBPK) modelling and simulation\napproach. From the literature review, only three CYP3A4 substrates showed higher Frel when formulated\nas CR. Several scenarios were investigated using the PBPK approach; in most of them, the oral absorption of\nCR formulations was lower as compared to the IR formulations. However, for highly permeable compounds\nthat were CYP3A4 substrates the reduction in absorption was compensated by an increase in\nthe fraction that escapes from first pass metabolism in the gut wall (FG), where the magnitude was dependent\non CYP3A4 affinity. The systematic simulations of various interplays between different parameters\ndemonstrated that BCS class 1 highly-cleared CYP3A4 substrates can display up to 220% higher relative\nbioavailability when formulated as CR compared to IR, in agreement with the observed data collected from\nthe literature. The results and methodology of this study can be employed during the formulation development\nprocess in order to optimize drug absorption, especially for CYP3A4 substrates....
This studymeasures the curcumin concentration in rat plasma by liquid chromatography and investigates the changes in the glucose\ntolerance and insulin sensitivity of streptozotocin-diabetic rats treated with curcumin-enriched yoghurt. The analytical method for\ncurcumin detection was linear from 10 to 500 ng/mL. The ????max and the time to reach ????max (????max) of curcumin in plasma were\n3.14 �± 0.9 ????g/mL and 5 minutes (10mg/kg, i.v.) and 0.06 �± 0.01 ????g/mL and 14 minutes (500mg/kg, p.o.). The elimination half-time\nwas 8.64 �± 2.31 (i.v.) and 32.70 �± 12.92 (p.o.) minutes. The oral bioavailability was about 0.47%. Changes in the glucose tolerance\nand insulin sensitivity were investigated in four groups: normal and diabetic rats treated with yoghurt (NYOG and DYOG, resp.)\nand treated with 90mg/kg/day curcumin incorporated in yoghurt (NC90 and DC90, resp.). After 15 days of treatment, the glucose\ntolerance and the insulin sensitivity were significantly improved in DC90 rats in comparison with DYOG, which can be associated\nwith an increase in the AKT phosphorylation levels and GLUT4 translocation in skeletal muscles. These findings can explain, at\nleast in part, the benefits of curcumin-enriched yoghurt to diabetes and substantiate evidences for the curcumin metabolite(s) as\nbeing responsible for the antidiabetic activity....
Nonadherence to prescribed medication is a\ncommon barrier to effective treatment, and current options\nto determine adherence are limited. This study describes\ndevelopment of an aggregate adherence measure based on\npopulation pharmacokinetics (PK), and its comparison to a\nsubjective questionnaire, the Morisky 8-item medication\nadherence scale (MMAS8), in a trial of psychiatric patients\non stable doses of oral aripiprazole. A comprehensive\nmodel was first built using plasma drug concentration data\nfrom 24 clinical studies comprising 448 patients with over\n13,500 observations. Application of this model to independent\npatient profiles for a given drug-dosing regimen\nwere used to generate the primary aggregate adherence\nmetric, a ratio of observed versus expected plasma exposures\nat steady-state. Although the metric is capable of\ncomparing relative adherence across groups, simulations\nshowed that the metric is not sufficiently sensitive as an\nindividual diagnostic in all cases. There were no trends\nobserved between results from calculated aggregate adherence\nmetrics and total scores from MMAS8 in a single visit\nclinical trial of 47 patients with bipolar 1 disorder or\nschizophrenia who were on stable doses of aripiprazole,\nalthough a strong association was observed for one\nMMAS8 question. The range of the metric calculated for\npatients was between 0.16 and 3.15. The described\napproach of a novel ââ?¬Ë?ââ?¬Ë?reverseââ?¬â?¢Ã¢â?¬â?¢ application of population\nPK to quantify relative adherence with an aggregate measure\nmay be influential for both clinical and pharmacometric\ncommunities....
The present study was performed to investigate the effect of quetiapine on the pharmacokinetics of pioglitazone. The blood samples were collected and analyzed for estimation of pioglitazone pharmacokinetics. The quetiapine alters the pharmacokinetics of pioglitazone. Quetiapine appears to produce pharmacokinetic interaction with pioglitazone. The increase in pioglitazone concentration might be due to interaction of quetiapine at metabolic enzyme CYP3A4. Increase in AUC indicates the raised bioavailability in presence of quetiapine. The results of present study indicated that quetiapine has influence on pharmacokinetics of pioglitazone. The concomitant administration of pioglitazone and quetiapine should be used in caution....
The purpose of this work was to develop a\nconsolidated set of guiding principles for reporting of\npopulation pharmacokinetic (PK) analyses based on input\nfrom a survey of practitioners as well as discussions between\nindustry, consulting and regulatory scientists. The\nsurvey found that identification of population covariate\neffects on drug exposure and support for dose selection\n(where population PK frequently serves as preparatory\nanalysis to exposureââ?¬â??response modeling) are the main areas\nof influence for population PK analysis. The proposed\nguidelines consider two main purposes of population PK\nreports (1) to present key analysis findings and their impact\non drug development decisions, and (2) as documentation\nof the analysis methods for the dual purpose of enabling\nreview of the analysis and facilitating future use of the\nmodels. This work also identified two main audiences for\nthe reports: (1) a technically competent group responsible\nfor in-depth review of the data, methodology, and results,\nand (2) a scientifically literate, but not technically adept\ngroup, whose main interest is in the implications of the\nanalysis for the broader drug development program. We\nrecommend a generalized question-based approach with\nsix questions that need to be addressed throughout the report.\nWe recommend eight sections (Synopsis, Introduction,\nData, Methods, Results, Discussion, Conclusions,\nAppendix) with suggestions for the target audience and\nlevel of detail for each section. A section providing general\nexpectations regarding population PK reporting from a\nregulatory perspective is also included. We consider this an\nimportant step towards industrialization of the field of\npharmacometrics such that non-technical audience also\nunderstands the role of pharmacometrics analyses in decision\nmaking. Population PK reports were chosen as representative\nreports to derive these recommendations;\nhowever, the guiding principles presented here are applicable\nfor all pharmacometric reports including PKPD and\nsimulation reports....
Rationale Data on safety, pharmacodynamics, and pharmacokinetics\nof tetrahydrocannabinol (THC) are lacking in dementia\npatients.\nMethods In this randomized, double-blind, placebo-controlled,\ncrossover trial, we evaluated the safety, pharmacodynamics,\nand pharmacokinetics of THC in ten patients with\ndementia (mean age 77.3Ã?±5.6). For 12 weeks, participants\nrandomly received oral THC (weeks 1ââ?¬â??6, 0.75 mg; weeks\n7ââ?¬â??12, 1.5 mg) or placebo twice daily for 3 days, separated\nby a 4-day washout period.\nResults Only 6 of the 98 reported adverse events were related\nto THC. Visual analog scale (VAS) feeling high, VAS external\nperception, body sway-eyes-open, and diastolic blood pressure\nwere not significantly different with THC. After the\n0.75-mg dose, VAS internal perception (0.025 units; 95 %\nCI 0.010ââ?¬â??0.040) and heart rate (2 beats/min; 95 % CI 0.4ââ?¬â??\n3.8) increased significantly. Body sway-eyes-closed increased\nonly after 1.5 mg (0.59Ã?°/s; 95%CI 0.13ââ?¬â??1.06). Systolic blood\npressure changed significantly after both doses of THC\n(0.75 mg, ?7 mmHg, 95 % CI ?11.4, ?3.0; 1.5 mg,\n5 mmHg, 95%CI 1.0ââ?¬â??9.2). The median Tmax was 1ââ?¬â??2 h, with\nTHC pharmacokinetics increasing linearly with increasing\ndose, with wide interindividual variability (CV% up to\n140 %). The mean Cmax (ng/mL) after the first dose (0ââ?¬â??6 h)\nwas 0.41 (0.18ââ?¬â??0.90) for the 0.75-mg dose and 1.01 (0.53ââ?¬â??\n1.92) for the 1.5-mg dose. After the second dose (6ââ?¬â??24 h), the\nCmax was 0.50 (0.27ââ?¬â??0.92) and 0.98 (0.46ââ?¬â??2.06), respectively.\nConclusions THC was rapidly absorbed and had dose-linear\npharmacokinetics with considerable interindividual variation.\nPharmacodynamic effects, including adverse events, were minor.\nFurther studies are warranted to evaluate the pharmacodynamics\nand efficacy of higher THC doses in older persons\nwith dementia....
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