Phase I trial of oral MAC-321 in subjects with advanced malignant solid tumors.

PURPOSE: MAC-321 is a novel taxane that has demonstrated exceptional activity in human xenograft models when administered intravenously and orally. Preclinical studies of MAC-321 have shown antitumor activity in MDR-expressing and paclitaxel-resistant tumors. This phase I dose escalation study was performed to determine the safety, tolerability, and pharmacokinetic profile of orally administered MAC-321 given once every 21 days. Preliminary antitumor activity of MAC-321 was also examined. METHODS: Key eligibility criteria included adult subjects with refractory solid tumors or solid tumors for which conventional therapy was unsuitable or did not exist, good performance status (ECOG ( 2), and adequate hematologic, hepatic, and renal functions. Plasma pharmacokinetic (PK) sampling was performed during the first cycle of therapy. RESULTS: Five dose levels of MAC-321 ranging from 25 to 75 mg/m(2) were evaluated in 18 subjects (four women and 14 men). MAC-321 was well tolerated at the first three dose levels (25, 37, 50 mg/m(2)). Two subjects developed dose-limiting toxicities (DLTs) at 75 mg/m(2); one subject with grade 3 and one subject with grade 4 neutropenia with fever. Three subjects treated at an intermediate dose level of 60 mg/m(2) had no DLTs. However, the study was terminated prior to completion of the maximal tolerated dose cohort after subjects treated with intravenous MAC-321 in a concurrent study experienced life-threatening toxicities. Other common toxicities included grades 1-2 fatigue and grades 1-2 diarrhea. There was substantial interpatient variability in the PK parameters. MAC-321 was rapidly absorbed with a mean C (max) value of less than 1 h. Mean C (max) and AUC values generally increased in a dose-related manner. The median terminal phase elimination half-life was 45 h (range 20-228 h). Disease stabilization was seen in four subjects with the following tumors: mesothelioma (14 cycles), chondrosarcoma (12 cycles), small cell carcinoma (10 cycles), and prostate carcinoma (6 cycles). CONCLUSIONS: MAC-321 can be safely administered orally once every 21 days up to a dose of 60 mg/m(2). The major DLT was neutropenic fever. Four subjects had disease stabilization.

Pharmacodynamic modeling of pantoprazole's irreversible effect on gastric acid secretion in humans and rats.

The relationship between the pharmacokinetics of pantoprazole, an irreversible proton pump inhibitor, and its effect on gastric acid secretion was evaluated in humans and rats. Pantoprazole pharmacokinetics were studied in 6 rats (5 mg/kg, i.v.) and 22 healthy volunteers (10 to 80 mg, i.v. and oral). Gastric acid secretion under maximum pentagastrin stimulation was measured after i.v. administration of placebo or pantoprazole in 31 rats (0.12 to 1.15 mg/kg) for 4 hours and in 31 subjects (20 to 120 mg) for 24 hours. Pantoprazole has short half-lives of 0.5 hours in rats and 0.8 hours in humans. After administration of the highest dose, acid secretion was fully inhibited within 1 hour and for the whole observation period in both species. An irreversible pharmacodynamic response model was successfully developed and validated. The apparent reaction rate constants of pantoprazole with the proton pumps were 0.691 L/mg/h in rats and 0.751 L/mg/h in humans, and the apparent recovery rates of the pumps were 0.053 h-1 and 0.031 h-1, respectively. The maximum inhibition and the overall effect of pantoprazole are related to exposure, and the onset is related to initial pantoprazole concentrations. It was concluded that this irreversible response model accurately describes the effect of i.v. and oral pantoprazole on gastric secretion and may be used to predict effects under other dosage regimens.

Pharmacokinetics of promethazine hydrochloride after administration of rectal suppositories and oral syrup to healthy subjects.

The pharmacokinetics of promethazine hydrochloride after administration of rectal suppositories at three dosage strengths and oral syrup were studied. The study had an open-label, randomized, crossover design. At intervals of five to nine days, healthy volunteers were given two 12.5-mg promethazine rectal suppositories, one 25-mg suppository, one 50-mg suppository, or 50 mg (10 mL) of promethazine oral syrup. Blood samples were collected before each dose and at intervals from 0.5 to 48 hours afterward. Promethazine concentration was determined by high-performance liquid chromatography, and pharmacokinetic values were calculated with noncompartmental methods. Thirty-six subjects (18 men and 18 women) completed the study. Absorption was highly variable for all the formulations. On average, absorption was more rapid and the maximum plasma concentration (Cmax) higher for the syrup than for the suppositories. Cmax was significantly lower for the 50-mg suppository (mean, 9.04 ng/mL) than for the syrup (19.3 ng/mL). The time to Cmax (tmax) was significantly shorter for the syrup (mean, 4.4 hours) than for the suppositories (6.7-8.6 hours). There were no significant differences in dose-normalized Cmax among the three suppository treatments. Area under the concentration-versus-time curve (AUC) was comparable between the syrup and the 50-mg suppository and between the treatments with two 12.5-mg suppositories and the 25-mg suppository. Elimination profiles were similar among all treatments (mean half-life [t1/2], 16-19 hours). There were no significant differences in pharmacokinetics on the basis of sex or race. The mean relative bioavailability for the three suppository treatments ranged from 70% to 97%. Individual relative bioavailabilities ranged from 4% to 343%. The pharmacokinetics of promethazine administered in oral syrup and rectal suppositories were highly variable, but, in general, the suppositories produced a lower Cmax and later tmax than the syrup. All formulations were comparable in terms of dose-normalized AUC and t1/2, and the three suppository treatments were comparable in terms of dose-normalized Cmax.

Lack of pharmacokinetic interaction between oral pantoprazole and cisapride in healthy adults.

Pantoprazole, an irreversible proton pump inhibitor, may be administered with cisapride, a prokinetic agent. As increased cisapride concentrations may result in longer electrocardiogram (ECG) QTc intervals, a crossover study was conducted in healthy subjects to evaluate the oral pharmacokinetic interaction between cisapride (20 mg) and pantoprazole (40 mg). After dosing, serial blood samples and 12-lead ECGs were collected, and cisapride plasma concentrations were quantitated. For cisapride alone, mean parameter values were the following: peak concentration (Cmax), 56 ng/mL; time to Cmax (tmax), 1.7 hours; area under the concentration-time curve (AUC), 426 ng x h/mL; and terminal half-life (t1/2), 5.8 hours. Pantoprazole coadministration did not alter cisapride AUC or other pharmacokinetic parameters except for a slight 17% decrease in Cmax' resulting in 90% confidence limits of 79% to 88%, which were marginally outside strict bioequivalence limits. In addition, cisapride did not affect ECG QTc intervals, with or without pantoprazole. Therefore, no dosage adjustment is needed when pantoprazole and cisapride are coadministered.

Absorption, metabolism, and other factors that influence drug exposure in toxicology studies.

Drug exposure in toxicology studies is dependent on input from the drug delivery system and elimination of the drug once absorbed. Although seemingly straightforward, absorption, metabolism, and other factors require a more complex interpretation of plasma concentrations and the resulting area under the plasma concentration versus time curve values at doses free from significant toxicity. Absorption may be saturable due to the intestinal, physiologic processes necessary for drug transfer, or intrinsic drug solubility limits may lead to a plateau in systemic plasma concentrations. Different vehicles or administration of drug with food or in the diet may be investigated in an effort to improve systemic exposure. Metabolic profiles may be examined to aid in the selection of a toxicology species more metabolically similar to humans. This will assist in providing adequate safety margins for metabolites as well as parent compound in comparison to humans. Safety assessment of drug metabolites has taken on added significance as our knowledge of metabolite pharmacokinetics in humans has increased. Correlation of free drug concentrations, determined in protein binding studies, may provide a better correlation with toxic effects than do total drug concentrations. Other factors, such as age, gender, and dosing interval need to be considered when interpreting toxicology studies.

Comparison of the pharmacokinetics and pharmacodynamics of the aldose reductase inhibitors, AL03152 (RS), AL03802 (R), and AL03803 (S).

The pharmacokinetics of AL03152 (RS) and its enantiomers, AL03802 (R) and AL03803 (S), were studied in the Sprague-Dawley rat following intravenous bolus administration. The enantiomers had differing pharmacokinetic profiles, while the racemic compound exhibited pharmacokinetic parameters approximating the mean values of the individual enantiomers. The total clearance (CLT) values of the two enantiomers were similar, but the intrinsic clearance (Cl(int)) was much greater for the S-enantiomer than for the R-enantiomer. The volume of distribution (Vss) for AL03802 (R) was threefold greater than that for AL03803 (S). The stereoselectivity in Vss could not be totally accounted for by the slight difference in serum protein binding of the isomers and resulted in a difference in the half-lives of the enantiomers. Only the R-isomer exhibited a persistent terminal elimination phase, consistent with more extensive tissue binding than the S-isomer. AL03152 enantiomers were equivalent in potency assessed from in vitro IC50 values toward rat lens aldose reductase and rat kidney L-hexonate dehydrogenase and lens EC50 values in diabetic rats.

Saturable tissue binding and imirestat pharmacokinetics in rats.

To investigate the hypothesis that the pharmacokinetics of imirestat, an aldose reductase inhibitor, are influenced by saturable binding to tissues, three experiments were done. (1) The nature of the dose dependence was characterized in rats. Two groups of nine adult male Sprague-Dawley rats received iv 14C-imirestat at doses of 2 or 8 mg/kg. Serial blood samples were obtained over 15 days. Volume of distribution at steady-state was significantly different between the high- and the low-dose groups (0.744 +/- 0.103 l and 1.10 +/- 0.228 L, respectively). Clearance was independent of dose over this fourfold range (approximately 15 ml/hr). (2) The effect of either statil or AL3152, both aldose reductase inhibitors and potential competitors for aldose reductase binding, on the pharmacokinetics of a single 0.2-mg/kg iv dose of imirestat was assessed. A 2.4-mg/kg loading dose of statil was administered and a constant-rate infusion (56 micrograms/hr/kg) was begun 16 hr before imirestat. A 2-mg/kg loading dose of AL3152 and a constant-rate infusion (115 micrograms/kg/hr) were also administered 16 hr before imirestat. The infusions were maintained throughout the study. AL3152 administration decreased the imirestat steady-state volume of distribution by a mean of 63%. Statil administration decreased it by a mean of 39%. (3) The dosing regimen of the second study was repeated and, at two sampling times, nine tissues and plasma were obtained from four rats per sampling time for determination of imirestat tissue-to-plasma concentration ratio. The tissue/plasma imirestat concentration ratio in the adrenals 24 hr after imirestat administration was 56.9 +/- 20.0 in the imirestat group, 17.7 +/- 1.27 in the statil-coadministered group, and 12.3 +/- 2.59 in the AL3152-coadministered group.(ABSTRACT TRUNCATED AT 250 WORDS)

Topical and systemic absorption of sodium pyrithione following topical application to the nails of the rhesus monkey.

A study was performed to investigate the local penetration into the nail, the systemic absorption into the rest of the body, and the routes of excretion of sodium pyrithione following topical application to the nail. Approximately 20 microliters of a film-forming 3% sodium 14C-pyrithione solution was applied once daily to 5 fingernails and 5 toenails of 4 rhesus monkeys for 6 or 7 days. Following dose removal on study day 7, 2 animals were sacrificed, and the treated nails were analyzed for radioactivity. The other 2 monkeys received the topical dose for 1 more day and were monitored during the postdosing period. Sodium 14C-pyrithione was absorbed slowly into and across the nail following topical application, with the nails serving as reservoirs for the drug. Further evidence of the slow movement of sodium pyrithione across the nail was provided by peak plasma 14C equivalents obtained on day 9, 1 day after the last dose had been removed from the nails. Only slight drug concentrations were measurable in plasma, with no radioactivity observed beyond day 12. The urinary excretion data exhibited a delay in peak urinary excretion (days 8 and 9), and an elimination half-life of 2 days, so that approximately 90% of the absorbed drug was eliminated within 1 week following treatment. Including a minor excretion pathway through the feces, total excretion as a percent of dosage was 8.5%, indicating that less than 10% of the applied topical dose of sodium pyrithione was absorbed systemically.(ABSTRACT TRUNCATED AT 250 WORDS)

Pulmonary inversion of 2-arylpropionic acids: influence of protein binding.

The possible contribution of pulmonary metabolism to the putative first-pass metabolism of 2-arylpropionic acid nonsteroidal antiinflammatory drugs has not been documented. Isolated perfused rabbit lungs, perfused with 4.5% bovine serum albumin or 5% dextran, were used to study the pulmonary elimination of (R)- and rac-ibuprofen, fenoprofen, and flurbiprofen. In the absence of protein binding, ibuprofen was metabolized via inversion and other pathways, whereas fenoprofen metabolism was essentially restricted to inversion of the (R)-enantiomer; fraction inverted (+/- SE) was 0.37 +/- 0.05 for (R)-ibuprofen and 0.85 +/- 0.03 for (R)-fenoprofen. In the presence of protein, neither ibuprofen nor fenoprofen was metabolized. Flurbiprofen did not undergo pulmonary elimination under any condition studied. This study illustrates that even though a tissue is capable of metabolism, particularly inversion of 2-arylpropionics, the quantitative importance of such elimination pathways may be minimal in the presence of the high degree of protein binding that is characteristic of these drugs.

Conversion of p-tyrosine to p-tyramine in the isolated perfused rat kidney: modulation by perfusate concentrations of p-tyrosine.

We used the isolated perfused rat kidney to evaluate the role of renal decarboxylation of p-tyrosine as the source of urinary p-tyramine. Kidneys were perfused with concentrations of p-tyrosine ranging from 0.02 mM to 2.0 mM. p-Tyramine was measured by a sensitive and specific radioenzymatic assay. An increase in the perfusate concentration of p-tyrosine resulted in a significant increase in p-tyramine production that was blocked by the addition of NSD-1015, an inhibitor of aromatic-1-amino decarboxylase (AADC). We conclude p-tyrosine is the precursor for the renal production of p-tyramine, renal AADC catalyzes the formation of urinary p-tyramine, synthesized p-tyramine is predominantly excreted in the urine, and p-tyramine synthesis is modulated by the arterial delivery of p-tyrosine to the kidney.

Dose-dependent pharmacokinetics of the aldose reductase inhibitor imirestat in man.

The pharmacokinetics of imirestat were studied in healthy volunteers following single and multiple oral doses. After single doses of 20 to 50 mg, imirestat plasma concentrations declined with an apparent elimination half-life of 50 to 70 hr over the 168 hr in which levels were measured. However, with lower doses (2 to 10 mg), an initial rapid decline in drug concentration was followed by a very slow terminal elimination phase with plasma concentrations decreasing little over the 1 week of sampling. This resulted in a decrease in apparent t 1/2 with increasing dose, from 272 +/- 138 hr at 2 mg to 66 +/- 30 hr at 50 mg. During once-daily dosing of 2 to 20 mg/day for 4 weeks, mean steady-state imirestat concentration appeared to be dose proportional, although the time required to achieve steady state decreased with increasing dose. The mean effective half-life for accumulation ranged from 54 to 98 hr, suggesting that the very slow elimination of drug at low concentrations did not produce disproportionate accumulation of drug at these doses. Mean oral clearance was independent of dose, ranging from 30 to 45 ml/min. At the 2-, 5-, and 20-mg doses, one subject in each group had steady-state concentrations two- to fourfold greater than any of the other five subjects at the same dose, although the reason for this was not apparent from these data. The overall kinetic profile of these data was suggestive of dose-dependent pharmacokinetics resulting from nonlinear tissue binding of imirestat.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular and intraocular pressure effects and plasma concentrations of apraclonidine.

We performed a double-masked, crossover study comparing the cardiovascular and intraocular pressure effects of 0.5% and 0.25% topical apraclonidine hydrochloride and 0.5% timolol maleate in 20 healthy female volunteers. The contralateral effects of unilateral apraclonidine and the plasma concentrations of apraclonidine were also assessed. All measurements were done 2, 5, and 8 hours after drop instillation. A 15-minute treadmill test was performed after the 2-hour measurements. All three active medications lowered intraocular pressure comparably. There was no significant contralateral intraocular pressure effect seen with apraclonidine. The apraclonidine plasma concentrations were variable and unrelated to the amount of intraocular pressure lowering and cardiovascular parameters measured. Apraclonidine did not affect blood pressure or heart rate any differently than placebo. Timolol, however, blunted exercise-induced tachycardia. There were no significant differences in pupillary diameters or interpalpebral fissure widths among treatment groups.

A simple high-performance liquid chromatographic method for the measurement of 2-methylsulfonylpyridine in plasma.

A simple and sensitive high-performance liquid chromatographic (HPLC) method for the analysis of 2-methylsulfonylpyridine (2-MSP) in plasma has been developed. Up to 1 mL of plasma containing 2-MSP and an internal standard was extracted with 3 mL of methylene chloride, usually twice, evaporated to dryness, resuspended in mobile phase, and chromatographed on two 15-cm C8 reversed-phase LC columns in series. The mobile phase was 5% acetonitrile in water with a flow rate of 1 mL/min and ultraviolet detection was at 260 nm. Extraction of plasma produced no interfering endogenous components and the recovery of 2-MSP was 60-70%. The intraday and interday statistics of 2-MSP standard curves from 10 to 320 ng in plasma demonstrate that the assay is sensitive and precise using either human or monkey plasma and any plasma volume up to 1 mL.

Determination of AL01576 concentration in rat lenses and plasma by bioassay for aldose reductase activity measurements.

Investigations on the disposition of the highly effective aldose reductase inhibitor AL01576 were carried out in pigmented rats after oral dosing and topical administration of a 0.1% ophthalmic suspension by means of an assay modified from a previously described method measuring aldose reductase activity. The crude enzyme extract of pig lenses was used as a test system. From the activity remaining after addition of the plasma or lens extracts, the concentration could be determined since the inhibition constant (IC50) of AL01576 is known. With this procedure, the concentration of AL01576 in plasma and lenses of Brown-Norway rats given different doses of the drug for 42 consecutive days were determined and compared with a gas chromatographic assay technique. These data indicate that AL01576 is absorbed into the lens with a substantial portion redistributing into the lens following systemic delivery. Drug concentrations were correlated with efficacy measurements, though they were lower in an animal group treated with naphthalene to provoke cataract formation. In a second animal series with Brown-Norway rats over 5 days, AL01576 was administered three times per day to the right eye only. During the washout period, AL01576 had a long persistence in plasma and lenses following this short-term topical ocular administration.

Effect of carbon monoxide on the cytochrome P-450-mediated metabolism of aniline and p-nitroanisole in the isolated perfused rabbit lung.

Carbon monoxide (CO), an environmental pollutant, inhibits the cytochrome P-450-mediated metabolism of xenobiotics in vitro. In recent years, the importance of the lung in the metabolic disposition of certain airborne and systemically administered xenobiotics has been demonstrated. The purpose of this investigation was to establish a threshold for the CO-induced inhibition of cytochrome P-450-mediated activities in the isolated perfused rabbit lung and to determine if these reactions are equally sensitive to this toxicant in this model. Neither the mixed-function oxidase-mediated hydroxylation nor the acetylation of aniline was altered by exposure to 7.5% CO/20% O2 for 2.5 h in the isolated perfused rabbit lung. p-Nitroanisole O-demethylation by isolated rabbit lungs ventilated with 7.5% CO/20% O2 was significantly decreased (approximately 37%) in comparison to controls. That these reactions are not similarly influenced by carbon monoxide may indicate that the constitutive isozymes of cytochrome P-450 in the rabbit lung are differentially sensitive to CO-induced inhibition.

Increased kidney glucose utilization induced by cyclosporine: lack of relation to magnesium excretion.

Cyclosporine enhances D-[5-3H]glucose utilization in homogenates of rat kidney medulla but not kidney cortex or liver. This is true whether cyclosporine is added to fresh tissue homogenates or is given to rats prior to sacrifice. Through the use of isolated perfused rat kidneys, an attempt was made to relate increased glucose utilization by cyclosporine to a possible consequence of cyclosporine nephrotoxicity, viz., loss of magnesium in urine. Although an enhanced rate of glucose utilization by cyclosporine was evident in isolated kidneys, glucose consumption was not related to urinary magnesium loss. In fact, kidneys from cyclosporine-treated rats actually showed a normal or even diminished urinary magnesium loss. The data suggest that cyclosporine-induced magnesium imbalance may be extrarenal in origin and that the kidney medulla may be a primary site of the nephrotoxic action of cyclosporine since the drug increases glucose utilization at this site.

The effect of carbon monoxide on aminopyrine metabolism in the isolated perfused rabbit lung.

Carbon monoxide (CO) is a ubiquitous environmental pollutant widely recognized for its ability to inhibit cytochrome P450-mediated metabolism of xenobiotics in vitro. In recent years, the importance of the lung in the metabolic disposition of certain airborne and systemically administered xenobiotics has been demonstrated. The purpose of this investigation was to establish a threshold for the CO-induced inhibition of cytochrome P450-mediated activity in the isolated perfused rabbit lung and to determine if hemoglobin would alter the carbon monoxide-cytochrome P450 interaction. On the basis of its half-life and the stoichiometry of its metabolism, aminopyrine was shown to be a good substrate for monitoring mixed function oxidase activity in the intact rabbit lung. First-order rate constants for aminopyrine metabolism were significantly lower in isolated rabbit lungs perfused with either artificial medium (39%) or whole blood (67%) and ventilated with a 7.5% CO/20% O2 mixture for 2.5 hr than in the respective control lungs ventilated with breathing air. The threshold level (7.5% CO) for this inhibition is the same in lungs perfused with artificial medium and in whole blood-perfused lungs and is well above environmentally relevant levels of exposure.