Phase I and pharmacokinetic (PK) study of MAG-CPT (PNU 166148): a polymeric derivative of camptothecin (CPT).

Polymeric cytotoxic conjugates are being developed with the aim of preferential delivery of the anticancer agent to tumour. MAG-CPT comprises the topoisomerase I inhibitor camptothecin linked to a water-soluble polymeric backbone methacryloylglycynamide (average molecular weight 18 kDa, 10% CPT by weight). It was administered as a 30-min infusion once every 4 weeks to patients with advanced solid malignancies. The objectives of our study were to determine the maximum tolerated dose, dose-limiting toxicities, and the plasma and urine pharmacokinetics of MAG-CPT, and to document responses to this treatment. The starting dose was 30 mg m(-2) (dose expressed as mg equivalent camptothecin). In total, 23 patients received 47 courses at six dose levels, with a maximum dose of 240 mg m(-2). Dose-limiting toxicities were myelosuppression, neutropaenic sepsis, and diarrhoea. One patient died after cycle 1 MAG-CPT at the maximum dose. The maximum tolerated dose and dose recommended for further clinical study was 200 mg m(-2). The half-lives of both MAG-CPT and released CPT were prolonged (>6 days) and measurable levels of MAG-CPT were retrieved from plasma and urine 4 weeks after treatment. However, subsequent pharmacodynamic studies of this agent have led to its withdrawal from clinical development.

A phase I and pharmacokinetic study of MAG-CPT, a water-soluble polymer conjugate of camptothecin.

Polymeric drug conjugates are a new and experimental class of drug delivery systems with pharmacokinetic promises. The antineoplastic drug camptothecin was linked to a water-soluble polymeric backbone (MAG-CPT) and administrated as a 30 min infusion over 3 consecutive days every 4 weeks to patients with malignant solid tumours. The objectives of our study were to determine the maximal tolerated dose, the dose-limiting toxicities, and the plasma and urine pharmacokinetics of MAG-CPT, and to document anti-tumour activity. The starting dose was 17 mg m(-2) day(-1). Sixteen patients received 39 courses at seven dose levels. Maximal tolerated dose was at 68 mg m(-2) day(-1) and dose-limiting toxicities consisted of cumulative bladder toxicity. MAG-CPT and free camptothecin were accumulated during days 1-3 and considerable amounts of MAG-CPT could still be retrieved in plasma and urine after 4-5 weeks. The half-lives of bound and free camptothecin were equal indicating that the kinetics of free camptothecin were release rate dependent. In summary, the pharmacokinetics of camptothecin were dramatically changed, showing controlled prolonged exposure of camptothecin. Haematological toxicity was relatively mild, but serious bladder toxicity was encountered which is typical for camptothecin and was found dose limiting.

Pharmacokinetics of reboxetine in elderly patients with depressive disorders.

OBJECTIVES: To examine the pharmacokinetic characteristics of the selective norepinephrine reuptake inhibitor, reboxetine, in elderly patients with depression. PATIENTS: Twelve female inpatients (mean age 80 +/- 4 years) with major depressive or dysthymic disorder were enrolled in a 4-week uncontrolled study of oral reboxetine 2-8 mg/day. METHODS: After a one-week washout period, patients were randomized into two groups (groups A and B, n = 6/group). Reboxetine was given twice daily, starting with 2 mg/day during week 1 and increasing by 2 mg/day each week to 8 mg/day in week 4. Pharmacokinetic evaluations were carried out at two dosage levels in each group: at the end of weeks 1 and 3 in group A (2 and 6 mg/day), and at the end of weeks 2 and 4 in group B (4 and 8 mg/day). Blood and urine samples were taken for determination of reboxetine pharmacokinetics. RESULTS: Reboxetine displayed linear pharmacokinetics, with dose-proportional changes, in elderly depressed patients. Mean total urinary recovery ranged from 4.06 to 6.17%. The mean area under the plasma concentration-time curve (AUCtau) and the maximum plasma drug concentration (Cmax) showed considerable variation between patients; at a dosage of 4 mg/day, AUCtau was 1,466-6,866 ngxh/ml and Cmax ranged from 169 to 663 ng/ml. CONCLUSIONS: The pharmacokinetics of reboxetine are linear across the dosage range of 2-8 mg/day in elderly depressed patients, although Cmax and AUCtau values are higher (and more variable) than in young adults. These results support the use of a lower starting dose (4 mg/day) of reboxetine in the elderly.

Polymer-bound camptothecin: initial biodistribution and antitumour activity studies.

Camptothecin (CPT) is a potent, antitumour drug acting mainly through inhibition of topoisomerase I during the S-phase of the cell cycle. Despite its impressive antitumour activity, clinical development was halted for unpredictable toxic events. Two soluble N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers were synthesised to contain CPT (5 wt.% and 10 wt.%). CPT was covalently linked at its alpha-hydroxyl group to the polymers through a Gly-Phe-Leu-Gly- spacer. In-vitro, CPT-conjugates were fairly resistant to hydrolysis in plasma as in buffer at neutral pH (0.2-0. 4% free CPT/h), while elastase and cysteine-proteases were able to release the active drug. Plasma levels in mice after intravenous administration of CPT-conjugates confirmed the modest hydrolysis in plasma. Plasma levels were approximately 5-fold lower than those observed at the highest tolerated dose of CPT administered in classical vehicles. Biodistribution in HT29 human colon carcinoma bearing mice was carried out after i.v. injection of [3H]CPT-conjugate and free [3H]CPT. Radioactivity uptake in tumour was evident only after [3H]CPT-conjugate treatment. Repeated intravenous administration of CPT-conjugates to HT29-bearing mice gave more than 90% tumour inhibition, some complete tumour regressions and no toxic deaths. The improved pharmacological profile on HT29 human colon carcinoma xenografts of the first poly(HPMA)-CPT conjugates might be ascribed to their prolonged intra-tumour retention and sustained release of the active drug.

Effect of rifabutin on ethambutol pharmacokinetics in healthy volunteers.

The effect of repeated administration of rifabutin on the pharmacokinetics and metabolism of ethambutol was evaluated in ten healthy volunteers. The subjects received a single oral administration of 1200 mg ethambutol on days 1 and 10 and a single daily oral dose of 300 mg rifabutin from days 3 to 9. No statistically significant difference was found in plasma pharmacokinetics (C(max), t(max), AUC, half-life and MRT) and in the renal clearance, whereas a significant decrease in the amount of unchanged ethambutol excreted in urine was observed. The decrease observed in ethambutol urinary excretion may be accounted for by taking into consideration the variability of the urinary excretion of ethambutol reported in the literature. However, a slight, likely not clinically relevant, induction or activation of kidney alcohol and/or aldehyde dehydrogenase isoenzymes by rifabutin cannot be ruled out at present. Evidence exists in the present study for autoinduction of rifabutin metabolism; this is shown by the lower plasma concentrations obtained 24 h after the seventh dose as compared to the theoretical concentrations.

Hemodynamic effects of reboxetine in healthy male volunteers.

BACKGROUND: Reboxetine [(R,S)-2[(R,S)-alpha-(2-ethoxyphenoxy)benzyl]morpholine methanesulfonate] is a racemic compound that consists of equal proportions of R,R- and S,S-enantiomers. This study investigated the hemodynamic effects of reboxetine and the R,R-enantiomer compared with placebo in volunteers. The pharmacokinetics of reboxetine and its enantiomers were also investigated in the study. METHODS: Nine healthy, male volunteers received single doses of 4 mg reboxetine, 2 mg R,R-enantiomer, and placebo at weekly intervals. Reboxetine and the R,R-enantiomer were well tolerated in all volunteers. RESULTS: The heart rates of patients in the supine and standing positions were increased after reboxetine administration compared with the R,R-enantiomer (P < .05, except supine heart rate at 6 hours) and placebo (P < .05). Supine systolic and diastolic blood pressure was also increased by 3 +/- 4 and 1 +/- 4 mm Hg, respectively, after reboxetine compared with R,R-enantiomer (-2 +/- 4 and -4 +/- 3 mm Hg) and placebo (-4 +/- 4 and -4 +/- 4 mm Hg) administration. The systolic and diastolic blood pressure measurements for subjects while standing did not differ significantly among treatments. There was no significant difference between the maximum plasma concentration, mean time to maximum plasma concentration, plasma half-life, or area under the plasma concentration-time curve (AUC) of the R,R-enantiomer after reboxetine or R,R-enantiomer administration. The ratio of the mean AUC values for the R,R- and S,S-enantiomers was 2.1. CONCLUSION: These findings suggest that the S,S-enantiomer is responsible for the hemodynamic effects of reboxetine in humans. Increases in supine blood pressure after reboxetine administration may be interpreted as regression to the mean value and not caused by any treatment effect.

Absolute bioavailability of reboxetine enantiomers and effect of gender on pharmacokinetics.

The absolute bioavailability of reboxetine enantiomers was assessed in six male and six female volunteers. In a two-way crossover study, subjects received 1.0 mg reboxetine orally and 0.3 mg reboxetine as an intravenous bolus. The R,R(-) and S,S(+) enantiomers in serial plasma and urine samples were determined by a validated LC-MS-MS method. There were no significant differences between treatments for clearance or dose-corrected AUC(0-infinity) values. The absolute bioavailability was 0.919 and 1.02 for R,R(-) reboxetine and S,S(+) reboxetine, respectively. A secondary objective of the study was to assess gender effects on pharmacokinetics of the enantiomers. Significant differences in volume of distribution between genders were observed, but differences in weight-corrected volumes were not significant. Weight-corrected systemic clearance and oral clearance tended to be lower in males, but this difference reached statistical significance only for weight-corrected oral clearance of R,R(-) reboxetine. C(max) after oral administration was 40 and 48% higher in women than men for R,R(-) reboxetine and S,S(+) reboxetine, respectively. These results indicate that reboxetine enantiomers are well absorbed after oral administration and that little first-pass metabolism occurs. There are no clinically significant effects of gender on the pharmacokinetics of reboxetine enantiomers.

Pharmacokinetics of reboxetine enantiomers in the dog.

Reboxetine, (RS)-2-[(RS)-alpha-(2-ethoxyphenoxy)benzyl]morpholine methanesulphonate, is a racemic compound and consists of a mixture of the (R,R)- and (S,S)-enantiomers. The pharmacokinetics of reboxetine enantiomers were determined in a crossover study in three male beagle dogs. Each animal received the following oral treatments, separated by 1-week washout period: 10 mg/kg reboxetine, 5 mg/kg (R,R)- and 5 mg/kg (S,S)-. Plasma and urinary levels of the reboxetine enantiomers were monitored up to 48 h post-dosing using an enantiospecific HPLC method with fluorimetric detection (LOQ: 1.1 ng/ml in plasma and 5 ng/ml in urine for each enantiomer). After reboxetine administration mean tmax was about 1 h for both enantiomers. Cmax and AUC were about 1.5 times higher for the (R,R)- than for the (S,S)-enantiomer, mean values +/- SD being 704 +/- 330 and 427 +/- 175 ng/ml for Cmax and 2,876 +/- 1,354 and 1,998 +/- 848 ng.h/ml for AUC, respectively. No differences between the (R,R)- and (S,S)-enantiomers were observed in t1/2 (3.9 h). Total recovery of the two enantiomers in urine was similar, the Ae (0-48 h) being 1.3 +/- 0.7 and 1.1 +/- 0.7% of the enantiomer dose for the (R,R)- and the (S,S)-enantiomers, respectively. No marked differences in the main plasma pharmacokinetic parameters were found for either enantiomer on administration of the single enantiomers or reboxetine. No chiral inversion was observed after administration of the separate enantiomers, as already observed in humans.

Pharmacokinetics of reboxetine in healthy volunteers. Single against repeated oral doses and lack of enzymatic alterations.

The pharmacokinetics of reboxetine have been investigated in 12 healthy male volunteers after a single 2 mg dose of reboxetine and at steady state, following the last administration of a multiple-dose regimen (2mg twice a day for 5 1/2 d). Reboxetine was analysed in plasma and urine samples collected up to 72 h post-dosing using an HPLC method with UV detection. The urinary excretion rate of 6-beta-hydroxycortisol, used as a marker for cytochrome P450IIIA activity, was also tested, and any possible alteration was correlated to reboxetine plasma levels. The dosing regimen was well tolerated by all subjects. Reboxetine pharmacokinetic parameters, calculated after the single dose using non-compartmental analysis, were in good agreement with those obtained in previous studies. Following the multiple-dosing regimen, no significant deviations from expectation based on linear superposition was observed. The accumulation ratio, based on repeated-dose/single-dose ratios of Cmax, AUC(0-12 h), and C(12 h) was approximately two. A slight rise was recorded for the average excretion rate of 6-beta-hydroxycortisol over 48 h by the end of treatment; however, the difference was not statistically significant and the mean excretion rates were within the normal reference range. Thus a significant induction of P450IIIA was not indicated.

Pharmacokinetics of reboxetine in healthy volunteers. Single oral doses, linearity and plasma protein binding.

The pharmacokinetics of reboxetine, a new antidepressant agent, were found to be close to linear in a crossover study comparing administration of single 2, 3, 4, and 5 mg capsule doses in 15 healthy male volunteers, and in the same study the capsules were bioequivalent to the proposed therapeutic tablet formulation (4 mg). Kinetic analysis was based on HPLC assay of reboxetine in plasma and urine collected up to 72 h after each administration. Plasma levels indicated a rapid absorption (tmax approximately equal to 2 h) and an elimination half-life of about 13 h. Clearance and volume of distribution were modest (ratios to bioavailability: CL/F approximately equal to 29 mL min-1; Vz/F approximately equal to 32 L); urinary excretion was approximately 9% of dose, corresponding to a renal clearance of only 3 mL min-1 (a value consistent with the rate of glomerular filtration of unbound drug). In vitro, binding to plasma proteins, estimated from radioactivity levels following dialysis of 14C-labelled reboxetine, appeared to be dominated by alpha 1-acid glycoprotein without marked saturation up to plasma concentrations of over 500 ng mL-1 (2.8-3.1% unbound with human plasma from three additional volunteers; 1.8-2.0% for 2 gL-1 orosomucoid alpha 1-acid glycoprotein, and 46.4-47.4% for 40 g L-1 albumin), whilst the mean Cmax in the current study was much lower (164 ng mL-1 after a 5mg dose).

Stereoselective and species-dependent kinetics of reboxetine in mouse and rat.

Reboxetine, (RS)-2-[(RS)-alpha-(2-ethoxyphenoxy)benzyl]morpholine methanesulphonate, is a racemic compound and consists of a mixture of the (R,R)- and (S,S)-enantiomers. In this study, brain and plasma levels of both enantiomers were determined in mice and rats after oral administration of reboxetine at doses (1.1 mg/kg, mouse; 20 mg/kg, rat) twice the respective ED50 values in the antireserpine test. Plasma and brain concentrations of each enantiomer were measured up to 6 h postdosing using an HPLC method with fluorimetric detection after derivatization with a chiral agent (FLEC). In mice and rats, brain and plasma levels of the (R,R)-enantiomer were always higher than those of the (S,S)-enantiomer. After normalization for dose, the mean AUC0-tz values of both the (R,R)- and (S,S)-enantiomers in mouse brain were about 23 and 32 times higher than in rat brain, respectively. In plasma, the corrected mean AUC0-tz values were about 5 (R,R) and 10 (S,S) times higher in mice than in rats. These results provide evidence for the higher bioavailability and/or lower clearance of both enantiomers in mice than in rats, and for a higher penetration of both enantiomers into mouse brain compared to rat brain.