Pharmacokinetics and pharmacodynamics of suberoylanilide hydroxamic acid in cats.
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ABSTRACT:
SUBMITTER: McDonnel SJ
PROVIDER: S-EPMC3949138 | biostudies-other | 2014 Apr
REPOSITORIES: biostudies-other
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Project description:Background and objectiveLysergic acid diethylamide (LSD) is used recreationally and in clinical research. The aim of the present study was to characterize the pharmacokinetics and exposure-response relationship of oral LSD.MethodsWe analyzed pharmacokinetic data from two published placebo-controlled, double-blind, cross-over studies using oral administration of LSD 100 and 200 µg in 24 and 16 subjects, respectively. The pharmacokinetics of the 100-µg dose is shown for the first time and data for the 200-µg dose were reanalyzed and included. Plasma concentrations of LSD, subjective effects, and vital signs were repeatedly assessed. Pharmacokinetic parameters were determined using compartmental modeling. Concentration-effect relationships were described using pharmacokinetic-pharmacodynamic modeling.ResultsGeometric mean (95% confidence interval) maximum plasma concentration values of 1.3 (1.2-1.9) and 3.1 (2.6-4.0) ng/mL were reached 1.4 and 1.5 h after administration of 100 and 200 µg LSD, respectively. The plasma half-life was 2.6 h (2.2-3.4 h). The subjective effects lasted (mean ± standard deviation) 8.2 ± 2.1 and 11.6 ± 1.7 h for the 100- and 200-µg LSD doses, respectively. Subjective peak effects were reached 2.8 and 2.5 h after administration of LSD 100 and 200 µg, respectively. A close relationship was observed between the LSD concentration and subjective response within subjects, with moderate counterclockwise hysteresis. Half-maximal effective concentration values were in the range of 1 ng/mL. No correlations were found between plasma LSD concentrations and the effects of LSD across subjects at or near maximum plasma concentration and within dose groups.ConclusionsThe present pharmacokinetic data are important for the evaluation of clinical study findings (e.g., functional magnetic resonance imaging studies) and the interpretation of LSD intoxication. Oral LSD presented dose-proportional pharmacokinetics and first-order elimination up to 12 h. The effects of LSD were related to changes in plasma concentrations over time, with no evidence of acute tolerance.Trial registrationNCT02308969, NCT01878942.
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Project description:"Microdoses" of lysergic acid diethylamide (LSD) are used recreationally to enhance mood and cognition. Increasing interest has also been seen in developing LSD into a medication. Therefore, we performed a pharmacokinetic-pharmacodynamic study using very low doses of LSD. Single doses of LSD base (5, 10, and 20 µg) and placebo were administered in a double-blind, randomized, placebo-controlled crossover study in 23 healthy participants. Test days were separated by at least 5 days. Plasma levels of LSD and subjective effects were assessed up to 6 hours after administration. Pharmacokinetic parameters were determined using compartmental modeling. Concentration-subjective effect relationships were described using pharmacokinetic-pharmacodynamic modeling. Mean (95% confidence interval) maximal LSD concentrations were 151 pg/mL (127-181), 279 pg/mL (243-320), and 500 pg/mL (413-607) after 5, 10, and 20 µg LSD administration, respectively. Maximal concentrations were reached after 1.1 hours. The mean elimination half-life was 2.7 hours (1.5-6.2). The 5 µg dose of LSD elicited no significant acute subjective effects. The 10 µg dose of LSD significantly increased ratings of "under the influence" and "good drug effect" compared with placebo. These effects began an average of 1.1 hours after 10 µg LSD administration, peaked at 2.5 hours, and ended at 5.1 hours. The 20 µg dose of LSD significantly increased ratings of "under the influence," "good drug effects," and "bad drug effects." LSD concentrations dose-proportionally increased at doses as low as 5-20 µg and decreased with a half-life of 3 hours. The threshold dose of LSD base for psychotropic effects was 10 µg.
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Project description:AimsThe population pharmacokinetics (PK) and pharmacodynamics (PD) of tranexamic acid (TXA) have not been studied to prevent postpartum haemorrhage (PPH) in pregnant women. It is unclear which TXA dose assures sufficient PPH prevention. This study investigated population PK/PD of TXA in pregnant women who underwent caesarean delivery to determine the optimal prophylactic doses of TXA for future studies.MethodsWe analysed concentration (PK) and maximum lysis (PD) data from 30 pregnant women scheduled for caesarean delivery who received 5, 10 or 15 mg/kg of TXA intravenously using population approach.ResultsTXA PK was best described by a two-compartment model with first-order elimination and the following parameters: clearance (between-subject variability) of 9.4 L/h (27.7%), central volume of 10.1 L (47.4%), intercompartmental clearance of 22.4 L/h (66.7%), peripheral volume of 14.0 L (13.1%) and additive error of 1.4 mg/L. The relationship between TXA concentration and maximum lysis was characterized by a sigmoid Emax model with baseline lysis of 97%, maximum inhibition of 89%, IC50 of 6.0 mg/L (65.3%), hill factor of 8.5 (86.3%) and additive error of 7.3%. Simulations demonstrated that 500 and 650 mg of TXA maintained therapeutic targets for 30 minutes and 1 hour, respectively, in 90% of patients.ConclusionThis is the first population PK and PD study of TXA in pregnant women undergoing caesarean delivery. Our analysis suggests that a 650 mg dose provides adequate PPH prophylaxis up to 1 hour, which is less than the currently used 1000 mg of TXA in pregnant women.
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Project description:The cholesterol ester transfer protein (CETP) inhibitor dalcetrapib has been under evaluation for its potential to prevent cardiovascular (CV) events for almost two decades. The current clinical development program, representing new advances in precision medicine and focused on a genetically defined population with acute coronary syndrome (ACS), is supported by a large body of pharmacokinetic and pharmacodynamic data as well as substantial clinical experience in over 13,000 patients and volunteers. Dalcetrapib treatment of 600 mg/day produces significant inhibition of CETP activity, and has been utilized in phase II and III studies, including CV endpoint trials. Numerous studies have investigated the interactions between dalcetrapib and most drugs commonly prescribed to CV patients and have not demonstrated any clinically significant effects. Evaluations in patients with renal and hepatic impairment demonstrate a greater exposure to dalcetrapib than in the non-impaired population, but long-term clinical studies including patients with mild to moderate hepatic and renal dysfunction demonstrate no increase in adverse events. Safety pharmacology and toxicology studies as well as the clinical safety experience support the continuing development of dalcetrapib as an adjunct to 'standard of care' for the ACS population. This article provides a full review of the pharmacokinetics, as well as pharmacodynamics and pharmacology, of dalcetrapib in the context of a large clinical program.
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Project description:Afatinib is an oral, irreversible ErbB family blocker that covalently binds to the kinase domains of epidermal growth factor receptor (EGFR), human EGFRs (HER) 2, and HER4, resulting in irreversible inhibition of tyrosine kinase autophosphorylation. Studies in healthy volunteers and patients with advanced solid tumours have shown that once-daily afatinib has time-independent pharmacokinetic characteristics. Maximum plasma concentrations of afatinib are reached approximately 2-5 h after oral administration and thereafter decline, at least bi-exponentially. Food reduces total exposure to afatinib. Over the clinical dose range of 20-50 mg, afatinib exposure increases slightly more than dose proportional. Afatinib metabolism is minimal, with unchanged drug predominantly excreted in the faeces and approximately 5 % in urine. Apart from the parent drug afatinib, the major circulation species in human plasma are the covalently bound adducts to plasma protein. The effective elimination half-life is approximately 37 h, consistent with an accumulation of drug exposure by 2.5- to 3.4-fold based on area under the plasma concentration-time curve (AUC) after multiple dosing. The pharmacokinetic profile of afatinib is consistent across a range of patient populations. Age, ethnicity, smoking status and hepatic function had no influence on afatinib pharmacokinetics, while females and patients with low body weight had increased exposure to afatinib. Renal function is correlated with afatinib exposure, but, as for sex and body weight, the effect size for patients with severe renal impairment (approximately 50 % increase in AUC) is only mildly relative to the extent of unexplained interpatient variability in afatinib exposure. Afatinib has a low potential as a victim or perpetrator of drug-drug interactions, especially with cytochrome P450-modulating agents. However, concomitant treatment with potent inhibitors or inducers of the P-glycoprotein transporter can affect the pharmacokinetics of afatinib. At a dose of 50 mg, afatinib does not have proarrhythmic potential.
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Project description:Cefiderocol is a new broad-spectrum cephalosporin antibiotic with promising activity against various Gram-negative bacteria including carbapenem-resistant strains. A chlorocatechol group in the C-3 side chain provides cefiderocol with a siderophore activity, improving its stability against β-lactamases and facilitating the transportation of cefiderocol across outer bacterial membranes. Cefiderocol shows linear pharmacokinetics over a broad range of clinically relevant doses, with unchanged renal excretion constituting the main route of elimination. Geometric means (coefficient of variation) of the volume of distribution and clearance in individuals with normal kidney function were 15.8 (15%) L and 4.70 (27%) L/h, respectively. In patients with end-stage renal disease, clearance was 1.10 (24%) L/h. Time above the minimum inhibitory concentration is the main predictor of efficacy. There is no evidence for clinically relevant interactions of cefiderocol with other drugs mediated by metabolizing enzymes or drug transporters. Simulations based on population pharmacokinetic modeling suggest that dosing regimens should be adjusted based on kidney function to optimize therapeutic exposure to cefiderocol. Clinical efficacy trials indicated that cefiderocol is non-inferior to imipenem/cilastatin in the treatment of complicated urinary tract infections and acute uncomplicated pyelonephritis, and to meropenem in the treatment of nosocomial pneumonia. In the one study currently available, cefiderocol performed similarly to the best available therapy in the treatment of severe carbapenem-resistant Gram-negative infections regarding clinical and microbiological efficacy. In summary, cefiderocol shows favorable pharmacokinetic/pharmacodynamic properties and an acceptable safety profile, suggesting that cefiderocol might be a viable option to treat infections with bacteria resistant to other antibiotics.
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Project description:Micafungin is a selective inhibitor of the synthesis of fungal 1,3-β-D-glucan, an essential component of the fungal cell wall. It is available as a powder for infusion only and is registered for the treatment of invasive and esophageal candidiasis in addition to prophylaxis of Candida infections in both adults and children. Average exposure after a single intravenous 100 mg dose in healthy adults is 133 mg h/L. Both exposure and maximum plasma concentration show linear dose proportional pharmacokinetics (PK) over a 0.15-8 mg/kg dose range. In healthy adults, the clearance (CL) is 10.4 mL/h/kg and volume of distribution is 0.2 L/kg; both are independent of the dose. Micafungin is metabolized by arylsulfatase, catechol-O-methyltransferase, and several cytochrome P450 (CYP) isoenzymes (3A4, 1A2, 2B6 and 2C), but no dose adjustments are necessary in patients with (severe) hepatic dysfunction. Exposure to micafungin is lower in hematology patients, and is even further lowered in critically ill patients (including burn patients) compared with healthy volunteers, which might have consequences for treatment efficacy. In children, an increased CL has been reported: 40-80 mL/h/kg in premature neonates and 20 mL/h/kg in children >4 months of age. Therefore, relatively higher doses of 4-10 mg/kg in premature neonates and 2-4 mg/kg in children with invasive candidiasis are used. However, these higher CLs may also be explained by the eightfold higher free fraction of unbound micafungin in premature neonates, meaning that an augmented dose might not be required.
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Project description: Not available
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Project description:Isavuconazole is a broad-spectrum azole anti-fungal not yet approved in children. We conducted a retrospective, single-center review of isavuconazole use and routine therapeutic drug monitoring in pediatric patients, extracting demographic, dosing, concentration, mortality and hepatoxicity data. We constructed a nonparametric population model using Pmetrics. Of 26 patients, 19 (73%) were male. The mean (SD) age and weight were 12.7 (5.5) years and 50.9 (26.8) kg. Eighty percent received between 9.7 and 10.6 mg/kg per dose. Ten (38%) subjects had proven fungal disease and eight (31%) had probable disease, mostly with Candida and Aspergillus spp. The predicted steady-state isavuconazole concentrations in our patients were similar to previous reports in children and adults, and simulations with the proposed dosing of 10 mg/kg/dose every 8 h for 2 days followed by once daily maintenance matched effective adult exposures. Attributable mortality (5 of 11 deaths) was associated with steady-state daily AUC < 60 mg∗h/L and higher AST/ALT with trough concentrations > 5 mg/L. Neither dose nor trough alone correlated well with AUC, but AUC can be estimated with one sample 10 h after the first maintenance dose or a trough concentration, if combined with a Bayesian approach or a peak and trough without a Bayesian approach.
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Project description:Selumetinib, a highly specific mitogen-activated protein kinase 1/2 inhibitor, is approved for children older than 2 years of age with neurofibromatosis 1 who have inoperable plexiform neurofibromas. By selectively binding to mitogen-activated protein kinase 1/2 proteins, selumetinib can arrest the mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathway that regulates critical cellular responses. Selumetinib has shown promising results as a single agent or in combination with conventional chemotherapy and other targeted therapies both preclinically and clinically, in multiple cancers including pediatric low-grade glioma, non-small cell lung cancer, and melanoma, among others. The pharmacokinetic profiles of selumetinib and its active metabolite N-desmethyl selumetinib have been well characterized in both adults and children. Both compounds exhibited rapid absorption and mean terminal elimination half-lives of about 7.5 h, with minimal accumulation at steady state. Three population pharmacokinetic models have been developed in adults and children, characterizing large inter- and intra-patient variabilities, and identifying significant covariates including food intake on selumetinib absorption, weight metrics, age, co-administration of cytochrome modulators, and Asian ethnicity on selumetinib apparent oral clearance. The most common side effects associated with selumetinib are dermatologic, gastrointestinal toxicities, and fatigue. Most toxicities are mild or moderate, generally tolerated and manageable. Cardiovascular and ocular toxicities remain less frequent but can be potentially more severe and require close monitoring. Overall, selumetinib exhibits a favorable safety profile and pharmacokinetic properties, with promising activity in multiple solid tumors, supporting current and further evaluation in combination with conventional chemotherapy and other targeted agents.
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