Recovery Of Unchanged Drug Research Articles

Pharmacokinetics, safety, and tolerability following single-dose migalastat hydrochloride (GR181413A/AT1001) in healthy male Japanese subjects

Objective:Fabry disease is a rare X-linked disease caused by mutations to the GLA gene, resulting in a deficiency of the lysosomal enzyme alpha-galactosidase A. This study evaluated the pharmacokinetics, safety, and tolerability of ascending single doses of oral migalastat hydrochloride (HCl), an investigational drug, in healthy Japanese volunteers.Methods:In this phase I, randomized, placebo-controlled, single-blind, ascending single-dose, cross-over study, migalastat HCl (50 mg, 150 mg, or 450 mg) or placebo was administered orally to 14 fasting male Japanese volunteers (aged 20–55 years) on 4 non-consecutive days. Main plasma and urine pharmacokinetic end-points included maximum observed plasma concentration (Cmax), time to Cmax (tmax), area under the plasma concentration–time curve (AUC), apparent terminal-phase half-life (t1/2), urinary recovery of unchanged drug, renal clearance, and percentage of drug excreted in urine. Safety end-points included adverse events, clinical signs and symptoms (e.g., hematology, chemistry, and urinalysis), vital signs (blood pressure and heart rate), and 12-lead electrocardiogram.Clinical trial registration number:ClinicalTrials.gov registration identifier is NCT01853852.Results:Median tmax of migalastat was 3.0–3.5 h. Migalastat HCl concentrations declined relatively rapidly, with a mean t1/2 of 3.2–4.0 h. The amount of migalastat HCl recovered in the urine and the percentage of migalastat HCl excreted unchanged over 24 h were consistent (∼45–50%) across the dose range. The AUC and Cmax of migalastat HCl were dose proportional from 50–450 mg. Safety results were similar to those observed in non-Japanese populations.Conclusions:This study demonstrated that ascending single doses of migalastat HCl (50 mg, 150 mg, 450 mg) are absorbed at a moderate rate and eliminated relatively rapidly, with a safety profile consistent with that observed in non-Japanese populations. These results confirm the dose-proportional pharmacokinetics of migalastat HCl from 50–450 mg. This study was limited by a small subject population and a short-term follow-up.

Pharmacokinetics of NXY-059, a nitrone-based free radical trapping agent, in healthy young and elderly subjects

The tolerability, safety, and pharmacokinetics of NXY-059, a nitrone-based free radical trapping agent under development for the treatment of acute ischemic stroke, were investigated in 2 double-blind, placebo-controlled dose-escalation studies in healthy subjects. In the first study in 6 panels of young male subjects (n = 48, 22-45 years), constant rate infusions lasted 8 hours and ranged from 0.16 to 5.25 μmol/kg/h (0.06 to 2.0 mg/kg/h). In the second study, elderly male and female subjects (n = 24, 57-72 years) were infused over 24 hours or 72 hours to reach target plasma levels of 30 μmol/L or 60 μmol/L, respectively, using doses in the range 1.4-4.0 μmol/kg/h. With a 1-hour loading infusion set at 3 times the maintenance infusion rate, the target plasma level was reached in 1 hour. Adverse events were mild or moderate, and no clinically relevant changes in vital signs, ECG recordings, or laboratory values were noted. Steady-state levels in both studies increased proportionally to the infusion rate, indicating linear kinetics. Renal elimination was predominant, the recovery of unchanged drug in urine being 80% to 90% irrespective of age. The average plasma clearance in young and elderly subjects was 7.0 L/h and 4.1 L/h, respectively. It was estimated that glomerular filtration and active tubular secretion of NXY-059 accounted for approximately two-thirds and one-third of its renal clearance, respectively. In the elderly, clearance of NXY-059 was significantly correlated to creatinine clearance. The renal clearance was insensitive to variations in urine pH and urine flow rate. It appears that NXY-059 is well tolerated and has a highly predictable pharmacokinetic profile. Copyright © 2002 by National Stroke Association

Prenatal and postpartum pharmacokinetics of stavudine (2',3'-didehydro-3'-deoxythymidine) and didanosine (dideoxyinosine) in pigtailed macaques (Macaca nemestrina).

Stavudine (5 mg/kg of body weight; n = 7) or didanosine (3.2 mg/kg; n = 4) was administered as an intravenous bolus to pregnant pigtailed macaques (Macaca nemestrina) near term and 4 to 5 weeks postpartum. No significant differences were found between the prenatal and postpartum total plasma drug clearance, steady-state volume of distribution, terminal plasma drug half-life, mean body residence time, or recovery of unchanged drug in urine. These data indicate that pregnancy does not affect the pharmacokinetics of stavudine or didanosine in M. nemestrina.

Species-dependent differences in the biochemical effects and metabolism of 5-benzylacyclouridine

The pharmacokinetics and biochemical effects of the uridine phosphorylase (UrdPase) inhibitor 5-benzylacyclouridine (BAU) were investigated in the mouse, rat and monkey. Following i.p. administration of BAU (30 mg kg ) in the mouse and i.v. administration in the rat and monkey, initial BAU plasma half-life values were 36, 36 and 25 min, and the areas under the plasma BAU concentration versus time curves (AUC) were 127, 80 and 76 μM·hr, respectively. Rats were also dosed p.o. and i.v. with BAU at 90 mg kg , and a comparison of the AUC values showed an oral bioavailability of 70%. Analyses of plasma samples by HPLC indicated that the metabolism of BAU differed in these species. A major BAU metabolite was observed in monkeys. Its concentration was greater than or equal to that of BAU in almost every plasma sample, and its elimination paralleled that of BAU. Urinary recovery of the metabolite was 10-fold higher than the recovery of unchanged drug. The compound was identified as the ether glucuronide of BAU by its UV absorption spectrum, its co-elution with BAU after incubation with β-glucuronidase, and liquid chromatography/mass spectrum analysis. A different metabolite was detected in rat plasma; its maximum concentration was 15% of the BAU level, and its elution position on the HPLC chromatogram was not affected by the action of β-glucuronidase. BAU had equivalent potency against UrdPase in liver extracts from the three species, with K i values of about 0.17 μM. However, the in vivo effects of BAU on plasma uridine concentrations were species dependent. In mice, a 30 mg/kg i.p. dose of BAU increased the plasma uridine concentration to 11 μM from a control level of 1.8 μM. In the rat, a 30 mg/kg i.v. dose of BAU increased plasma uridine to 2.1 from 1.1 μM control levels, and a 300 mg/kg oral dose resulted in a peak plasma uridine concentration of only 6 μM. In the monkey, BAU (30 mg/kg, i.v.) had no effect on plasma uridine despite the presence of 10–100 μM BAU levels in plasma for 1.5 hr. These data show that there are significant differences in the biochemical effects and metabolism of BAU in CD-1 mice, CD rats and cynomolgus monkeys.

High-performance liquid chromatographic analysis of idarubicin and fluorescent metabolites in biological fluids.

A specific, sensitive, and reliable high-performance liquid chromatographic (HPLC) method for the determination of idarubicin (IDA) and its known fluorescent metabolites idarubicinol (IDAol) and 4-demethoxy-daunomycinone (AG1) in biological fluids (human plasma and urine) was developed and tested. Plasma samples were solid-phase-extracted (C18 bonded silica cartridges). Complete separation of unchanged drugs and metabolites was achieved on a Cyanopropyl chromatographic column (25 cm x 4.6 mm inside diameter; particle size, 5 microns) using fluorescence detection (excitation wavelength, 470 nm; emission wavelength, 580 nm). Sensitivity was better than 0.2 ng/ml for all analytes; rates of recovery of unchanged drug and metabolites were better than 84.5% (IDA), 80.3% (IDAol), and 83.9% (AG1). The interassay coefficient of variation was 6.5% for IDA, 5.8% for IDAol, and 9.8% for AG1. Mean intra-assay precision was 4.6% for IDA, 5.9% for IDAol, and 5.0% for AG1 at sample concentrations of above 1 ng/ml and 12.1% for IDA, 10.8% for IDAol, and 14.1% for AG1 at sample concentrations of below 1 ng/ml.

Nonlinear disposition of intravenous 2',3'-dideoxyinosine in rats.

The pharmacokinetics of 2',3'-dideoxyinosine (ddI) were examined in rats given intravenous doses of 8, 40, or 200 mg/kg. The concentrations of ddI in whole blood and plasma were identical. The concentration decline was multiexponential, with mean half-lives of 2 and 20 min for the first and second phases, respectively. At the highest dose, a slower third phase with a half-life of 56 min was observed. The total-body clearances were 99, 77, and 37 ml/min-kg for the 8, 40, and 200 mg/kg doses. The steady-state volume of distribution showed a trend for a decrease with increasing doses, but the difference was not statistically significant. Twenty-four-hour urinary recovery of unchanged drug for the three doses was similar at about 20%, suggesting that a major fraction of the dose was metabolized. Urinary excretion of ddI metabolite, hypoxanthine, accounted for less than 5% of the dose. Renal and metabolic clearances decreased with increased doses. ddI was metabolized in blood; the addition of inorganic phosphate, a cosubstrate in phosphorylase-mediated nucleoside catabolism, enhanced the degradation by about fourfold. In summary, these data indicate equal distribution of ddI in the extracellular and intracellular spaces in blood, its enzymatic degradation in blood, and nonlinear elimination kinetics.

A study of the pharmacokinetics and pharmacodynamics of nifedipine in combination with atenolol

This double-blind randomized, crossover study was undertaken to determine the pharmacokinetic properties of nifedipine retard and atenolol when given separately, as a free or a fixed combination, compared with placebo in 15 healthy male volunteers. There was no difference between the three atenolol formulations in time to maximum blood concentration or elimination half-life. The fixed combination showed significant differences in both maximum observed blood concentrations (+16 per cent) and total area under the curve (+16 per cent) compared to atenolol alone. Urinary recovery of unchanged drug from the fixed combination was also slightly increased but the difference was not statistically significant. Furthermore, statistical evaluation of the plasma pharmacokinetics of nifedipine retard and urinary recovery of nifedipine metabolite showed that all three formulations were indistinguishable. Thus, it is concluded that the fixed combination of nifedipine and atenolol is bioequivalent to the free combination and that the bioavailability of both drugs in the fixed combination is equivalent to that of the single entities.

Effect of mequitazine on the pharmacokinetics of theophylline in asthmatic patients

The effect of an oral anti-allergic drug, mequitazine, on the pharmacokinetics of theophylline has been investigated in seven asthmatic patients. They received chronic theophylline therapy (a sustained-release theophylline tablet 200-400 mg b.d. at 12 h intervals) and coadministered mequitazine 6 mg for 3 weeks. Plasma theophylline concentration-time curves and the urinary excretion of theophylline and its major metabolites before and after coadministration of mequitazine were compared. No significant change in the pharmacokinetic parameters of theophylline or in the urinary recovery of unchanged drug and its metabolites was observed. Thus, mequitazine did not influence the pharmacokinetics of theophylline and it should be safe for coadministration to asthmatic patients on chronic theophylline therapy.

Pharmacokinetics of famotidine in elderly patients with and without renal insufficiency and in healthy young volunteers

The pharmacokinetics of the H2-receptor antagonist famotidine, after oral administration of a 20 mg tablet, has been studied in 10 elderly patients with normal renal function (CLCR greater than or equal to 59 ml.min-1, Mean = 80 ml.min-1), 5 elderly patients with renal insufficiency (CLCR less than or equal to 38 ml.min-1, Mean = 15 ml.min-1), and 6 healthy young volunteers. Elimination half-life in the elderly patients with renal insufficiency was significantly prolonged compared to the elderly patients with normal renal function and the young volunteers. The correlation coefficient between creatinine clearance and the elimination rate constant of famotidine was 0.672. Mean urinary recovery of unchanged drug up to 24 h in the young volunteers was 44%. The mean renal clearance of famotidine in the young volunteers (270 ml.min-1) was substantially greater than the creatinine clearance, 128 ml.min-1, which suggests the possibility of tubular secretion of famotidine.

Pharmacokinetics of cadralazine in hypertensive patients.

Pharmacokinetics of cadralazine, urinary recovery of its putative active metabolite 3-hydrazino-6-aminopiridazine derivative (ISF 2405) and clinical effects were assessed in a placebo-controlled trial in 8 hypertensive in-patients, after acute oral administration of cadralazine. After a 2-week placebo-washout period, the protocol envisaged two consecutive days of monitoring of blood pressure and heart rate. On the first day a placebo tablet was given (9 am), while on the second day patients received a 30 mg cadralazine tablet in single-blind conditions. Blood and urine samples were obtained during the active drug day until 12 h after administration. Concentration of cadralazine in plasma and urine was detected by a specific HPLC method, while the metabolite ISF 2405 was detected in urine by a GC-MS method. Cadralazine caused gradual and long-lasting pressure decrease, statistically significant in comparison to placebo between 3 and 12 hours from drug intake, accompanied by a significant increase in heart rate. Cadralazine by oral route was promptly absorbed with a mean peak time of 1.3 h. Thereafter it followed a monoexponential decay curve, with a plasma half life of 3.1 h. The relative different bioavailability of oral cadralazine among patients was not correlated with cardiovascular changes. Urine recovery of unchanged drug after 12 h was high, reaching 67.3%, while concentration of metabolite ISF 2405 was about 1/1000 of parent compound.

Pharmacokinetics of xamoterol after intravenous and oral administration to volunteers.

The pharmacokinetics of xamoterol, a beta-adrenoceptor partial agonist under clinical evaluation for the treatment of mild to moderate heart failure, have been studied in 12 healthy male subjects. They received 14 mg i.v. and oral doses of 50 and 200 mg as a tablet and 200 mg as a solution in a 4 way cross-over design. After i.v. dosing the elimination half-life was 7.7 h, the total body clearance was 224 ml.min-1 and the volume of distribution at steady-state (Vss) was 48 l. Sixty-two percent of the dose was recovered unchanged in urine. After oral doses, the absolute bioavailability of xamoterol was shown to be 5% irrespective of whether the dose was administered as a tablet or solution. Peak plasma concentrations occurred at about 2 h for the tablet dose and slightly earlier (1.4 h) for the solution. Peak plasma concentration, AUC and urinary recovery of unchanged drug increased in proportion to dose. The apparent elimination half-life after oral doses (16 h) was significantly longer than that observed after an intravenous dose. Despite the low bioavailability, the degree of inter-subject variability of oral bioavailability was small probably indicating that the controlling factor is the hydrophilic nature of the molecule rather than extensive first pass metabolism or poor dissolution of xamoterol from the tablet formulation.

Enprofylline pharmacokinetics in children with asthma.

The pharmacokinetics of intravenous enprofylline has been studied in 8 children with asthma. The mean plasma half-life of enprofylline (1.0 h) was considerably shorter than that previously reported in adults. The half-life determined from log urine excretion rate data was identical to the plasma half-life, so urine excretion could be used as a non-invasive method to study the elimination rate. As in adults, urinary recovery of unchanged drug averaged 89%, and the volume of distribution, Vz, averaged 0.58 l/kg. Clearance was higher in children than in adults when calculated per kg body weight, but not when calculated per m2 body surface area. The dosage of enprofylline in children would be more accurate if calculated in proportion to surface area rather than to body weight. Data agree with published information on creatinine clearance, which, adjusted for body surface area, stays constant from the age of 3 years until early adult life.

Cimetidine kinetics during resuscitation from burn shock.

Severely burned patients suffer from rapidly changing metabolic and hemodynamic abnormalities that could alter drug kinetics. The kinetics of cimetidine, commonly used in the prophylaxis of acute stress erosions, were studied during fluid resuscitation of 11 patients with mean burn sizes of 45% total body surface area. Six patients were studied after the completion of fluid resuscitation. Total clearance, steady-state volume of distribution, and cimetidine t1/2 did not change between the early period after burn and after fluid resuscitation, but before the completion of fluid resuscitation patients had lower renal and greater nonrenal cimetidine clearance than after resuscitation. The increase in nonrenal cimetidine clearance resulted in decreased urinary recovery of unchanged drug, 50.7 +/- 14% during fluid resuscitation and 81.0% +/- 6% after resuscitation.

Absorption of enprofylline from the gastrointestinal tract in healthy subjects.

Enprofylline, a new potent bronchodilator xanthine drug, was given orally as an aqueous solution to 6 healthy subjects in single doses of 2, 4 and 6 mg/kg. The two lower doses produced plasma concentrations in the range 1-4 mg/l, i.e. in the assumed "therapeutic interval" according to previous animal studies. A high 24 h urine recovery of unchanged drug, with mean values for the three dose levels ranging from 85 to 91% of the given dose, indicated good absorption and little metabolism. The dose-corrected area under the plasma concentration-time curve rose with dose as the latter was increased from 2 to 6 mg/kg. This indicates that the elimination of enprofylline is capacity-limited at high doses. Double peaks in the plasma concentration-time curves at the higher dose levels suggested intermittent and delayed gastric emptying as a possible explanation. This hypothesis was confirmed by studies in 6 other healthy subjects, who received the drug solution by three different routes; by mouth, via a catheter in the duodenum, and rectally via a catheter in the colon. The corresponding time to peak values (mean +/- SEM) were 32.5 +/- 8.7, 13.3 +/- 2.5, and 157 +/- 23 min.

The pharmacokinetics of tetroxopim in the dog

The pharmacokinetics and metabolism of the newly developed antibacterial tetroxoprim (TXP) were investigated in four male beagle dogs using a 2-(14C)-labelled drug. TXP was administered intravenously and orally at doses of 5 mg/kg bodyweight. Counting of the total 14C-radioactivity shows that the drug was absorbed completely and eliminated almost exclusively by the kidneys. The quantitative absorption of TXP from the canine gastro-intestinal tract was ascertained by comparison of the AUC-values and the renal recoveries of unchanged drug following i.v. and oral dosage. The terminal half-lives of non-metabolized compound in plasma were 4.64 and 4.83 for i.v. and oral dosing respectively. Following either i.v. or oral TXP administration, the major route of excretion was renal elimination of the compound as its major metabolite U-1 (81-82.2% of dose) and as unchanged mother substance (11.4-12.3% of dose).

Pharmacokinetics of Phenylethylmalonamide (PEMA) in Normal Subjects and in Patients Treated with Antiepileptic Drugs

The pharmacokinetics of phenylethylmalonamide (PEMA), a major metabolite of primidone, were investigated following administration of single oral doses (400 mg) to six normal subjects and six patients receiving chronic treatment with antiepileptic drugs. Peak serum PEMA levels were usually attained with 2-4 h after intake. The oral bioavailability estimated on the basis of the recovery of unchanged drug in the urine of normal subjects was at least 80%. Half-life values ranged from 17 to 25 h in normal subjects and from 10 to 23 h in the patients. No statistically significant difference in any of the calculated kinetic parameters could be found between the two groups. The data indicate that PEMA is readily absorbed from the gastrointestinal tract and that it is eliminated predominantly unchanged in the urine of man.

Clinical kinetics of 1,4-dihydroxy-5,8-bis [[2- [(2-hydroxyethyl)amino ]ethyl] amino]-9,10-anthracenedione

The clinical kinetics of 1, 4-dihydroxy-5,8-bis[[ 2-[(2-hydroxyethyl) amino] ethyl] amino]-9,10-anthracenedione dihydrochloride (DHAQ) are reported. DHAQ, 1 to 3 mg/m2, was administered as an intravenous bolus to six patients with metastatic cancer. Plasma clearance of the drug followed a biphasic pattern with a harmonic mean initial half-life (t 1/2) of 13.7 min and a terminal t 1/2 of 37.4 hr. Recovery of unchanged drug in the urine was 6.8% at 24 hr and 7.3% at 72 hr, while the corresponding recovery of total radioactivity was 9.4% and 11.3%. Apparent volume of distribution of DHAQ was about 13.8 +/- 2.9 l/kg. Total clearance was 238.7 ml/kg/hr, twice the creatinine clearance.

Human pharmacokinetics of tolfenamic acid, a new anti-inflammatory agent.

The pharmacokinetics of tolfenamic acid, a new anti-inflammatory agent was studied in six healthy volunteers after an intravenous dose of 100 mg and oral doses of 100, 200, 400 and 800 mg. The disposition of intravenous tolfenamic acid could be described by two-compartment open model, with a central compartment volume (Vdc) of 5.6 +/- 0.31 (mean +/- SE), volume during beta-phase (Vd beta) of 31 +/- 21, and a total elimination rate constant (k 10) 1.6 +/- 0.1 h-1. The terminal elimination half-life was 2.5 +/- 0.6 h and the total plasma clearance 155 +/- 15 ml/min. The elimination occurred principally by extrarenal mechanisms, the recovery of unchanged drug together with is glucuronide in urine averaging only 8.8% of the intravenous dose. The binding of tolfenamic acid to plasma proteins averaged 99.7%. The gastrointestinal absorption had a mean half-life of 1.7 +/- 0.1 h. Based on comparison of areas under the plasma concentration time-curves after intravenous and oral administration, the biovailability of tolfenamic acid capsules averaged 60%. The rate and extent of absorption and the rate of elimination of tolfenamic acid were independent of dose.

The pharmacokinetics of trichlormethiazide in hypertensive patients with normal and compromised renal function.

The pharmacokinetics of trichlormethiazide (TCZ) was studied in twelve patients after a single 4 mg dose. Seven patients had normal renal function with creatinine clearance greater than 90 ml/min. Five patients had compromised renal function with creatinine clearances averaging 48 +/- 29 ml/min. The TCZ plasma half life and area under the plasma concentration-time curve (AUC) were significantly greater in patients with impaired function, compared to patients with normal renal function. There were no significant differences between the two patient groups in terms of either rate of drug absorption or total urinary recovery of unchanged drug. Furthermore, there was no correlation between peak drug levels or AUC and renal excretion of water or electrolytes.