Showing papers on "Pharmacokinetics published in 2009"
TL;DR: In the elderly, hepatic drug clearance of some drugs can be reduced and CYP-mediated phase I reactions are more likely to be impaired than phase II metabolism, which is relatively preserved in the elderly.
Abstract: Aging involves progressive impairments in the functional reserve of multiple organs, which might also affect drug metabolism and pharmacokinetics. In addition, the elderly population will develop multiple diseases and, consequently, often has to take several drugs. As the hepatic first-pass effect of highly cleared drugs could be reduced (due to decreases in liver mass and perfusion), the bioavailability of some drugs can be increased in the elderly. Significant changes in body composition occur with advancing age. Lipophilic drugs may have an increased volume of distribution (Vd) with a prolonged half-life, and water-soluble drugs tend to have a smaller Vd. In the elderly, hepatic drug clearance of some drugs can be reduced by up to 30% and CYP-mediated phase I reactions are more likely to be impaired than phase II metabolism, which is relatively preserved in the elderly. Concerning the most important CYP3A4 studies with human liver microsomes and clinical studies with the validated probe, midazolam, it is indicated that there are no significant differences in CYP3A4 activity between young and old populations. Finally, renal excretion is decreased (up to 50%) in about two thirds of elderly subjects, but confounding factors such as hypertension and coronary heart disease account also for a decline in kidney function. In conclusion, age-related physiological and pharmacokinetic changes as well as the presence of comorbidity and polypharmacy will complicate drug therapy in the elderly.
629 citations
TL;DR: Apixaban is an orally bioavailable inhibitor of factor Xa with elimination pathways that include metabolism and renal excretion with no serious adverse events or discontinuations due to adverse effects.
Abstract: The metabolism and disposition of [(14)C]apixaban, an orally bioavailable, highly selective, and direct acting/reversible factor Xa inhibitor, was investigated in 10 healthy male subjects without (group 1, n=6) and with bile collection (group 2, n=4) after a single 20-mg oral dose. Urine, blood, and feces samples were collected from all subjects. Bile samples were also collected for 3 to 8 h after dosing from group 2 subjects. There were no serious adverse events or discontinuations due to adverse effects. In plasma, apixaban was the major circulating component and O-demethyl apixaban sulfate, a stable and water-soluble metabolite, was the significant metabolite. The exposure of apixaban (C(max) and area under the plasma concentration versus time curve) in subjects with bile collection was generally similar to that in subjects without bile collection. The administered dose was recovered in feces (group 1, 56.0%; group 2, 46.7%) and urine (group 1, 24.5%; group 2, 28.8%), with the parent drug representing approximately half of the recovered dose. Biliary excretion represented a minor elimination pathway (2.44% of the administered dose) from group 2 subjects within the limited collection period. Metabolic pathways identified for apixaban included O-demethylation, hydroxylation, and sulfation of hydroxylated O-demethyl apixaban. Thus, apixaban is an orally bioavailable inhibitor of factor Xa with elimination pathways that include metabolism and renal excretion.
579 citations
TL;DR: It is found that the plasma colistin concentrations are insufficient before steady state and raise the question of whether the administration of a loading dose would benefit critically ill patients.
Abstract: Colistin is used to treat infections caused by multidrug-resistant gram-negative bacteria (MDR-GNB). It is administered intravenously in the form of colistin methanesulfonate (CMS), which is hydrolyzed in vivo to the active drug. However, pharmacokinetic data are limited. The aim of the present study was to characterize the pharmacokinetics of CMS and colistin in a population of critically ill patients. Patients receiving colistin for the treatment of infections caused by MDR-GNB were enrolled in the study; however, patients receiving a renal replacement therapy were excluded. CMS was administered at a dose of 3 million units (240 mg) every 8 h. Venous blood was collected immediately before and at multiple occasions after the first and the fourth infusions. Plasma CMS and colistin concentrations were determined by a novel liquid chromatography-tandem mass spectrometry method after a rapid precipitation step that avoids the significant degradation of CMS and colistin. Population pharmacokinetic analysis was performed with the NONMEM program. Eighteen patients (6 females; mean age, 63.6 years; mean creatinine clearance, 82.3 ml/min) were included in the study. For CMS, a two-compartment model best described the pharmacokinetics, and the half-lives of the two phases were estimated to be 0.046 h and 2.3 h, respectively. The clearance of CMS was 13.7 liters/h. For colistin, a one-compartment model was sufficient to describe the data, and the estimated half-life was 14.4 h. The predicted maximum concentrations of drug in plasma were 0.60 mg/liter and 2.3 mg/liter for the first dose and at steady state, respectively. Colistin displayed a half-life that was significantly long in relation to the dosing interval. The implications of these findings are that the plasma colistin concentrations are insufficient before steady state and raise the question of whether the administration of a loading dose would benefit critically ill patients.
472 citations
TL;DR: This review seeks to discuss the influence intestinal and hepatic drug transporters have on pharmacokinetic parameters, including bioavailability, exposure, clearance, volume of distribution, and half-life, for orally dosed drugs.
Abstract: Drug transporters are recognized as key players in the processes of drug absorption, distribution, metabolism, and elimination. The localization of uptake and efflux transporters in organs responsible for drug biotransformation and excretion gives transporter proteins a unique gatekeeper function in controlling drug access to metabolizing enzymes and excretory pathways. This review seeks to discuss the influence intestinal and hepatic drug transporters have on pharmacokinetic parameters, including bioavailability, exposure, clearance, volume of distribution, and half-life, for orally dosed drugs. This review also describes in detail the Biopharmaceutics Drug Disposition Classification System (BDDCS) and explains how many of the effects drug transporters exert on oral drug pharmacokinetic parameters can be predicted by this classification scheme.
382 citations
TL;DR: The pharmacokinetic characteristics; absorption, distribution, metabolism and excretion (ADME), of the available TKIs are reviewed and results from additional studies on the effect of drug transporters and drug-drug interactions have been incorporated.
375 citations
TL;DR: Radioactivity profiles in excreta were similar across species, and Unchanged rivaroxaban was the major compound in plasma at all time points investigated, across all species.
Abstract: Rivaroxaban is a novel, oral, direct factor Xa inhibitor for the prevention and treatment of thromboembolic disorders. The objective of this study was to investigate the in vivo metabolism and excretion of rivaroxaban in rats, dogs, and humans. Single doses of [(14)C]rivaroxaban (3 and 1 mg/kg) were administered to rats (orally/intravenously) and dogs (orally), respectively. A single oral dose of [(14)C]rivaroxaban (10 mg) was administered to healthy human males (n = 4). Plasma and excreta were collected and profiled for radioactivity. Recovery of total radioactivity was high and > or = 92% in all species. Unchanged rivaroxaban was the major compound in plasma at all time points investigated, across all species. No major or pharmacologically active circulating metabolites were detected. Rivaroxaban and its metabolites were rapidly excreted; urinary excretion of radioactivity was 25 and 52%, and fecal excretion was 67 and 43% of the dose in rats and dogs, respectively. In humans, 66% of the dose was excreted renally (36% unchanged drug) and 28% in the feces. Radioactivity profiles in excreta were similar across species. Three metabolic pathways were identified: oxidative degradation of the morpholinone moiety (major pathway) and hydrolysis of the central amide bond and of the lactam amide bond in the morpholinone ring (minor pathways). M-1, the main metabolite in excreta of all species, was eliminated via both renal and fecal/biliary routes. In total, 82 to 89% of the dose administered was assigned to unchanged rivaroxaban and its metabolites in the excreta of rats, dogs, and humans.
351 citations
TL;DR: Dapagliflozin demonstrates pharmacokinetic (PK) characteristics and dose‐dependent glucosuria that are sustained over 24 h, which indicates that it is suitable for administration in once‐daily doses and suggests that further investigation of its efficacy in T2DM patients is warranted.
Abstract: Dapagliflozin selectively inhibits renal glucose reabsorption by inhibiting sodium-glucose cotransporter-2 (SGLT2). It was developed as an insulin-independent treatment approach for type 2 diabetes mellitus (T2DM). The safety, tolerability, pharmacokinetics, and pharmacodynamics of the drug were evaluated in single-ascending-dose (SAD; 2.5-500 mg) and multiple-ascending-dose (MAD; 2.5-100 mg daily for 14 days) studies in healthy subjects. Dapagliflozin exhibited dose-proportional plasma concentrations with a half-life of approximately 17 h. The amount of glucosuria was also dose-dependent. Cumulative amounts of glucose excreted on day 1, relating to doses from 2.5-100 mg (MAD), ranged from 18 to 62 g; day 14 values were comparable to day 1 values, with no apparent changes in glycemic parameters. Doses of approximately 20-50 mg provided close-to-maximal SGLT2 inhibition for at least 24 h. Dapagliflozin demonstrates pharmacokinetic (PK) characteristics and dose-dependent glucosuria that are sustained over 24 h, which indicates that it is suitable for administration in once-daily doses and suggests that further investigation of its efficacy in T2DM patients is warranted.
320 citations
TL;DR: The general tolerability and encouraging antitumor activity in taxane-refractory patients warrant further evaluations of XRP6258.
Abstract: Purpose: To assess the feasibility of administering XRP6258, a new taxane with a low affinity for the multidrug resistance 1 protein, as a 1-hour i.v. infusion every 3 weeks. The study also sought to determine the maximum tolerated dose and the recommended dose, to describe the pharmacokinetic (PK) behavior of the compound, and to seek preliminary evidence of anticancer activity. Experimental Design: Twenty-five patients with advanced solid malignancies were treated with 102 courses of XRP6258 at four dose levels ranging from 10 to 25 mg/m 2 . Dose escalation was based on the occurrence of dose-limiting toxicity (DLT) at each dose level, provided that PK variables were favorable. The maximum tolerated dose was defined as the dose at which at least two patients developed a DLT at the first course. Results: Neutropenia was the principal DLT, with one patient experiencing febrile neutropenia and two others showing prolonged grade 4 neutropenia at the 25 mg/m 2 dose level. Nonhematologic toxicities, including nausea, vomiting, diarrhea, neurotoxicity, and fatigue, were generally mild to moderate in severity. XRP6258 exhibited dose-proportional PK, a triphasic elimination profile, a long terminal half-life (77.3 hours), a high clearance (mean CL, 53.5 L/h), and a large volume of distribution (mean V ss , 2,034 L/m 2 ). Objective antitumor activity included partial responses in two patients with metastatic prostate carcinoma, one unconfirmed partial response, and two minor responses. Conclusion: The recommended phase II dose of XRP6258 on this schedule is 20 mg/m 2 . The general tolerability and encouraging antitumor activity in taxane-refractory patients warrant further evaluations of XRP6258.
315 citations
TL;DR: The results suggest that the five-carbon linker-containing analogues of curcumin may be favorable for theCurcumin-based drug development both pharmacokinetically and pharmacologically.
306 citations
TL;DR: The rapid conclusion of this trial demonstrates the feasibility of conducting proof-of-principle phase 0 trials as part of an alternative paradigm for early drug development in oncology.
Abstract: Purpose We conducted the first phase 0 clinical trial in oncology of a therapeutic agent under the Exploratory Investigational New Drug Guidance of the US Food and Drug Administration. It was a first-in-human study of the poly (ADP-ribose) polymerase (PARP) inhibitor ABT-888 in patients with advanced malignancies. Patients and Methods ABT-888 was administered as a single oral dose of 10, 25, or 50 mg to determine the dose range and time course over which ABT-888 inhibits PARP activity in tumor samples and peripheral blood mononuclear cells, and to evaluate ABT-888 pharmacokinetics. Blood samples and tumor biopsies were obtained pre- and postdrug administration for evaluation of PARP activity and pharmacokinetics. A novel statistical approach was developed and utilized to study pharmacodynamic modulation as the primary end point for trials of limited sample size. Results Thirteen patients with advanced malignancies received the study drug; nine patients underwent paired tumor biopsies. ABT-888 demonstrated...
305 citations
TL;DR: Differences in plasma protein binding and metabolism did not explain the species-related differences in brain uptake of three radiolabeled P-glycoprotein substrates across species using positron emission tomography, which is important for interpretation of brain drug delivery when extrapolating preclinical data to humans.
Abstract: Species differences occur in the brain concentrations of drugs, but the reasons for these differences are not yet apparent. This study was designed to compare brain uptake of three radiolabeled P-glycoprotein (P-gp) substrates across species using positron emission tomography. Brain concentrations and brain-to-plasma ratios were compared; [11C]verapamil in rats, guinea pigs, and monkeys; [11C](S)-(2-methoxy-5-(5-trifluoromethyltetrazol-1-yl)-phenylmethylamino)-2(S)-phenylpiperidine (GR205171) in rats, guinea pigs, monkeys, and humans; and [18F]altanserin in rats, minipigs, and humans. The fraction of the unbound radioligand in plasma was studied along with its metabolism. The effect of P-gp inhibition was investigated by administering cyclosporin A (CsA). Pronounced species differences were found in the brain and brain-to-plasma concentrations of [11C]verapamil, [11C]GR205171, and [18F]altanserin with higher brain distribution in humans, monkeys, and minipigs than in rats and guinea pigs. For example, the brain-to-plasma ratio of [11C]GR205171 was almost 9-fold higher in humans compared with rats. The species differences were still present after P-gp inhibition, although the increase in brain concentrations after P-gp inhibition was somewhat greater in rats than in the other species. Differences in plasma protein binding and metabolism did not explain the species-related differences. The findings are important for interpretation of brain drug delivery when extrapolating preclinical data to humans. Compounds found to be P-gp substrates in rodents are likely to also be substrates in higher species, but sufficient blood-brain barrier permeability may be retained in humans to allow the compound to act at intracerebral targets.
TL;DR: The recently introduced open-target-controlled infusion (TCI) systems can be programmed with any pharmacokinetic model, and allow either plasma- or effect-site targeting, and the Schnider model should always be used in effect- site targeting mode.
Abstract: The recently introduced open-target-controlled infusion (TCI) systems can be programmed with any pharmacokinetic model, and allow either plasma- or effect-site targeting. With effect-site targeting the goal is to achieve a user-defined target effect-site concentration as rapidly as possible, by manipulating the plasma concentration around the target. Currently systems are pre-programmed with the Marsh and Schnider pharmacokinetic models for propofol. The former is an adapted version of the Gepts model, in which the rate constants are fixed, whereas compartment volumes and clearances are weight proportional. The Schnider model was developed during combined pharmacokinetic-pharmacodynamic modelling studies. It has fixed values for V1, V3, k(13), and k(31), adjusts V2, k(12), and k(21) for age, and adjusts k(10) according to total weight, lean body mass (LBM), and height. In plasma targeting mode, the small, fixed V1 results in very small initial doses on starting the system or on increasing the target concentration in comparison with the Marsh model. The Schnider model should thus always be used in effect-site targeting mode, in which larger initial doses are administered, albeit still smaller than for the Marsh model. Users of the Schnider model should be aware that in the morbidly obese the LBM equation can generate paradoxical values resulting in excessive increases in maintenance infusion rates. Finally, the two currently available open TCI systems implement different methods of effect-site targeting for the Schnider model, and in a small subset of patients the induction doses generated by the two methods can differ significantly.
TL;DR: Examination of body composition adds information to an overall picture of nutrition of the elderly, since the body is not a simple two-compartment system and the concept of body cell mass would provide a better estimate than lean body mass of metabolically active tissue.
Abstract: he changes in composition of the aging T human body is of both gerontologic and geriatric interest and reflects genetic factors and environmental factors such as physical activity, nutrition, and disease, as well as the normal aging processes. In the study of normal aging, that is, aging per se, long-term trends in body compartments are important. In the field of clinical geriatrics, body composition is also of great interest in the study of obesity, malignant disease, and clinical pharmacology and biochemistry. Changes of body cell mass, body fat, and body water occur frequently in both disease and aging. These changes in body compartments may alter the pharmacokinetic and pharmacodynamic properties of drugs used in old age. The amount of body fat and the amount of body cell mass are important parameters when judging the net effect of energy intake and expenditure. Thus, examination of body composition adds information to an overall picture of nutrition of the elderly. Such overall knowledge also requires data on actual dietary habits of elderly populations in different countries. Not only intakes of energy, nutrients, and food items are important, but also distribution and composition data on meals and data on medical, psychologic, and socioeconomic conditions are prerequisites for the analysis of the relationship between requirements and actual intake. The need for broad epidemiologic approaches to these questions is obvious. Concepts The frequently used concept of “lean body mass” has two meanings, namely, body weight minus neutral fat, but including some lipids such as phospholipids, the exact amount of which is unknown. Lean body mass is, according to this meaning, similar to, but not identical with, fat-free body mass. Although lean body mass has a relatively constant specific gravity, from a biologic point of view it is a heterogenous body component with varying energy consumption, since it also comprises-apart from body cel I massfat-f ree ext race1 I u lar solids and extracellular water. Furthermore, since the water content of adipose tissue may show great variation and is also difficult to estimate, the definition of lean body mass should be body weight minus body fat, that is, fat-free mass. Many workers, nowadays, however, avoid the concept of a lean body mass and fat-free mass, since the body is not a simple two-compartment system. Moore and collaborators’ many years ago suggested that the concept of body cell mass would provide a better estimate than lean body mass of metabolically active tissue. Many workers now prefer to divide body weight into body cell mass, extracellular water, body fat, and fat-free extracellular solids that are present primarily in bone and connective tissuea2 For a review of the concepts of body compartments, see references 1, 3, 4, and 5.
TL;DR: The clinical pharmacokinetics and in vitro inhibition of digoxin were examined to predict the P‐glycoprotein (P‐gp) component of drug–drug interactions and found that digoxin is likely to show the highest perturbation, via inhibition of P‐gp, because of the absence of metabolic clearance.
Abstract: The clinical pharmacokinetics and in vitro inhibition of digoxin were examined to predict the P-glycoprotein (P-gp) component of drug-drug interactions. Coadministered drugs (co-meds) in clinical trials (N = 123) resulted in a small, 0.1 is predictive of clinical digoxin interactions (AUC and C(max)).
TL;DR: A first-in-human study evaluated the safety, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of AMG 386 in adults with advanced solid tumors as discussed by the authors.
Abstract: Purpose AMG 386 is an investigational peptide-Fc fusion protein (ie, peptibody) that inhibits angiogenesis by preventing the interaction of angiopoietin-1 and angiopoietin-2 with their receptor, Tie2. This first-in-human study evaluated the safety, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of AMG 386 in adults with advanced solid tumors. Patients and Methods Patients in sequential cohorts received weekly intravenous AMG 386 doses of 0.3, 1, 3, 10, or 30 mg/kg. Results Thirty-two patients were enrolled on the study and received AMG 386. One occurrence of dose-limiting toxicity was seen at 30 mg/kg: respiratory arrest, which likely was caused by tumor burden that was possibly related to AMG 386. The most common toxicities were fatigue and peripheral edema. Proteinuria (n = 11) was observed without clinical sequelae. Only four patients (12%) experienced treatment-related toxicities greater than grade 1. A maximum-tolerated dose was not reached. PK was dose-linear and the mean terminal-p...
TL;DR: Seven patients with various types of solid tumours refractory to standard therapy were treated with escalating doses of KP1019 twice weekly for 3 weeks, and the pharmacokinetic disposition was characterised by a small volume of distribution, low clearance and long half-life.
Abstract: A phase I and pharmacokinetic study was carried out with the new ruthenium complex indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019, FFC14A). Seven patients with various types of solid tumours refractory to standard therapy were treated with escalating doses of KP1019 (25-600 mg) twice weekly for 3 weeks. No dose-limiting toxicity occurred. Ruthenium plasma concentration-time profiles after the first dose and under multiple-dose conditions were analysed using a compartmental approach. The pharmacokinetic disposition was characterised by a small volume of distribution, low clearance and long half-life. Only a small fraction of ruthenium was excreted renally. The area under the curve values increased proportionally with dose indicating linear pharmacokinetics.
TL;DR: The absence of toxicity and the demonstration of activity at doses above 6 mg warrant further disease-directed studies of IMP321 in combined regimens (e.g., chemoimmunotherapy).
Abstract: Purpose: To evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of IMP321, a recombinant soluble LAG-3Ig fusion protein which agonizes MHC class II–driven dendritic cell activation. Experimental Design: Patients with advanced renal cell carcinoma were treated with escalating doses of IMP321 s.c. Blood samples were assayed to determine plasma pharmacokinetic parameters, detect human anti-IMP321 antibody formation, and determine long-lived CD8 T cell responses. Results: Twenty-one advanced renal cell carcinoma patients received 119 injections of IMP321 at doses ranging from 0.050 to 30 mg/injection s.c. biweekly for 6 injections. No clinically significant adverse events were observed. Good systemic exposure to the product was obtained following s.c. injections of doses above 6 mg. IMP321 induced both sustained CD8 T-cell activation and an increase in the percentage of long-lived effector-memory CD8 T cells in all patients at doses above 6 mg. Tumor growth was reduced and progression-free survival was better in those patients receiving higher doses (>6 mg) of IMP321: 7 of 8 evaluable patients treated at the higher doses experienced stable disease at 3 months compared with only 3 of 11 in the lower dose group ( P = 0.015). Conclusion: The absence of toxicity and the demonstration of activity at doses above 6 mg warrant further disease-directed studies of IMP321 in combined regimens (e.g., chemoimmunotherapy). (Clin Cancer Res 2009;15(19):6225–31)
TL;DR: The pharmacokinetic properties of drugs are closely related to their pharmacological efficacy and can be used to predict and optimise the value of the parasiticide effects and to design programmes for parasite control.
Abstract: The pharmacokinetic properties of drugs are closely related to their pharmacological efficacy. The kinetics of ivermectin are characterised, in general terms, by a slow absorption process, a broad distribution in the organism, low metabolism, and slow excretion. The kinetics vary according to the route of administration, formulation, animal species, body condition, age, and physiological status, all of which contribute to differences in drug efficacy. Characterisation of ivermectin kinetics can be used to predict and optimise the value of the parasiticide effects and to design programmes for parasite control. This article reviews the pharmacokinetics of ivermectin in several domestic animal species.
TL;DR: The present population pharmacokinetic analysis evaluated voriconazole plasma concentration-time data from three studies of pediatric patients of 2 to <12 years of age, incorporating a range of single or multiple intravenous (i.v.) and/or oral (p.o.) doses and found the pediatric area-under-the-curve (AUC) distribution exhibited the least overall difference from the adult AUC distribution.
Abstract: Voriconazole is a potent triazole with broad-spectrum antifungal activity against clinically significant and emerging pathogens. The present population pharmacokinetic analysis evaluated voriconazole plasma concentration-time data from three studies of pediatric patients of 2 to <12 years of age, incorporating a range of single or multiple intravenous (i.v.) and/or oral (p.o.) doses. An appropriate pharmacokinetic model for this patient population was created using the nonlinear mixed-effect modeling approach. The final model described voriconazole elimination by a Michaelis-Menten process and distribution by a two-compartment model. It also incorporated a statistically significant (P < 0.001) influence of the CYP2C19 genotype and of the alanine aminotransferase level on clearance. The model was used in a number of deterministic simulations (based on various fixed, mg/kg of body weight, and individually adjusted doses) aimed at finding suitable i.v. and p.o. voriconazole dosing regimens for pediatric patients. As a result, 7 mg/kg twice a day (BID) i.v. or 200 mg BID p.o., irrespective of body weight, was recommended for this patient population. At these doses, the pediatric area-under-the-curve (AUC) distribution exhibited the least overall difference from the adult AUC distribution (at dose levels used in clinical practice). Loading doses or individual dosage adjustments according to baseline covariates are not considered necessary in administering voriconazole to children.
TL;DR: This study revealed that the ABC phenomenon is induced by PEG-modified PLA-nanoparticles, and considers that NP-L33s may be useful clinically for the sustained-release and targeted delivery of PGE1.
Abstract: Purpose
We recently developed prostaglandin E1 (PGE1)-encapsulated nanoparticles, prepared with a poly(lactide) homopolymer (PLA, Mw = 17,500) and monomethoxy poly(ethyleneglycol)-PLA block copolymer (PEG-PLA) (NP-L20). In this study, we tested whether the accelerated blood clearance (ABC) phenomenon is observed with NP-L20 and other PEG-modified PLA-nanoparticles in rats.
TL;DR: The safety and lack of immunogenicity of prGCD are demonstrated and a prolonged half-life compared to imiglucerase, the commercial enzyme that is manufactured in a costly mammalian cell system is revealed.
Abstract: Gaucher disease is a progressive lysosomal storage disorder caused by the deficiency of glucocerebrosidase leading to the dysfunction in multiple organ systems. Intravenous enzyme replacement is the accepted standard of treatment. In the current report, we evaluate the safety and pharmacokinetics of a novel human recombinant glucocerebrosidase enzyme expressed in transformed plant cells (prGCD), administered to primates and human subjects. Short term (28 days) and long term (9 months) repeated injections with a standard dose of 60 Units/kg and a high dose of 300 Units/kg were administered to monkeys (n = 4/sex/dose). Neither clinical drug-related adverse effects nor neutralizing antibodies were detected in the animals. In a phase I clinical trial, six healthy volunteers were treated by intravenous infusions with escalating single doses of prGCD. Doses of up to 60 Units/kg were administered at weekly intervals. prGCD infusions were very well tolerated. Anti-prGCD antibodies were not detected. The pharmacokinetic profile of the prGCD revealed a prolonged half-life compared to imiglucerase, the commercial enzyme that is manufactured in a costly mammalian cell system. These studies demonstrate the safety and lack of immunogenicity of prGCD. Following these encouraging results, a pivotal phase III clinical trial for prGCD was FDA approved and is currently ongoing.
TL;DR: The pharmacodynamic effects described here are the first demonstration of “target engagement” by an LXR agonist in humans and have shown promise in animal models of atherosclerosis.
Abstract: Liver X-receptor (LXR) agonists have been postulated to enhance reverse cholesterol transport (RCT), a process believed to shuttle cholesterol from the periphery back to the liver. Enhancing RCT via the upregulation of cholesterol transporters such as the adenosine triphosphate-binding cassettes ABCA1 and ABCG1 could therefore inhibit the progression of atherosclerosis. LXR-623 is a synthetic ligand for LXRs alpha and beta that has shown promise in animal models of atherosclerosis. The authors present results from a single ascending-dose study of the safety, pharmacokinetics, and pharmacodynamics of LXR-623 in healthy participants. LXR-623 was absorbed rapidly with peak concentrations (C(max)) achieved at approximately 2 hours. The C(max) and area under the concentration-time curve increased in a dose-proportional manner. The mean terminal disposition half-life was between 41 and 43 hours independently of dose. LXR activation resulted in a dose-dependent increase in ABCA1 and ABCG1 expression. The effect of LXR-623 concentration on ABCA1 and ABCG1 expression was further characterized via a population pharmacokinetic-pharmacodynamic analysis, yielding EC(50) estimates of 526 ng/mL and 729 ng/mL, respectively. Central nervous system-related adverse events were observed at the 2 top doses tested. The pharmacodynamic effects described here are the first demonstration of "target engagement" by an LXR agonist in humans.
TL;DR: Silymarin has limited effect on the pharmacokinetics of several drugs in vivo; despite sily marin decreasing the activity of cytochrome P-450 (CYPs) enzymes, UDP-glucuronosyltransferase (UGT) enzyme, and reducing P-glycoprotein (P-gp) transport.
TL;DR: The maximum tolerated dose (MTD) of YM155 was determined to be 8.0 mg/m2/d, and the safety profile, plasma concentrations achieved, and antitumor activity observed merit further studies with this survivin suppressant, alone and in combination regimens.
Abstract: Purpose: YM155, a novel molecular targeted agent, suppresses survivin, a member of the inhibitor of apoptosis protein family that is overexpressed in many tumor types. The aim of this study was to determine the maximum tolerated dose (MTD) and to assess the safety, pharmacokinetics, and antitumor activity of YM155 in patients with advanced refractory solid tumors. Experimental Design: Patients with advanced refractory solid tumors were treated with escalating doses of YM155 administered by continuous i.v. infusion for 168 hours in 21-day cycles. Results: Of the 34 patients enrolled, 33 (median age, 59 years) received at least 1 dose of YM155 (range, 1-19 cycles). The dose levels studied were 1.8, 3.6, 4.8, 6.0, 8.0, and 10.6 mg/m 2 /d. The MTD was determined to be 8.0 mg/m 2 /d, based on a dose-limiting toxicity of increased blood creatinine observed in 2 patients receiving 10.6 mg/m 2 /d. The most common adverse reactions judged to be related to YM155 were urine microalbumin present; fever; injection-site phlebitis; fatigue; and decreased hemoglobin/anemia, blood albumin, and lymphocyte count. The pharmacokinetic profile was almost linear over the dosing range and was similar between cycles 1 and 2. Urinary excretion of YM155 showed no definite difference among doses. Stable disease was achieved in nine patients. Conclusions: YM155 was safely administered to patients with advanced refractory solid tumors by 168-hour continuous i.v. infusion in 21-day cycles. The MTD was determined to be 8.0 mg/m 2 /d. The safety profile, plasma concentrations achieved, and antitumor activity observed merit further studies with this survivin suppressant, alone and in combination regimens.
TL;DR: The pharmacokinetics of voriconazole after a single oral dose in comparison with intravenous and oral administration in healthy individuals stratified according to the cytochrome P450 (CYP) 2C19 genotype were determined and the predominant metabolic pathway is the hydroxylation that seems to be influenced by the CYP2C 19 genotype.
Abstract: WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Pharmacokinetic variability of voriconazole is largely caused by CYP3A4- and CYP2C19-mediated metabolism.
• Oral bioavailability of voriconazole has been claimed to be almost 100%, thus facilitating a change from intravenous to oral application without dose adjustment.
WHAT THIS STUDY ADDS
• For the first time voriconazole exposure after intravenous and oral administration in relation to CYP2C19 activity is reported.
• In addition, the predominant metabolic pathway is the hydroxylation that seems to be influenced by the CYP2C19 genotype.
• Enterohepatic circulation of both hydroxylated metabolites must be anticipated.
AIMS The aim was to determine the pharmacokinetics of voriconazole after a single oral dose in comparison with intravenous (i.v.) administration in healthy individuals stratified according to the cytochrome P450 (CYP) 2C19 genotype. In addition, the possible metabolic pathways and their modulation according to CYP2C19 genotype were investigated after oral and i.v. administration of voriconazole.
METHODS In a single-centre, open-label, two-period crossover study 20 participants received single doses of 400 mg voriconazole orally and 400 mg voriconazole intravenously in randomized order. Blood and urine samples were collected up to 96 h post dose and the voriconazole and three major metabolites were quantified by high-performance liquid chromatography coupled to mass spectroscopy.
RESULTS Absolute oral bioavailability of voriconazole was 82.6% (74.1, 91.0). It ranged from 94.4% (78.8, 109.9) in CYP2C19 poor metabolizers to 75.2% (62.9, 87.4) in extensive metabolizers. In contrast to voriconazole and its N-oxide, the plasma concentrations of both hydroxylated metabolites showed a large second peak after 24 h. Independent of the route of administration, voriconazole partial metabolic hydroxylation after i.v. administration was eightfold higher compared with N-oxidation [48.8 ml min−1 (30.5, 67.1) vs. 6.1 ml min−1 (4.1, 8.0)]. The formation of the metabolites was related to CYP2C19 activity.
CONCLUSIONS Independent of the route of administration, voriconazole exposure was three times higher in CYP2C19 poor metabolizers compared with extensive metabolizers. Voriconazole has a high bioavailability with no large differences between the CYP2C19 genotypes. The hydroxylation pathway of voriconazole elimination exceeded the N-oxidation, both influenced by the CYP2C19 genotype.
TL;DR: The data suggest that 15 mg/kg dosing in premature neonates corresponds to an exposure of approximately 5mg/kg in adults, and no adverse events related to micafungin were observed.
Abstract: Background
Determining the safety and pharmacokinetics of antifungal agents in neonates is important. A previous single-dose pharmacokinetic study of micafungin in neonates demonstrated that doses of 0.75 to 3 mg/kg produced lower plasma micafungin concentrations than in older patients because of increased apparent plasma clearance of micafungin in neonates. The primary objective of this study was to assess the safety and pharmacokinetics of an increased (15 mg/kg/day) dose of micafungin.
TL;DR: The low F of kaempferol is attributed in part to extensive first-pass metabolism by glucuronidation and other metabolic pathways in the gut and in the liver.
Abstract: The purpose of this study was to compare the hepatic and small intestinal metabolism, and to examine bioavailability and gastro-intestinal first-pass effects, of kaempferol in rats. Liver and small intestinal microsomes fortified with either NADPH or UDPGA were incubated with varying concentrations of kaempferol for up to 120 min. Based on the values of the kinetic constants (K(m) and V(max)), the propensity for UDPGA-dependent conjugation compared with NADPH-dependent oxidative metabolism was higher for both hepatic and small intestinal microsomes. Male Sprague-Dawley rats were administered kaempferol intravenously (i.v.) (10, 25 mg/kg) or orally (100, 250 mg/kg). Gastro-intestinal first-pass effects were observed by collecting portal blood after oral administration of 100 mg/kg kaempferol. Pharmacokinetic parameters were obtained by non-compartmental analysis using WinNonlin. After i.v. administration, the plasma concentration-time profiles for 10 and 25 mg/kg were consistent with high clearance (approximately 3 L/hr/kg) and large volumes of distribution (8-12 L/hr/kg). The disposition was characterized by a terminal half-life value of 3-4 h. After oral administration the plasma concentration-time profiles demonstrated fairly rapid absorption (t(max) approximately 1-2 h). The area under the curve (AUC) values after i.v. and oral doses increased approximately proportional to the dose. The bioavailability (F) was poor at approximately 2%. Analysis of portal plasma after oral administration revealed low to moderate absorption. Taken together, the low F of kaempferol is attributed in part to extensive first-pass metabolism by glucuronidation and other metabolic pathways in the gut and in the liver.
TL;DR: Overall, PA-824 was well tolerated following oral doses once daily for up to 7 days, and pharmacokinetic parameters were consistent with a once-a-day regimen, and the investigation of this novel compound for the treatment of tuberculosis is supported.
Abstract: PA-824 is a novel antibacterial agent that has shown in vitro activity against both drug-sensitive and drug-resistant Mycobacterium tuberculosis. The compound's MIC is between 0.015 and 0.25 microg/ml for drug-sensitive strains and between 0.03 and 0.53 microg/ml for drug-resistant strains. In addition, it is active against nonreplicating anaerobic Mycobacterium tuberculosis. The safety, tolerability, and pharmacokinetics of PA-824 were evaluated in two escalating-dose clinical studies, one a single-dose study and the other a multiple-dose study (up to 7 days of daily dosing). In 58 healthy subjects dosed with PA-824 in these studies, the drug candidate was well tolerated, with no significant or serious adverse events. In both studies, following oral administration PA-824 reached maximal plasma levels in 4 to 5 h independently of the dose. Maximal blood levels averaged approximately 3 microg/ml (1,500-mg dose) in the single-dose study and 3.8 microg/ml (600-mg dose) in the multiple-dose study. Steady state was achieved after 5 to 6 days of daily dosing, with an accumulation ratio of approximately 2. The elimination half-life averaged 16 to 20 h. Overall, PA-824 was well tolerated following oral doses once daily for up to 7 days, and pharmacokinetic parameters were consistent with a once-a-day regimen. The results of these studies, combined with the demonstrated activity of PA-824 against drug-sensitive and multidrug-resistant Mycobacterium tuberculosis, support the investigation of this novel compound for the treatment of tuberculosis.
TL;DR: The diverse metabolic pathways combined with a lack of significant P450 metabolism make vildagliptin less susceptible to potential pharmacokinetic interactions with comedications of P450 inhibitors/inducers.
Abstract: The absorption, metabolism, and excretion of (1-[[3-hydroxy-1-adamantyl) amino] acetyl]-2-cyano-( S )-pyrrolidine (vildagliptin), an orally active and highly selective dipeptidyl peptidase 4 inhibitor developed for the treatment of type 2 diabetes, were evaluated in four healthy male subjects after a single p.o. 100-mg dose of [14C]vildagliptin. Serial blood and complete urine and feces were collected for 168 h postdose. Vildagliptin was rapidly absorbed, and peak plasma concentrations were attained at 1.1 h postdose. The fraction of drug absorbed was calculated to be at least 85.4%. Unchanged drug and a carboxylic acid metabolite (M20.7) were the major circulating components in plasma, accounting for 25.7% (vildagliptin) and 55% (M20.7) of total plasma radioactivity area under the curve. The terminal half-life of vildagliptin was 2.8 h. Complete recovery of the dose was achieved within 7 days, with 85.4% recovered in urine (22.6% unchanged drug) and the remainder in feces (4.54% unchanged drug). Vildagliptin was extensively metabolized via at least four pathways before excretion, with the major metabolite M20.7 resulting from cyano group hydrolysis, which is not mediated by cytochrome P450 (P450) enzymes. Minor metabolites resulted from amide bond hydrolysis (M15.3), glucuronidation (M20.2), or oxidation on the pyrrolidine moiety of vildagliptin (M20.9 and M21.6). The diverse metabolic pathways combined with a lack of significant P450 metabolism (1.6% of the dose) make vildagliptin less susceptible to potential pharmacokinetic interactions with comedications of P450 inhibitors/inducers. Furthermore, as vildagliptin is not a P450 inhibitor, it is unlikely that vildagliptin would affect the metabolic clearance of comedications metabolized by P450 enzymes.
TL;DR: There was no PK interaction between the probe drugs when administered in combination as a cocktail, relative to the probes administered alone, as the 90% CI of the PK parameters was within the prespecified bioequivalence limits.
Abstract: WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Numerous cocktails using concurrent administration of several cytochrome P450 (CYP) isoform-selective probe drugs have been reported to investigate drug–drug interactions in vivo.
• This approach has several advantages: characterize the inhibitory or induction potential of compounds in development toward the CYP enzymes identified in vitro in an in vivo situation, assess several enzymes in the same trial, and have complete in vivo information about potential CYP-based drug interactions.
WHAT THIS STUDY ADDS
• This study describes a new cocktail containing five probe drugs that has never been published.
• This cocktail can be used to test the effects of a new chemical entity on multiple CYP isoforms in a single clinical study: CYP1A2 (caffeine), CYP2C9 (warfarin), CYP2C19 (omeprazole), CYP2D6 (metoprolol), and CYP3A (midazolam) and was designed to overcome potential liabilities of other reported cocktails.
AIMS To assess the pharmacokinetics (PK) of selective substrates of CYP1A2 (caffeine), CYP2C9 (S-warfarin), CYP2C19 (omeprazole), CYP2D6 (metoprolol) and CYP3A (midazolam) when administered orally and concurrently as a cocktail relative to the drugs administered alone.
METHODS This was an open-label, single-dose, randomized, six-treatment six-period six-sequence William's design study with a wash-out of 7 or 14 days. Thirty healthy male subjects received 100 mg caffeine, 100 mg metoprolol, 0.03 mg kg−1 midazolam, 20 mg omeprazole and 10 mg warfarin individually and in combination (cocktail). Poor metabolizers of CYP2C9, 2C19 and 2D6 were excluded. Plasma samples were obtained up to 48 h for caffeine, metoprolol and omeprazole, 12 h for midazolam, 312 h for warfarin and the cocktail. Three different validated liquid chromatography tandem mass spectrometry methods were used. Noncompartmental PK parameters were calculated. Log-transformed Cmax, AUClast and AUC for each analyte were analysed with a linear mixed effects model with fixed term for treatment, sequence and period, and random term for subject within sequence. Point estimates (90% CI) for treatment ratios (individual/cocktail) were computed for each analyte Cmax, AUClast and AUC.
RESULTS There was no PK interaction between the probe drugs when administered in combination as a cocktail, relative to the probes administered alone, as the 90% CI of the PK parameters was within the prespecified bioequivalence limits of 0.80, 1.25.
CONCLUSION The lack of interaction between probes indicates that this cocktail could be used to evaluate the potential for multiple drug–drug interactions in vivo.