Current Issue : October - December Volume : 2016 Issue Number : 4 Articles : 6 Articles
The systems which combine the advantages of gastroretentive and pulsatile approaches are urgently needed to enhance drug absorption and allow its delivery at the time necessary to alleviate chronopathological complications. The current work aimed to explore the pharmacokinetics of theophylline anhydrous (THE) following oral administration of THE-loaded core-in-cup tablets and Quibron®-T tablets in six healthy, non-smoking, male volunteers at 100 mg doses. The pharmacokinetic parameters for the two treatments were determined from the plasma concentration time data adopting the non-compartmental module. The maximum drug concentration (Cmax), the time to reach Cmax (Tmax), the mean residence time from zero to infinity (MRT(0– ∞), h), the area under the plasma concentration–time curve up to the last measured sampling time at 24 hour (AUC0–24) and up to infinity (AUC0–∞) were estimated. The results proved that Quibron®-T tablets showed a mean Cmax of 6.55 ng/ml at a median Tmax of 3 h. Statistically significant (P < 0.05) and higher mean Cmax value (9.61 µg/ml) was estimated at a median Tmax of 7 h for THE-loaded core-in-cup tablets. The rapid release of the drug following a TL of 5 hours could prove the pulsatile delivery of THE in human volunteers. This study paves the way for the pulsatile delivery of other sparingly-soluble drugs....
Background: Prolonged intermittent renal replacement therapy (PIRRT) is a growing option to treat acute kidney\ninjury in critically ill patients, but absent pharmacokinetic data challenge optimal drug dosing. Inappropriate\nantibiotic dosing can cause widespread bacterial resistance and decreased antibiotic utility. The purpose of this\nstudy was to evaluate probability of target attainment (PTA) of various ciprofloxacin and levofloxacin regimens in\ncritically ill patients receiving PIRRT, utilizing Monte Carlo simulation (MCS).\nMethods: The models incorporated published body weights and pharmacokinetic parameters (volume of distribution,\nnon-renal clearance, and extraction coefficients) and their associated variability and ranges. Four different PIRRT\neffluent/duration combinations (4 L/h Ã?â?? 10 h or 5 L/h Ã?â?? 8 h in hemodialysis or hemofiltration, respectively) occurring at\nthe beginning or 14-16 h after drug administration were modeled. MCS predicted drug disposition during the first 72 h\nin 5000 virtual patients for each dosing regimen. Desired pharmacodynamic targets to calculate PTA were the\n24-h area under the curve/minimum inhibitory concentration (AUC24h:MIC) of ââ?°Â¥125 and ââ?°Â¥50 for Gram-negative and\nGram-positive infections, respectively. The ââ?¬Å?successfulââ?¬Â doses were the ones with PTA of ~90 % in all PIRRT settings.\nResults: No conventional, FDA-approved regimens attained ~90 % of PTA for Gram-negative infection with\nPseudomonas aeruginosa at the MIC of 1 and 2 mg/L for ciprofloxacin and levofloxacin, respectively. The successful\ndoses (ciprofloxacin 1200 mg loading dose, 800 mg q12h, and levofloxacin 2000 mg loading dose, 1000 mg q24h\npost-PIRRT) greatly exceed the maximum FDA-approved doses. For Gram-positive infections, a levofloxacin 750 mg\nloading dose and 500 mg q24h post-PIRRT successfully attained PTA ~90 % at the MIC of 1 mg/L for Streptococcus\npneumoniae.\nConclusions: Ciprofloxacin and levofloxacin cannot be recommended as empiric monotherapy for serious Gramnegative\ninfections in patients receiving PIRRT due to suboptimal efficacy. This MCS prediction supports rational dosing\ndecisions to treat infected patients receiving PIRRT and should be used until clinical pharmacokinetic trials are\nconducted in this population....
The objective of the present study was to investigate the influence of the encapsulation\nefficiency and size of liposome on the oral bioavailability of griseofulvin-loaded liposomes.\nGriseofulvin-loaded liposomes with desired characteristics were prepared from pro-liposome\nusing various techniques. To study the effect of encapsulation efficiency, three preparations of\ngriseofulvin, namely, griseofulvin aqueous suspension and two griseofulvin-loaded liposomes with\ndifferent amounts of griseofulvin encapsulated [i.e., F1 (32%) and F2(98%)], were administered to\nrats. On the other hand, to study the effect of liposome size, the rats were given three different\ngriseofulvin-loaded liposomes of various sizes, generated via different mechanical dispersion\ntechniques [i.e., FTS (142 nm), MS (357 nm) and NS (813 nm)], but with essentially similar\nencapsulation efficiencies (about 93%). Results indicated that the extent of bioavailability of\ngriseofulvin was improved 1.7ââ?¬â??2.0 times when given in the form of liposomes (F1) compared to\ngriseofulvin suspension. Besides that, there was an approximately two-fold enhancement of the\nextent of bioavailability following administration of griseofulvin-loaded liposomes with higher\nencapsulation efficiency (F2), compared to those of F1. Also, the results showed that the extent of\nbioavailability of liposomal formulations with smaller sizes were higher by approximately three\ntimes compared to liposomal formulation of a larger size. Nevertheless, a further size reduction of\ngriseofulvin-loaded liposome (ââ?°Â¤400 nm) did not promote the uptake or bioavailability of griseofulvin.\nIn conclusion, high drug encapsulation efficiency and small liposome size could enhance the oral\nbioavailability of griseofulvin-loaded liposomes and therefore these two parameters deserve careful\nconsideration during formulation....
Background and Objective A novel tiotropium bromide\nmonodose capsule dry powder inhaler (DPI) formulation\nand device have been developed. The formulation was\nbased on a spray-dried matrix that enhances the\naerosolizaton properties, allowing a less active tiotropium\nmetered dose (13 lg/capsule) while maintaining the same\ndelivered dose (10 lg/actuation). This study describes the\npharmacokinetic bioequivalence to the reference product.\nMethods This randomized, two-stage, crossover, semi-replicate\n(three-way) study was performed in healthy volunteers. In\neach study period, subjects received a single dose of two\ncapsules (20 lg delivered dose) of the study medication, separated\nby a 14-day washout period: tiotropium 10 lg delivered\ndose (Laboratorios Liconsa, Spain) and Spiriva HandiHaler\n(Boehringer Ingelheim Pharma GmbH & Co KG, Germany).\nBlood samples were obtained up to 48 h post-dose to evaluate\nthe comparative bioavailability. Tiotropium was measured in\nplasma by means of dual stage liquidââ?¬â??liquid extraction followed\nby the two-dimensional ultra-high performance liquid\nchromatography sensitive sub-pg/mL bioanalytical method.\nThemain pharmacokinetic parameters were maximum plasma\nconcentration (Cmax), area under the concentrationââ?¬â??time curve\n(AUC) from time zero hours to the last observed concentration\nat time t (AUCt), and AUC from time zero hours to 30 min\n(AUC0.5). Bioequivalence was accepted if the 90.20 % confidence\ninterval (CI) for the ratio test/reference of the primary\npharmacokinetic parameters lay within the acceptance range of\n80ââ?¬â??125 %. Safety assessment was a secondary endpoint.\nResults A total of 30 subjects were randomized and bioequivalence\nwas demonstrated for all primary pharmacokinetic\nparameters: Cmax (CI 87.26ââ?¬â??106.60 %), AUCt (CI 101.33ââ?¬â??\n111.64 %), and AUC0.5 (CI 97.95ââ?¬â??113.49 %). Both study\ntreatmentswere well tolerated (four non-serious adverse events\n[AEs] were reported in four subjects: one AE before any product\nadministration, two AEs after test product administration;\nand one AE after reference product administration).\nConclusions Both products containing tiotropium 10 lg\ndelivered-dose DPI were bioequivalent and showed good\ntolerability and a similar safety profile....
Introduction: The pharmacokinetics of nevirapine in paediatric populations are important to\nconsider for those receiving anti-retroviral treatment in resource limited settings. High rate of\nadherence is required to achieve therapeutic success with good record keeping system for\nmonitoring and follow-ups.\nDiscussion: Children up to 2 years old have a higher rate of elimination for nevirapine compared\nto adult population and older children. Elimination rate in children less than 8 years are about twice\nthose in adults. Prescriptions for the drug based on body surface area have been found to be too\ncomplex for use in resource limited settings and calculations based on weight bands are used.\nThough weight bands make drug administration easier the lower weight bands are likely to receive\nsub therapeutic doses when drug is administered especially when adult fixed dose combinations\nare used. Chewable paediatric tablets offer better pharmacokinetic profile compared to liquids or\noral tablets, however availability of such dosage forms remains low. Solid dosage forms tend to\ngive better nevirapine exposure when taken whole and not broken into halves or quarters as is the case in resource limited settings. Absorption and bioavailability of nevirapine may be affected by\nnutritional status when they is changes in fat/lean body mass ratio and physiological function due\nto malnutrition.\nConclusion: Effective antiretroviral treatment is limited by low availability of formulations for\nnevirapine only or fixed dose combinations for use in paediatric populations. Paediatric\nformulations are more accurate in achieving trough concentrations and sufficient nevirapine\nexposure. Adult tablets usually have to be broken in halves or quarters and this can affect the\nbioavailability of nevirapine and lead to sub therapeutic concentrations....
Background: Glucocorticoids (GCs), such as prednisone, are the standard of care for several inflammatory and\nimmunologically mediated diseases, but their chronic systemic administration is severely limited by serious adverse\neffects that are both dose and time dependent. Short-term treatment (7ââ?¬â??14 days) with oral prednisone is used for\nmany acute inflammatory and allergic conditions. This study was conducted to characterize the safety and\npharmacodynamic (PD) doseââ?¬â??response of a 7-day course of oral prednisone on biomarkers of GC receptor agonism.\nMethods: In this randomized, single-blind, placebo-controlled, crossover study (A9001309), 37 healthy subjects\nreceived placebo or a prednisone dose from 2.5ââ?¬â??60 mg daily over 7 days in each of three treatment periods. White\nblood cell counts and plasma samples for measuring cortisol, osteocalcin and procollagen type 1 N-propeptide (P1NP)\nwere obtained at 2, 4, 8, and 12 h post-dose on Day 1, immediately prior to dosing on Days 1, 2, and 4, and at nominal\ndosing time on Days 0 and 8. Urine samples for urinary N-terminal cross-linked telopeptide of type 1 collagen\n(uNTX) were collected on Days 0, 1, 2, 4, and 8. Serum samples for adiponectin were obtained prior to dosing\non days 0, 1, 4 and 8.\nResults: Daily doses of prednisone up to 60 mg resulted in dose- and time-dependent decreases in plasma osteocalcin,\nplasma P1NP, serum cortisol, and absolute blood eosinophil counts. Absolute blood neutrophil counts increased, while\nblood lymphocyte counts rebounded to an increased level following an initial rapid decrease after dosing. An increase\nwas observed for uNTX and adiponectin. The incidence of adverse effects with prednisone was not dose related, and\nnervous system disorders, mainly headache, were the most frequently reported adverse effects.\nConclusions: This characterization provides important and relevant information on safety and PD responses of\nshort-term prednisone dosing over the commonly-used clinical dose range, and also provides a reference for\nearly clinical development of dissociated agents targeting a differentiated PD profile....
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