Sensor Noise in LISA Pathfinder: In-Flight Performance of the Optical Test Mass Readout.

We report on the first subpicometer interferometer flown in space. It was part of ESA's Laser Interferometer Space Antenna (LISA) Pathfinder mission and performed the fundamental measurement of the positional and angular motion of two free-falling test masses. The interferometer worked immediately, stably, and reliably from switch on until the end of the mission with exceptionally low residual noise of 32.0_{-1.7}^{+2.4} fm/sqrt[Hz], significantly better than required. We present an upper limit for the sensor performance at millihertz frequencies and a model for the measured sensitivity above 200 mHz.

Analysis of the accuracy of actuation electronics in the laser interferometer space antenna pathfinder.

The Laser Interferometer Space Antenna Pathfinder (LPF) main observable, labeled Δg, is the differential force per unit mass acting on the two test masses under free fall conditions after the contribution of all non-gravitational forces has been compensated. At low frequencies, the differential force is compensated by an applied electrostatic actuation force, which then must be subtracted from the measured acceleration to obtain Δg. Any inaccuracy in the actuation force contaminates the residual acceleration. This study investigates the accuracy of the electrostatic actuation system and its impact on the LPF main observable. It is shown that the inaccuracy is mainly caused by the rounding errors in the waveform processing and also by the random error caused by the analog to digital converter random noise in the control loop. Both errors are one order of magnitude smaller than the resolution of the commanded voltages. We developed a simulator based on the LPF design to compute the close-to-reality actuation voltages and, consequently, the resulting actuation forces. The simulator is applied during post-processing the LPF data.

LISA Pathfinder Performance Confirmed in an Open-Loop Configuration: Results from the Free-Fall Actuation Mode.

We report on the results of the LISA Pathfinder (LPF) free-fall mode experiment, in which the control force needed to compensate the quasistatic differential force acting on two test masses is applied intermittently as a series of "impulse" forces lasting a few seconds and separated by roughly 350 s periods of true free fall. This represents an alternative to the normal LPF mode of operation in which this balancing force is applied continuously, with the advantage that the acceleration noise during free fall is measured in the absence of the actuation force, thus eliminating associated noise and force calibration errors. The differential acceleration noise measurement presented here with the free-fall mode agrees with noise measured with the continuous actuation scheme, representing an important and independent confirmation of the LPF result. An additional measurement with larger actuation forces also shows that the technique can be used to eliminate actuation noise when this is a dominant factor.

Beyond the Required LISA Free-Fall Performance: New LISA Pathfinder Results down to 20 µHz.

In the months since the publication of the first results, the noise performance of LISA Pathfinder has improved because of reduced Brownian noise due to the continued decrease in pressure around the test masses, from a better correction of noninertial effects, and from a better calibration of the electrostatic force actuation. In addition, the availability of numerous long noise measurement runs, during which no perturbation is purposely applied to the test masses, has allowed the measurement of noise with good statistics down to 20 µHz. The Letter presents the measured differential acceleration noise figure, which is at (1.74±0.05) fm s^{-2}/sqrt[Hz] above 2 mHz and (6±1)×10 fm s^{-2}/sqrt[Hz] at 20 µHz, and discusses the physical sources for the measured noise. This performance provides an experimental benchmark demonstrating the ability to realize the low-frequency science potential of the LISA mission, recently selected by the European Space Agency.

Charge-Induced Force Noise on Free-Falling Test Masses: Results from LISA Pathfinder.

We report on electrostatic measurements made on board the European Space Agency mission LISA Pathfinder. Detailed measurements of the charge-induced electrostatic forces exerted on free-falling test masses (TMs) inside the capacitive gravitational reference sensor are the first made in a relevant environment for a space-based gravitational wave detector. Employing a combination of charge control and electric-field compensation, we show that the level of charge-induced acceleration noise on a single TM can be maintained at a level close to 1.0 fm s^{-2} Hz^{-1/2} across the 0.1-100 mHz frequency band that is crucial to an observatory such as the Laser Interferometer Space Antenna (LISA). Using dedicated measurements that detect these effects in the differential acceleration between the two test masses, we resolve the stochastic nature of the TM charge buildup due to interplanetary cosmic rays and the TM charge-to-force coupling through stray electric fields in the sensor. All our measurements are in good agreement with predictions based on a relatively simple electrostatic model of the LISA Pathfinder instrument.

Sub-Femto-g Free Fall for Space-Based Gravitational Wave Observatories: LISA Pathfinder Results.

We report the first results of the LISA Pathfinder in-flight experiment. The results demonstrate that two free-falling reference test masses, such as those needed for a space-based gravitational wave observatory like LISA, can be put in free fall with a relative acceleration noise with a square root of the power spectral density of 5.2±0.1 fm s^{-2}/sqrt[Hz], or (0.54±0.01)×10^{-15} g/sqrt[Hz], with g the standard gravity, for frequencies between 0.7 and 20 mHz. This value is lower than the LISA Pathfinder requirement by more than a factor 5 and within a factor 1.25 of the requirement for the LISA mission, and is compatible with Brownian noise from viscous damping due to the residual gas surrounding the test masses. Above 60 mHz the acceleration noise is dominated by interferometer displacement readout noise at a level of (34.8±0.3) fm/sqrt[Hz], about 2 orders of magnitude better than requirements. At f≤0.5 mHz we observe a low-frequency tail that stays below 12 fm s^{-2}/sqrt[Hz] down to 0.1 mHz. This performance would allow for a space-based gravitational wave observatory with a sensitivity close to what was originally foreseen for LISA.

Differential phase-noise properties of a ytterbium-doped fiber amplifier for the Laser Interferometer Space Antenna.

The interferometric gravitational-wave detector Laser Interferometer Space Antenna (LISA) needs to transfer clock information among its three spacecraft in the form of phase-modulation sidebands. For this reason phase noise introduced by the optical chain between the carrier and a sideband must be low. We have measured this differential phase noise for a ytterbium-doped fiber amplifier emitting up to 2 W. For 1 W of output power as required for LISA, the measured differential phase noise was within its requirement. For 2 W output power the amplifier exhibited stimulated Brillouin scattering and showed a differential phase-noise factor of up to 15 higher. Dependencies on operating parameters and optical length noise of the amplifier were also measured.

Stable operation of a 300-m laser interferometer with sufficient sensitivity to detect gravitational-wave events within our galaxy.

TAMA300, an interferometric gravitational-wave detector with 300-m baseline length, has been developed and operated with sufficient sensitivity to detect gravitational-wave events within our galaxy and sufficient stability for observations; the interferometer was operated for over 10 hours stably and continuously. With a strain-equivalent noise level of h approximately 5x10(-21)/sqrt[Hz], a signal-to-noise ratio of 30 is expected for gravitational waves generated by a coalescence of 1.4M-1.4M binary neutron stars at 10 kpc distance. We evaluated the stability of the detector sensitivity with a 2-week data-taking run, collecting 160 hours of data to be analyzed in the search for gravitational waves.

Amino acid kinetics in patients with sepsis.

BACKGROUND: In patients with sepsis and systemic inflammatory response syndrome, amino acid extraction by the liver is enhanced, resulting in decreased plasma amino acid concentrations. Systematic investigations of the elimination of intravenously infused amino acids have not been performed. OBJECTIVE: The objective of this study was to compare the elimination of 17 amino acids in patients with sepsis and in healthy control subjects. DESIGN: Elimination of amino acids was evaluated in 9 patients with sepsis and in 8 healthy control subjects by using a combined loading and maintenance infusion of 375 mg amino acids/kg body wt for 60 min. Pharmacokinetic variables were analyzed from plasma curves. RESULTS: With the exception of lysine, methionine, glutamate, ornithine, phenylalanine, and tyrosine, plasma concentrations of amino acids were lower in the patients with sepsis than in the control subjects; phenylalanine was the only amino acid whose plasma concentration increased (P < 0.001). In patients with sepsis, whole-body clearance (Cl(tot)) of total amino acids was 74% higher than in control subjects (x +/- SEM: 13,161 +/- 1659 and 7566 +/- 91 mL/min, respectively; P < 0.01), the Cl(tot) of essential amino acids was 64% higher (P < 0.02), that of nonessential amino acids was 82% higher (P < 0.01), and that of both branched-chain amino acids and glucogenic amino acids was 97% higher (P < 0.001). With the exception of phenylalanine, ornithine, proline, and glutamate, the Cl(tot) of all amino acids was elevated. The Cl(tot) of phenylalanine and ornithine decreased slightly (NS). CONCLUSIONS: In patients with sepsis, plasma concentrations of most amino acids are greatly decreased and the elimination of amino acids from the intravascular space during intravenous infusion is greatly enhanced.

Steady-state pharmacokinetics of lithium in healthy volunteers receiving concomitant meloxicam.

AIMS: This open, controlled study investigated the effect of concomitant 15 mg oral meloxicam on the pharmacokinetics of lithium in healthy male volunteers. METHODS: On days 1-14 lithium was coadministered with meloxicam to 16 volunteers; on days 10-14 lithium was administered in individualized dosage regimes to achieve stable lithium plasma concentrations in the lower therapeutic range of 0.3-0.7 mmol l(-1). A 12 h steady-state concentration profile for lithium was obtained at day 14, after which meloxicam was withdrawn. The lithium dose remained unchanged from day 15 to day 22, at which time a second lithium concentration profile was determined. RESULTS: Lithium and meloxicam were well tolerated throughout the study and all 16 volunteers completed the study. Lithium predose concentrations (Cpre,ss) and area under the curve (AUCss) values both increased by 21% (paired t-test P = 0.0002; 90% confidence intervals for test/reference ratios: 113-130% and 115-128%, respectively) when lithium was coadministered with meloxicam compared with values obtained for lithium alone. The geometric mean lithium Cpre,ss was 0.65 mmol l(-1) when coadministered with meloxicam and 0.54 mmol l(-1) for lithium alone. Lithium Cmax,ss values were increased by 16% by coadministration of meloxicam, from 0.97 mmol l(-1) to 1.12 mmol l(-1). The total plasma clearance of lithium was lower with concomitant meloxicam administration (82.5% of value for lithium alone). CONCLUSIONS: Meloxicam (15 mg) moderately increased the plasma concentration of lithium in healthy volunteers, but by a magnitude thought to be of low clinical relevance. Nevertheless, lithium plasma concentrations should be closely monitored in patients receiving concomitant meloxicam and lithium therapy.

Absorption of lefradafiban from different sites of the gastrointestinal tract.

AIMS: Fibrinogen receptor antagonists show a close relationship between plasma concentrations and inhibitory effect. Optimal efficacy at an acceptable bleeding risk requires low inter- and intrasubject variability on low peak trough fluctuation in receptor occupancy and therefore also of plasma concentrations. Therefore, the enteral absorption of lefradafiban, an orally available fibrinogen receptor antagonist prodrug, was investigated after local administrations to different sites of the gastrointestinal tract in order to investigate the feasibility of an oral extended release formulation. METHODS: Twelve healthy male subjects received in a randomised, open-labelled, four-period crossover trial four consecutive administrations of lefradafiban: 1. orally; 2. administration into the jejunum, 3. administration into the lower jejunum/ileum (300 cm distally to the teeth), and 4. administration into the lumen of the sigmoid region (30 cm proximally to the anus). Local intestinal administrations were performed through a gastrointestinal tube. RESULTS: Compared with oral administration, ratios [mean (two-sided 90% confidence intervals)] of maximum drug plasma concentrations and AUC(0,24 h) of fradafiban were 1.05 (0.80, 1.39) and 1.06 (0.85,1.31) after jejunal, 0.98 (0.75,1.30) and 0.98 (0.79,1.21) after ileal, 0.52 (0.39,0.69) and 0.68 (0.55,0.85) after colonic administration. Urinary excretion of fradafiban was about 16% of the dose after oral, jejunal and ileal applications whereas after rectal administration about 11% were excreted. CONCLUSIONS: Lefradafiban is absorbed throughout the entire gastrointestinal tract. Therefore, an extended release formulation seems to be feasible with regard to bioavailability.

Precision of measurement of tissue concentrations by RLG.

Existing investigations about the precision of radioluminography (RLG) are restricted to descriptive analysis of the tissue samples. The aim of the present experiments was to obtain a general prospective statement about the precision that the RLG method can achieve. Several pharmaceutical companies in Europe participated in the experiments. Albino rats of various strains were dosed with various (14)C-labeled compounds. Whole-body sections were produced, and blood calibration scales were set up with standard radioactivity sources of dog or rat blood. Photostimulated luminescence was detected using Fuji imaging plate BAS-III. For each organ separately, variability was investigated on each of the levels: rat, section of rat, region within section, and residual, with the help of variance components. The producing company was seen as a fixed factor and adjusted for. A mixed linear model was fitted to the log-transformed data. The variance component (SD estimate) for the residual term gave the desired prospective statement about the achievable precision of the RLG method. Exponential back transformation from the logarithmic to the natural scale transformed the SD estimates to multiplication factors. In total, 29 organs were investigated. The RLG method was comparable in precision to the dissection/combustion method.

Disposition and chemical stability of telmisartan 1-O-acylglucuronide.

Telmisartan 1-O-acylglucuronide, the principal metabolite of telmisartan in humans, was characterized in terms of chemical stability and the structure of its isomerization products was elucidated. In addition, pharmacokinetics of telmisartan 1-O-acylglucuronide were assessed in rats after i.v. dosing. Similar to other acylglucuronides, telmisartan 1-O-acylglucuronide and diclofenac 1-O-acylglucuronide, which was used for comparison, showed the formation of different isomeric acylglucuronides on incubation in aqueous buffer. The isomeric acylglucuronides of telmisartan consisted of the 2-O-, 3-O-, and 4-O-acylglucuronides (alpha,beta-anomers). First order degradation half-lives of 26 and 0. 5 h were observed on incubation in buffer of pH 7.4 for the 1-O-acylglucuronides of telmisartan and diclofenac, respectively. This indicated that the 1-O-acylglucuronide of telmisartan was among the most stable acylglucuronides reported to date. The high stability of telmisartan 1-O-acylglucuronide was confirmed by in vitro experiments that indicated only very low covalent binding of telmisartan acylglucuronide to human serum albumin but a considerable amount of covalently bound radioactivity with the acylglucuronide of diclofenac. After i.v. dosing to rats, telmisartan 1-O-acylglucuronide was rapidly cleared from plasma with a clearance of 180 ml/min/kg, compared with 15.6 ml/min/kg for the parent compound. Because telmisartan 1-O-acylglucuronide exhibited a comparably high chemical stability together with a high clearance that resulted in low systemic exposure, the amount of covalent binding to proteins should be negligible compared with other frequently used drugs, such as furosemide, ibuprofen, or salicylic acid.

Pharmacokinetics of meloxicam in animals and the relevance to humans.

The pharmacokinetic profile of the new nonsteroidal anti-inflammatory drug meloxicam was investigated in a number of animal species, including mice, rats, dogs, mini-pigs, and baboons, after administration of [14C]meloxicam. The plasma concentration-time profiles for meloxicam in rats and dogs were comparable to that in humans, whereas there were marked differences between humans and mice, mini-pigs, and baboons. The highest tissue concentrations of meloxicam in rats and mini-pigs were seen in the liver and kidneys. In contrast, low concentrations of meloxicam were found in the central nervous system, compared with those in plasma. The excretion balance in mini-pigs resembled that in humans, with almost equal concentrations being eliminated in the urine and the feces. As in humans, meloxicam circulated mainly in the form of the parent compound in the plasma of mice, rats, dogs, mini-pigs, and baboons. The main metabolites in rats, mini-pigs, and humans were a 5'-hydroxymethyl derivative (AF-UH 1 SE) and a 5'-carboxy metabolite (UH-AC 110 SE). The percentage of meloxicam binding to protein was higher in rats and humans (>99%) than in other species. The pharmacokinetic profile of meloxicam in rats most closely resembles that in humans; therefore, reliable clinical predictions can be made from studies in this rodent species.

PK/PD simulations as a tool for rational design of clinical dosage regimens: an example with Fradafiban.

In clinical studies, pharmacodynamic effects should be achieved, e.g. maintenance of certain effects with reversibly acting drugs. Available data base for early phase II studies is frequently kinetics in healthy volunteers from phase I studies and pharmacodynamic effects from in vivo or ex vivo data. Using the fibrinogen receptor antagonist Fradafiban as an example, a procedure to achieve rational dosage regimens is described. Applied methods were: curve fitting of plasma concentrations obtained in phase I studies, correlation of fibrinogen receptor occupancy (FRO) to plasma concentrations using a sigmoid Emax model with Hill coefficient for PK/PD correlation, simulation of time course of FRO for various dosage regimens, using estimates for variability from PK and PD data in order to estimate not only mean values but also expected range of FRO. In a phase II study with Fradafiban administered intravenously, therapeutically active plasma levels had to be achieved rapidly and maintained over 24 hours employing a simple infusion regimen in 20 patients and 3 dose groups. For the target dose, a FRO of 80% should be achieved in most patients. Using the tools mentioned above, a rapid initial infusion rate of 10 mg over 30 minutes, followed by a maintenance infusion of 30 mg for the remaining 23.5 hours for the target dose resulted in a median predicted FRO of 82%. For the lower dose, a 5/15 mg infusion over 0.5/23.5 hours, achieving a predicted FRO of 68% was used and the upper dose (15/45 mg) resulted in 87% FRO. Median experimental results were 84% FRO for the target dose and 73% and 88%, respectively, for the lower and upper dose. As these results fit reasonably well to the predictions, it can be concluded that kinetics in the mostly elderly patients is similar to kinetics in healthy young volunteers. Furthermore, FRO in patients is nearly identical to that in spiked human plasma. Taken together, it could be proven that PK/PD methods are a useful tool for design of clinical studies of Fradafiban.

Comparative cardiac toxicity of the i.v. administered benzimidazole pyridazinon derivative Pimobendan and its enantiomers in female Beagle dogs.

The new positive-inotropic and vasodilatating drug Pimobendan (racemate), 4,5-dihydro-6-[2-(4-methoxyphenyl)-1H-benzimidazole-5-yl]-5-methyl-3 (2-H)-pyridazinone, and its enantiomers were investigated with regard to their cardiotoxicity in young adult female Chbb: Beagle dogs. The racemate and the (-)-isomer (eutomer) were intravenously injected once daily for 4 consecutive weeks at doses of 0.25, 0.75 and 2.25 mg/kg, and the (+)-isomer (distomer) at doses of 0.75, 2.25 and 6.75 mg/kg, respectively. Clinical signs, hematological, clinico-chemical, ophthalmologic and electrophysiological parameters were monitored. Plasma concentration-time profiles of the parent compound and the major metabolite UD-CG 212 were established on day 1 and in week 4 using an HPLC assay. Partial areas under the curves from 0.08 h to 1 h (AUC0.08-1 h) as well as the plasma concentration at time point 0.5 h/C0.5 h) were used for statistical calculations. Necropsy and histopathologic examination were performed after completion of the treatment period. Reduction of the blood pressure occurred already at low dosages of the racemate and the eutomer, but only in high dose distomer-treated animals. A tendency to tachycardia developed only in high dose females receiving the racemate. Consequently, with respect to the pharmacological effects and the adverse events, the racemate is equivalent to the eutomer. Plasma concentrations of parent compound and metabolite were dose-linear for racemate, eutomer and distomer within the dose range 0.25-2.25 mg/kg.d at both time points. There were no significant effects of form or repeated administration. A moderate increase of AUC0.08 1 h and C0.5 h could be seen on day 23 for the distomer indicating a stereoselektive metabolism of the latter. Histologic changes of the valvular and parietal endocardium being termed jet lesion were observed after administration of the racemate (> or = 0.75 mg/kg.d) and the eutomer (> or = 0.25 mg/kg.d) at distinctly lower doses than after the distomer (> or = 2.25 mg/kg.d). Furthermore, extent and severity of the morphologic lesions were found to be higher in dogs exposed to the racemate or the eutomer than in those receiving the distomer. The results gave evidence that the so-called cardiotoxicity by Pimobendan in dogs resulted from the exaggerated pharmacodynamic effect but not from the chemical nature of the compound per se. They corroborate also the previously raised assumption that the exaggerated pharmacodynamic activity of cardiotonic compounds in the broadest sense accounts for their morphologic adverse effects in experimental animals.

Clinical pharmacokinetics of meloxicam.

Meloxicam (CAS 71125-38-7, UH-AC 62 XX) is a new non-steroidal anti-inflammatory drug (NSAID) which was developed for the treatment of osteoarthritis and rheumatoid arthritis. The basic clinical pharmacokinetics of meloxicam (7.5-30 mg) have been investigated in 78 healthy male volunteers after single and multiple dosing via oral, intravenous and rectal routes. Plasma concentrations of meloxicam were determined by validated high performance liquid chromatography (HPLC) methods. The pharmaco-kinetic profile of meloxicam is characterized by almost complete absorption over a prolonged phase-avoiding high initial drug concentrations- and is bound to plasma proteins by more than 99.5%. Meloxicam is metabolized to four biologically inactive metabolites and excreted in urine and faeces with an elimination half-life (t1/2) of around 20 h. This is reflected in a total plasma clearance of 7 to 8 ml/min. Steady state is achieved within 3 to 5 days. In addition, the pharmacokinetic parameters are linear over the entire dose range, there are no changes with multiple dosing and bioequivalence was shown for a number of different formulations. The results indicate that meloxicam is suitable for once-daily administration and that a switch from one formulation to another is easily possible if necessary or convenient for the patient.

Duration of action and pharmacokinetics of the oral antidiabetic drug gliquidone in patients with non-insulin-dependent (type 2) diabetes mellitus.

The duration of action and the pharmacokinetics of gliquidone (1-cyclohexyl-3-[[4-[2-(3,4-dihydro-7-methoxy-4,4-dimethyl-1, 3-dioxo-2(1H)-isochinolyl)ethyl]phenyl]-sulfonyl]-urea, AR-DF 26 SE, CAS 33342-05-1, Glurenorm, Beglynor) were investigated in 32 patients with non-insulin-dependent (type 2) diabetes mellitus over 16 h. In a single-blinded cross-over design vs. placebo, one 30 mg tablet gliquidone was administered 15 min before breakfast. Concomitant to the measurement of glucose and insulin, the gliquidone plasma levels of 20 subjects were determined by a new specific liquid chromatographic (HPLC) assay method with fluorescence detection, and the pharmacokinetic parameters calculated. Following the gliquidone administration, the mean plasma glucose profiles of the responders were up to 15% lower than with placebo (p < 0.005) between 8 a.m. and 6 p.m., representing a duration of the blood sugar-lowering effect of 8 to 10 h. Insulin values were raised, with peaks over 40% higher, during or shortly after meals. Subsequently, the insulin levels returned to approximately the same levels obtained with placebo during the postprandial phase. Plasma concentrations of gliquidone showed pronounced interindividual variability. The mean maximum concentration in plasma Cmax was 0.65 microgram/ml, (range: 0.12-2.14 micrograms/ml, coefficient of variation (CV): 82%). The median time to reach maximum plasma concentrations tmax was 2.25 h (range: 1.25-4.75 h). The areas under the plasma concentration-time curve from zero time to infinity (AUC0-infinity) and the mean terminal elimination half-lives (t1/2 beta) were computed from those patients (N = 8) who exhibited at least five plasma levels above the limit of quantitation in the terminal log-linear phase using a two-compartment model: the mean AUC0-infinity was 5.1 micrograms.h/ml (range: 1.5-10.1 micrograms.h/ml, CV 56%). The dominant half-life t1/2 alpha derived from therapeutically relevant plasma levels of gliquidone (> 80 ng/ml) was approximately 1.2 h (range: 0.4-3.0 h. CV: 71%) and the mean terminal half-life t1/2 beta was approximately 8 h (range: 5.7-9.4 h, CV: 17%). From the pharmacodynamic behavior as well as from the pharmacokinetic parameters it can be deduced that gliquidone belongs to the class of short-acting sulfonylureas used in antidiabetic therapy.

Meloxicam pharmacokinetics in renal impairment.

AIMS: The aim of the present study was to determine how the pharmacokinetics of meloxicam are affected by kidney dysfunction and consequently to define the appropriate dose for the use of meloxicam in patients with mild or moderate renal impairment. METHODS: Meloxicam was administered to subjects with mild (creatinine clearance 41-60 ml min-1) to moderate (20-40 ml min-1) renal impairment compared with normal renal function (> 60 ml min-1). Thirty-eight subjects received meloxicam 15 mg once daily over 9 days. Meloxicam plasma concentrations were determined from blood samples taken during the study and pharmacokinetic parameters calculated according to noncompartmental methods. RESULTS: Subjects with no or mild renal impairment showed similar pharmacokinetic profiles (geometric mean AUCSS (%gCV) 55 (33%) vs 55 (38%) micrograms ml-1 h). Subjects with moderate renal impairment demonstrated lower total plasma meloxicam concentrations (AUCSS 35 (50%) micrograms ml-1 h, with corresponding higher plasma clearance (P = 0.013) compared with subjects with no renal impairment. However, this was combined with higher meloxicam free fractions in moderately impaired subjects such that free meloxicam concentrations were similar in all three groups. Meloxicam was well tolerated with few adverse events occurring and no difference in incidence observable between groups. CONCLUSIONS: On the basis of these results there is no necessity for a dosage adjustment when administering meloxicam to patients with mild to moderate renal impairment.

Lack of interaction between meloxicam and warfarin in healthy volunteers.

OBJECTIVE: The effect of multiple oral doses of meloxicam 15 mg on the pharmacodynamics and pharmacokinetics of warfarin was investigated in healthy male volunteers. Warfarin was administered in an individualized dose to achieve a stable reduction in prothrombin times calculated as International Normalized Ratio (INR) values. Then INR- and a drug concentration-time profile was determined. For the interaction phase, meloxicam was added for 7 days and then INR measurements and the warfarin drug profiles were repeated for comparison. Overall, warfarin treatment lasted for 30 days. RESULTS: Warfarin and meloxicam were well tolerated by healthy volunteers in this study. Thirteen healthy volunteers with stable INR values entered the interaction phase. Prothrombin times, expressed as mean INR values, were not significantly altered by concomitant meloxicam treatment, being 1.20 for warfarin alone and 1.27 for warfarin with meloxicam cotreatment. R- and S-warfarin pharmacokinetics were similar for both treatments. Geometric mean (% gCV) AUCss values for the more potent S-enantiomer were 5.07 mg.h.l-1 (27.5%) for warfarin alone and 5.64 mg.h.l-1 (28.1%) during the interaction phase. Respective AUCss values for R-warfarin were 7.31 mg.h.l-1 (43.8%) and 7.58 mg.h.l-1 (39.1%). CONCLUSION: The concomitant administration of the new non-steroidal anti-inflammatory drug (NSAID) meloxicam affected neither the pharmacodynamics nor the pharmacokinetics of a titrated warfarin dose. A combination of both drugs should nevertheless be avoided and, if necessary, INR monitoring is considered mandatory.