Current Issue : April - June Volume : 2015 Issue Number : 2 Articles : 6 Articles
KAF156 belongs to a new class of antimalarial, the imidazolopiperazines, and is currently in clinical development for the treatment\nof uncomplicated malaria. This first-in-human, single- and multiple-ascending-dose study in 70 healthy male volunteers\ndetermined the maximum oral dose of KAF156 tolerated by healthy adults and derived pharmacokinetic data (including preliminary\nfood effect) to enable dose calculations for malaria patients. KAF156 was studied in single-dose cohorts (10 to 1,200 mg,\nincluding one 400-mg food effect cohort (4 to 10 subjects/cohort), and in multiple-dose cohorts (60 to 600 mg once daily for 3\ndays; 8 subjects/cohort). The follow-up period was 6 to 14 days after the last dose. KAF156 was tolerated, with self-limited mild\nto moderate gastrointestinal and neurological adverse events. In treated subjects after single doses, headache (n4; 11.1%),\ndiarrhea (n3; 8.3%), dizziness (n3; 8.3%), and abdominal pain (n2; 5.6%) were the most common adverse events. Headache\n(n4; 16.7%), nausea (n3; 12.5%), upper respiratory tract infection (n3; 12.5%), and dizziness (n2; 8.3%) were the\nmost common adverse events following multiple doses. KAF156 time to maximum concentration (Tmax) was between 1.0 and 6.0\nh. Both the area under the concentration-time curve (AUC) and maximum concentration (Cmax) increased more than dose-proportionally\nin both single- and multiple-ascending-dose cohorts (terminal half-life, 42.5 to 70.7 h). There was no significant accumulation\nover 3-day repeated administration. The extent of absorption was not significantly affected by food at a single dose\nof 400 mg, while mean Cmax decreased from 778 ng/ml to 627 ng/ml and Tmax was delayed from a median of 3.0 h under fasting\nconditions to 6.0 h under fed conditions. Renal elimination is a minor route....
The effect of lovastatin on pharmacokinetics of pioglitazone has been carried out in albino rats. The rats were divided into 5 groups. Group 1: Normal control rats: Treated with vehicle (1% DMSO), Group 2: Diabetic control rats: Diabetes induction and no treatment, Group 3: Treatment Group: Diabetic rats treated with oral administration of pioglitazone (3 mg/kg), Group 4: Treatment Group: Diabetic rats treated with combination of lovastatin (2 mg/kg) and pioglitazone (1.5 mg/kg), Group 5: Treatment Group: Diabetic rats treated with combination of lovastatin (2 mg/kg) and pioglitazone (3 mg/kg).Treatment was continued for 7 days and on the last day blood was collected through retro orbital puncture. The pharmacokinetic parameters like half life, area under curve, clearance, peak time and peak concentration of pioglitazone, with and without combination of lovastatin treatment were determined. The increase in pioglitazone concentration might be due to interaction of lovastatin at metabolic enzyme (Cytochrome P450 3A4). Increase in area under curve of pioglitazone indicates the raised bioavailability in presence of lovastatin. The results of the present study indicated that lovastatin has influence on pharmacokinetics of pioglitazone. The concomitant administration of pioglitazone and lovastatin should be used in caution....
Poor response to tuberculosis (TB) therapy might be attributable to subtherapeutic levels in drug-compliant patients. Pharmacokinetic\n(PK) parameters can be affected by several factors, such as comorbidities or the interaction of TB drugs with food. This\nstudy aimed to determine the PK of isoniazid (INH) in a Peruvian TB population under observed daily and twice-weekly (i.e.,\nbiweekly) therapy. Isoniazid levels were analyzed at 2 and 6 h after drug intake using liquid chromatography mass spectrometric\nmethods. A total of 107 recruited patients had available PK data; of these 107 patients, 42.1% received biweekly isoniazid. The\nmean biweekly dose (12.8 mg/kg of body weight/day) was significantly lower than the nominal dose of 15 mg/kg/day (P<0.001),\nand this effect was particularly marked in patients with concurrent diabetes and in males. The median maximum plasma concentration\n(Cmax) and area under the concentration-time curve from 0 to 6 h (AUC0ââ?¬â??6) were 2.77 mg/liter and 9.71 mgÃ?·h/liter,\nrespectively, for daily administration and 8.74 mg/liter and 37.8 mgÃ?·h/liter, respectively, for biweekly administration. There were\nno differences in the Cmax with respect to gender, diabetes mellitus (DM) status, or HIV status. Food was weakly associated with\nlower levels of isoniazid during the continuation phase. Overall, 34% of patients during the intensive phase and 33.3% during\nthe continuation phase did not reach the Cmax reference value. However, low levels of INH were not associated with poorer clinical\noutcomes. In our population, INH exposure was affected by weight-adjusted dose and by food, but comorbidities did not indicate\nany effect on PK. We were unable to demonstrate a clear relationship between the Cmax and treatment outcome in this\ndata set. Twice-weekly weight-adjusted dosing of INH appears to be quite robust with respect to important potentially influential\npatient factors under program conditions....
Dihydroartemisinin-piperaquine is an artemisinin-based combination treatment (ACT) recommended by theWHOfor uncomplicated\nPlasmodium falciparum malaria, and it is being used increasingly for resistant vivax malaria where combination with\nprimaquine is required for radical cure. TheWHOrecently reinforced its recommendations to add a single dose of primaquine\nto ACTs to reduce P. falciparum transmission in low-transmission settings. The pharmacokinetics of primaquine and dihydroartemisinin-\npiperaquine were evaluated in 16 healthy Thai adult volunteers in a randomized crossover study. Volunteers were\nrandomized to two groups of three sequential hospital admissions to receive 30 mg (base) primaquine, 3 tablets of dihydroartemisinin-\npiperaquine (120/960 mg), and the drugs together at the same doses. Blood sampling was performed over 3 days following\nprimaquine and 36 days following dihydroartemisinin-piperaquine dosing. Pharmacokinetic assessment was done with a\nnoncompartmental approach. The drugs were well tolerated. There were no statistically significant differences in dihydroartemisinin\nand piperaquine pharmacokinetics with or without primaquine. Dihydroartemisinin-piperaquine coadministration\nsignificantly increased plasma primaquine levels; geometric mean ratios (90% confidence interval [CI]) of primaquine combined\nversus primaquine alone for maximum concentration (Cmax), area under the concentration-time curve from 0 h to the end of the\nstudy (AUC0ââ?¬â??last), and area under the concentration-time curve from 0 h to infinity (AUC0ââ?¬â??) were 148% (117 to 187%), 129%\n(103 to 163%), and 128% (102 to 161%), respectively. This interaction is similar to that described recently with chloroquine and\nmay result in an enhanced radical curative effect. (This study has been registered at ClinicalTrials.gov under registration no.\nNCT01525511.)...
Despite the growing number of cancer cases\nand cancer surgeries around the world, the pharmacokinetics\n(PK) and pharmacodynamics (PD) of anesthetics\nused in this population are poorly understood. Patients\noperated due to cancer are usually in severe state and often\nrequire chemotherapy. It might affect the PK/PD of drugs\nused in this population. Therefore, in this study we\nexplored the PK/PD of propofol in cancer patients having a\nmajor lung surgery. 23 patients that underwent a propofolââ?¬â??\nfentanyl total intravenous anesthesia were included in the\nanalysis. A large set of demographic, biochemical and\nhemodynamic parameters was collected for the purpose of\ncovariate analysis. Nonlinear mixed effect modeling in\nNONMEM was used to analyze the collected data. A threecompartment\nmodel was sufficient to describe PK of propofol.\nThe anesthetic effect (AAI index) was linked to the\npropofol effect site concentrations through a sigmoidal\nEmax model. A slightly higher value of clearance, a lower\nvalue of distribution clearance, and a decreased volume of\nperipheral compartment were observed in our patients, as\ncompared with the literature values reported for healthy\nvolunteers by Schnider et al. and by Eleveld et al. Despite\nthese differences, both models led to a clinically insignificant\nbias of -8 and -1 % in concentration predictions, as\nreflected by the median performance error. The Ce50 and\npropofol biophase concentration at the time of postoperative\norientation were low and equaled 1.40 and 1.13 mg/L.\nThe population PK/PD model was proposed for cancer\npatients undergoing a major lung surgery. The large body\nof studied covariates did not affect PK/PD of propofol\nsignificantly. The modification of propofol dosage in the\ngroup of patients under study is not necessary when TCIguided\nadministration of propofol by means of the Schnider\nmodel is used....
A comparative pharmacokinetic study of berberine and palmatine after oral administration of Rhizoma Coptidis extract (96mg/kg,\ncontaining berberine 22mg/kg and palmatine 5mg/kg based on body weight) was performed in normal and postinflammation\nirritable bowel syndrome (PI-IBS) rats, induced by in tracolonic instillation of acetic acid and restraint stress. Quantification\nof berberine and palmatine in rat plasma was achieved by using a sensitive and rapid UPLC-MS/MS method. Plasma samples\nwere collected at 13 different time points and the pharmacokinetic parameters were analyzed by WinNonlin software. The\nsignificant differences in the pharmacokinetic behaviors, such as ????max, AUC(0ââ?¬â??????), ????????/????, and CL/????, of berberine and palmatine\nwere found between normal and PI-IBS model rats. The results indicated that PI-IBS pathological conditions in rats could alter the\npharmacokinetic behavior of drug. Preclinical pharmacokinetic studies are usually carried out on healthy animals. However, we\nshould pay more attention to the fact that the change of pharmacokinetic behavior plays an important role on efficacy. It is essential\nto investigate the pharmacokinetics of the drug in disease status....
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