Maximum Tolerated Dose and Pharmacokinetics of Paclitaxel Micellar in Patients with Recurrent Malignant Solid Tumours: A Dose-Escalation Study.

INTRODUCTION: A water-soluble Cremophor EL-free formulation of paclitaxel, in which retinoic acid derivates solubilize paclitaxel by forming micelles (paclitaxel micellar), was studied for the first time in man to establish the maximum tolerated dose (MTD) and to characterize the pharmacokinetics (PK). METHODS: This was an open-label, one-arm, dose-escalating study in patients with advanced solid malignant tumours, for which no standard therapy was available or had failed. Paclitaxel micellar was given as 1-h intravenous infusion every 21 days for 3 cycles, mainly without premedication. Plasma samples were collected during 24 h at the first cycle and paclitaxel concentrations were assayed by high-performance liquid chromatography. PK was evaluated using a two-compartment model. RESULTS: Thirty-four patients received paclitaxel micellar at doses ranging between 90 and 275 mg/m2. MTD was established as 250 mg/m2. Fatigue and neuropathy were the most frequent dose-limiting toxicities. No hypersensitivity reactions were observed. PK of paclitaxel was evaluated in 25 data sets. Paclitaxel micellar had a rapid initial distribution phase, mean half-life 0.55 h, estimated to be completed 3 h after dosing and a mean terminal half-life of 8.8 h. Mean clearance was 13.4 L/h/m2 with fivefold interindividual variability. The residual areas after 10 h and 24 h were 15.7 ± 8.6% and 5.7 ± 3.9% of the area under the plasma concentration-time curve to infinite time (AUCinf), respectively. CONCLUSION: No new side effects unknown for paclitaxel were observed. Maximum plasma concentration (Cmax) and AUCinf showed a tendency to increase linearly with dose within the 150-275 mg/m2 dose range. The possibility to administer paclitaxel micellar without steroid premedication makes it an attractive candidate for further studies in combination with immunotherapy. TRIAL REGISTRATION: EudraCT no: 2004-001821-54. FUNDING: Oasmia Pharmaceutical AB.

Pharmacokinetics of Total and Unbound Paclitaxel After Administration of Paclitaxel Micellar or Nab-Paclitaxel: An Open, Randomized, Cross-Over, Explorative Study in Breast Cancer Patients.

INTRODUCTION: Paclitaxel micellar is a novel formulation of paclitaxel in which retinoic acid derivates solubilize paclitaxel. The aim of the present study was to compare the unbound and total plasma pharmacokinetics of the new formulation with those of nanoparticle albumin-bound (nab)-paclitaxel and to further assess its safety. METHODS: In this open, randomized, cross-over study, 28 female patients with breast cancer were given paclitaxel micellar and nab-paclitaxel as a 1-h intravenous infusion at a dose of 260 mg/m2. Plasma samples were collected during 10 h, which were projected to cover at least 80% of the area to infinite time, AUCinf. Unbound paclitaxel was measured in ultrafiltrate of plasma. Total paclitaxel in plasma was measured after protein precipitation with acetonitrile. Both assays used ultra-performance liquid chromatography (UPLC) followed by MS/MS for drug quantification. The unbound fraction, fu, was calculated as the ratio between the unbound and the total concentration. RESULTS: No difference in fu of paclitaxel between the two formulations was observed. Statistical comparison of AUC0-10h and Cmax of unbound paclitaxel demonstrated that the two formulations met the criteria for bioequivalence. Regarding total paclitaxel levels, Cmax but not AUC0-10h met the criteria. This study supports a safe administration of paclitaxel micellar. CONCLUSION: The two formulations, paclitaxel micellar and nab-paclitaxel, behaved similarly following infusion. Probably, both formulations dissociate immediately in the blood, whereupon released paclitaxel rapidly distributes into tissue. Judged from the bioequivalence demonstrated for unbound paclitaxel, the two formulations are considered clinically equivalent. TRIAL REGISTRATION: EudraCT no.: 2010-019838-27. FUNDING: Oasmia Pharmaceutical AB.

Presystemic elimination of budesonide in man when administered locally at different levels in the gut, with and without local inhibition by ketoconazole.

The CYP3A4 substrate budesonide was used to investigate gut wall first-pass metabolism in jejunum, ileum and colon of eight healthy men. Three milligram budesonide in solution was installed at each location by intubation, with or without immediate prior local administration of 16mg ketoconazole. Simultaneously, deuterium-labelled budesonide (0.2mg) was administered intravenously. Pharmacokinetics of unlabelled and labelled budesonide in plasma was evaluated using LC-MS/MS. Ketoconazole increased budesonide systemic availability significantly in jejunum (from 11.8 to 21.7%) and ileum (from 15.9 to 31.8%). T(max) and MAT were unaffected. No significant effects were noted after colon administrations, nor were there any effects on the pharmacokinetics of intravenously administered budesonide. The increased bioavailability is most probably explained as inhibition of gut wall metabolism. The data are in accordance with the well-known CYP3A activity in the small intestine, evidently capable of metabolising at least half the absorbed dose of budesonide. In contrast, the results indicate that this enzyme activity is insignificant in the colon.

A convenient method for local drug administration at predefined sites in the entire gastrointestinal tract: experiences from 13 phase I studies.

For local administration of drugs or enzyme inhibitors in the human gut, a small-bore, smooth tube was introduced through the nose, retrieved from the pharynx, equipped with a firm radio-opaque capsule, and swallowed. Peristalsis moves the capsule to the desired location in the gut where it is anchored before administration via the tube. Drug uptake is followed by plasma sampling. One capsule type is used for solutions, another for solid formulations. With solutions, repeated administrations could be done with the capsule being anchored for 24h or longer or, alternatively, at several locations along the gut. This communication presents the method and an overview of 13 uptake and enzyme/transporter localization studies. Altogether, 268 intubations were undertaken in a total of 128 subjects. Plasma concentrations found with terbutaline and metoprolol are presented showing that terbutaline has its best uptake in the upper small intestine, whereas metoprolol shows the same bioavailability along the whole gut. Subjects could undertake most of their normal activities while carrying the equipment. No serious adverse events (AEs) occurred. Possibly intubation-related AEs were abdominal pain (n=8) and constipation (n=5). In conclusion, the method has been found to be safe, convenient and multifunctional for studies of drug uptake at predetermined gut locations in healthy subjects.

NXY-059 does not significantly interact with furosemide in healthy volunteers.

NXY-059 is a free radical-trapping neuroprotectant that reduces infarct size and preserves brain function in animal models of acute ischemic stroke. Acute ischemic stroke patients receiving NXY-059 may also be exposed to diuretics for treatment of heart failure or hypertension. NXY-059 and furosemide are partly eliminated by active tubular secretion via an organic anion transporter. This double-blind, randomized, crossover, placebo-controlled study investigated whether an infusion of NXY-059 (15 mg/mL) during 12 hours affects the diuretic and saluretic effects of a 30-mg intravenous bolus dose of furosemide (10 mg/mL) administered after 6 hours' infusion, in 13 male and 11 female healthy subjects. The net increase in urine volume and sodium excretion in the interval of 6 to 12 hours was 4.15 L and 178 mmol/L, respectively, during NXY-059 treatment (P = .93) and 4.34 L and 190 mmol/L, respectively, during placebo treatment (P = .54). NXY-059 reduced the renal clearance of furosemide by 19% (P = .019), and furosemide reduced the renal clearance of NXY-059 by 8% (P = .005). NXY-059 was well tolerated.

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 micromol/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 micromol/L or 60 micromol/L, respectively, using doses in the range 1.4-4.0 micromol/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.

Differentiating mucosal and hepatic metabolism of budesonide by local pretreatment with increasing doses of ketoconazole in the proximal jejunum.

Many drugs undergo first-pass metabolism both in the gut mucosa and the liver, but little is known about the relative efficiency of these two pathways. The objective of this study was to differentiate between mucosal and hepatic metabolism using budesonide as a probe. After a light breakfast, budesonide, 3mg, was infused locally in the proximal jejunum of eight healthy men on seven occasions, on six occasions after administering the CYP3A4 inhibitor ketoconazole 5 min before in the same jejunal position. The dose range of local inhibitor was 1-128 mg, the highest dose also preceded by an oral dose of 200mg given 12h earlier. Simultaneously with intrajejunal budesonide, deuterium-labelled budesonide (0.2mg) was administered intravenously. Pharmacokinetics of unlabelled and labelled budesonide in plasma was evaluated after LC-MS/MS analysis. Bioavailability of budesonide without inhibition was 27(12-42)%. All ketoconazole doses increased budesonide bioavailability. However, systemic clearance of labelled budesonide was unaffected by ketoconazole doses up to 16 mg but decreased significantly at doses of 64 mg and above. At the two highest doses (128 mg and above) bioavailability approached 100%, showing that budesonide was completely absorbed from jejunum. Ketoconazole doses up to 16 mg appeared to inhibit only mucosal enzymes, while higher doses inhibited also hepatic metabolism. Applying sigmoid E(max)-models of the mean inhibitions in mucosa and liver indicated that, in this study performed under fed conditions, their uninhibited extraction ratios of budesonide were approximately 0.32 and 0.60, respectively. Ketoconazole doses that inhibited half the metabolism were estimated at about 1mg in the mucosa and about 50mg in the liver. In conclusion, this study gave a rough estimate of the relation between mucosal and hepatic first-pass metabolism of budesonide.

Clinical efficacy and pharmacokinetic profiles of intranasal and oral cetirizine in a repeated allergen challenge model of allergic rhinitis.

BACKGROUND: Intranasal and oral antihistamines are effective in treating allergic rhinitis. Studies comparing these routes of administration of an antihistamine regarding efficacy and pharmacokinetic profile are lacking. OBJECTIVE: To compare topical and oral routes of administration of cetirizine regarding efficacy, plasma exudation, and systemic drug levels in a repeated allergen challenge model of allergic rhinitis. METHODS: Oral cetirizine dihydrochloride, 10 mg once daily, and topical cetirizine dinitrate in a dose corresponding to 4.4 mg of the dihydrochloride salt twice daily were given to grass pollen-sensitive individuals for 12 days in a double-blind, placebo-controlled, crossover design. Timothy grass pollen allergen challenges were given once daily for 7 days using a nasal spray device. Nasal symptoms and peak inspiratory flow were recorded in the morning, 10 minutes after allergen challenge, and in the evening. The pharmacokinetics of the treatments was monitored in 8 patients. The remaining 28 patients were challenged topically with histamine 12 and 24 hours after the final topical and oral cetirizine doses, respectively. Nasal lavage levels of alpha2-macroglobulin were determined to evaluate histamine-induced mucosal plasma exudation. RESULTS: During the last 3 days of the repeated allergen challenge model, chronic symptoms were established. Both treatments reduced symptoms 10 minutes after allergen challenge (P < .001 vs placebo). Neither treatment reduced morning and evening symptoms or nasal peak inspiratory flow. Topical, but not oral, cetirizine reduced histamine-induced plasma exudation (P < .01 vs placebo) when systemic drug levels were similar in the 2 treatment regimens. CONCLUSIONS: Topical and oral cetirizine reduced acute nasal symptoms produced by allergen challenges in patients with established chronic symptoms. There were also antihistaminic effects of topical cetirizine not related to systemic drug levels.

Effect of NXY-059, a novel neuroprotectant, on the pharmacokinetics of a single dose of digoxin in healthy subjects.

OBJECTIVE: NXY-059 is a novel free-radical trapping neuroprotectant. Digoxin treatment is common in acute ischaemic stroke, the intended patient population for NXY-059. Since both digoxin and NXY-059 are eliminated primarily renally, with a substantial contribution by active renal secretion, and because digoxin has a narrow therapeutic window, this open, randomised, crossover, two-period study investigated whether NXY-059 affects the pharmacokinetics (PK) of digoxin. RESEARCH DESIGN AND METHODS: Twenty-two healthy subjects received 0.5 mg oral digoxin 2 h after the start of 60-h intravenous infusions of NXY-059 and placebo separated by a 14-day washout. Blood and urine were collected for 60 h. Digoxin concentrations were measured by a novel liquid chromatography-mass spectrometry assay. MAIN OUTCOME MEASURES: The ratio of the geometric mean (90% confidence interval) between NXY-059 and placebo for the digoxin area under the concentration-versus-time curve was 0.91 (0.83-0.99) and was within the predefined range for no interaction (0.80-1.25). No safety concerns were raised in the study. No serious adverse events were recorded. The most common adverse event was headache with similar frequencies in the two treatments. CONCLUSIONS: NXY-059 had no clinically significant effect on the PK of digoxin.

Pharmacokinetics in renally impaired subjects of NXY-059, a nitrone-based, free-radical trapping agent developed for the treatment of acute stroke.

OBJECTIVE: NXY-059 is a nitrone-based, free-radical trapping agent being developed for the treatment of acute ischaemic stroke. Elimination of NXY-059 is primarily renal. The objective of the study was to investigate the pharmacokinetics of NXY-059 in subjects with renal impairment. METHODS: Twenty-four subjects with a glomerular filtration rate (GFR) ranging from 19 ml/min to 100 ml/min received NXY-059 intravenously over a 24-h period. Drug in plasma and urine was measured for 72 h. One-hour loading infusion rates were proportional to body weight, while maintenance infusion rates were proportional to GFR. Target plasma levels were 60 micro mol/l for subjects with mild (GFR 50-100 ml/min) and moderate (GFR 30-49 ml/min) renal impairment, and 30 micro mol/l for subjects with severe renal impairment (GFR <30 ml/min). GFR was measured as sinistrin clearance. RESULTS: The data indicated no tolerability or safety concerns with NXY-059. The half-life, which normally is approximately 2-4 h, was in the order of 10-12 h in subjects with moderate and severe renal impairment. The distribution parameters steady-state volume of distribution (V(ss)) and unbound fraction in plasma at 13-15 l and 0.53-0.58, respectively, were virtually the same as previously observed in healthy subjects. Plasma clearance of NXY-059, which ranged from 9 ml/min to 76 ml/min, was directly proportional to kidney function (GFR) with no discernible contribution by non-renal clearance. The correlation coefficient squared (r(2)) was 0.93, both when the renal function parameter was GFR and when it was creatinine clearance estimated from serum creatinine, age, weight and sex. CONCLUSION: Non-renal elimination of NXY-059 appeared to be insignificant even in subjects with low renal capacity. Patients with renal impairment should have their dose of NXY-059 adjusted for renal function, conveniently assessed from serum creatinine.

Pharmacokinetics and sedative effects in healthy subjects and subjects with impaired liver function after continuous infusion of clomethiazole.

OBJECTIVE: Clomethiazole is virtually completely eliminated by hepatic metabolism. This study was designed to assess the impact of liver impairment on its elimination and sedative effects. METHODS: Eight patients with mild liver impairment (Child-Pugh grade A), eight patients with moderate/severe liver impairment (Child-Pugh grade B/C) and eight healthy subjects of similar age were given 68 mg/kg clomethiazole edisilate according to a 24-h infusion scheme aimed at producing minimum sedation as it was intended for clinical use in patients with stroke. Concentrations of clomethiazole and its active alpha-carbon hydroxylated metabolite NLA-715 were followed in plasma and urine for 96 h and 24 h, respectively. Sedation was monitored using a scale from 1 to 6. RESULTS: The fraction excreted unchanged in urine was less than 0.2% for clomethiazole and less than 0.4% for NLA-715. Urine concentrations of clomethiazole were strongly correlated (r(2)=0.60) to plasma concentrations and approximately equal to unbound plasma concentrations. Plasma levels of NLA-715 increased steadily during the infusion, eventually reaching mean levels exceeding those of clomethiazole in all groups. Plasma clearance of clomethiazole in subjects with mildly impaired liver function was not statistically different from that of healthy controls (40 l/h vs 44 l/h). In subjects with moderate/severe liver impairment, there was a 50% reduction in clearance. Sedation was not observed except in two subjects in the Child-Pugh A group showing mild sedation. CONCLUSION: The reduced clomethiazole clearance in patients with moderate/severe liver impairment seems to call for a reduction of clomethiazole dosage. However, sedation was not observed in this group at the investigated dose level.