Pharmacokinetics and safety of multiple doses of daptomycin 6 mg/kg in noninfected adults undergoing hemodialysis or continuous ambulatory peritoneal dialysis.

AIMS: The purpose of this study was to characterize the pharmacokinetics and tolerability of daptomycin in subjects undergoing hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD). METHOD: 16 noninfected adults on stable dialysis regimens were enrolled. Daptomycin 6 mg/kg was administered after HD during a 48 h - 48 h - 72 h dialysis week or before a CAPD dwell time over a 48 h - 48 h - 48 h dialysis week. Pharmacokinetic parameters were described, and adverse events were monitored. RESULTS: Daptomycin had mean half-lives in HD subjects of 28.0 and 35.9 h on Days 1 and 5, with corresponding values of 25.8 and 26.7 h in CAPD subjects. Steady state was reached by Day 5 in both groups. At steady state, HD subjects had a mean peak plasma concentration (Cmax) of 81.6 µg/ml and a mean trough concentration of 15.3 µg/ml (on Day 8). In CAPD subjects, Cmax was 93.9 µg/ml and the trough was 20.7 µg/ml (on Day 7). Adverse events were experienced by 71.4% and 66.7% of HD and CAPD subjects, respectively. Most of these were mild or moderate in intensity; however, 2 subjects experienced muscle spasms and mild creatine phosphokinase elevations although neither event was considered to be related to study drug. CONCLUSIONS: The pharmacokinetics of daptomycin 6 mg/kg support a dosing regimen of every 48 h in CAPD and thrice-weekly dosing in HD.

A pilot study of high-dose short duration daptomycin for the treatment of patients with complicated skin and skin structure infections caused by gram-positive bacteria.

BACKGROUND: Methicillin-susceptible and -resistant (MRSA) Staphylococcus aureus are significant causes of complicated skin and skin structure infections (cSSSI). The bactericidal antibiotic daptomycin is approved for gram-positive cSSSI at 4 mg/kg/day for 7-14 days, but the optimal dose level and duration of therapy have not been firmly established. This pilot study evaluated the efficacy and safety of daptomycin at 10 mg/kg every 24 h for 4 days [high-dose short duration (HDSD) regimen] vs. standard of care therapy with vancomycin or semi-synthetic penicillin for the treatment of cSSSI. METHODS: This was a semi-single blind, randomised, multicentre, comparative trial. The primary efficacy end-point was the clinical response 7-14 days posttherapy. RESULTS: One hundred patients were randomised; 48 in each arm were treated. The treatment groups were well balanced with respect to demographics, comorbidities and the type of infection (75% because of MRSA). Overall, clinical success rates were 75.0% (36/48) for daptomycin and 87.5% (42/48) for comparator (95% confidence interval for the difference: -27.9, 2.9). The median duration of comparator therapy was 8 days. Two comparator patients and no daptomycin patients experienced treatment-related serious adverse events requiring hospitalisation. CONCLUSION: We found that the HDSD regimen had a safety profile similar to that seen in previous studies. Although the differences were not statistically significant, clinical success rates for comparator were higher than for daptomycin. In post hoc analyses HDSD daptomycin performed better in some subgroups (e.g. outpatients) than in others (e.g. certain MRSA infections). These observations require confirmation in larger trials.

The pharmacokinetic and pharmacodynamic characteristics of a long-acting growth hormone (GH) preparation (nutropin depot) in GH-deficient adults.

A pharmacokinetic-pharmacodynamic study of a long-acting GH [Nutropin Depot; somatropin (rDNA origin) for injectable suspension] was performed in 25 patients with adult GH deficiency. Single doses of 0.25 mg/kg and 0.5 mg/kg, based on ideal body weight, were administered sc. After either dose, serum GH concentrations rose rapidly in both sexes. In men, the lower dose maintained serum IGF-I levels within 1 SD of the mean for age and sex for 14-17 d; the higher dose raised IGF-I levels 2 SD above the mean. In most women, all of whom were receiving oral estrogen, the lower dose did not normalize IGF-I levels; the higher dose maintained IGF-I near the mean for approximately 14 d. Increases in IGF binding protein-3 and acid-labile subunit levels were observed in both sexes; however, a sex-related difference was not obvious. Fasting glucose and insulin concentrations were transiently elevated in men receiving the higher dose. Patients tolerated the injections well. We concluded that a single injection of Nutropin Depot at these doses in patients with adult GH deficiency increased serum IGF-I to within normal limits for 14-17 d. Estrogen-treated women required approximately twice the dose needed in men to produce comparable IGF-I concentrations.

Phase I trial of lobradimil (RMP-7) and carboplatin in children with brain tumors.

PURPOSE: To determine the maximum tolerated dose (MTD), the incidence and severity of toxicities, and the pharmacokinetics of lobradimil administered intravenously over 10 min in combination with carboplatin in children with refractory brain tumors. METHODS: A group of 25 children with primary brain tumors received carboplatin and lobradimil on two consecutive days every 28 days. The 10-min lobradimil infusion began 5 min before the end of the carboplatin infusion. Four lobradimil dose levels (100, 300, 450 and 600 ng/kg ideal body weight, IBW) were studied in cohorts of 4 to 13 patients. Carboplatin was adaptively dosed based on the glomerular filtration rate to achieve a target plasma area under the concentration-time curve (AUC) of 7.0 mg min/ml per course (5.0 mg min/ml for patients who had previously received craniospinal radiation or myeloablative chemotherapy). RESULTS: Lobradimil toxicity was immediate, tolerable and rapidly reversible. The most frequent toxicities were hypotension, flushing, headache and gastrointestinal complaints. One patient on the 600 ng/kg dose level had a seizure during the lobradimil infusion. The incidence and severity of lobradimil toxicities were not dose-related and the lobradimil dose was not escalated beyond the 600 ng/kg IBW dose level. Two patients had partial responses and ten patients had stable disease. Myelosuppression (thrombocytopenia more prominent than neutropenia) was the primary toxicity attributed to carboplatin. Lobradimil pharmacokinetics were characterized by rapid clearance from the plasma compartment and substantial interpatient variability. CONCLUSIONS: The combination of carboplatin and lobradimil is safe and tolerable. An MTD for lobradimil was not defined because toxicity was not dose-related. The recommended pediatric phase II dose of lobradimil is 600 ng/kg IBW.

Prolonged intercostal nerve blockade in sheep using controlled-release of bupivacaine and dexamethasone from polymer microspheres.

BACKGROUND: Previous work from the authors' group characterized a prolonged percutaneous blockade of the sciatic nerve in rats using bupivacaine-dexamethasone microspheres. The goals of the current study are to examine the (1) efficacy of bupivacaine microspheres with and without dexamethasone for intercostal blockade in sheep; (2) scaling of dose and duration with a 100-fold increase in body size from rats to sheep; (3) local toxicity and adverse systemic reactions to bupivacaine microspheres with and without dexamethasone. METHODS: Intercostal blocks were performed percutaneously in sedated sheep. Sensory blockade was measured at repeated time points by absent flinch response to skin pinch. Plasma bupivacaine concentrations were measured using high performance liquid chromatography. Chest wall specimens were examined by light microscopy. RESULTS: The duration of intercostal blockade increased with bupivacaine dose for animals receiving from 8 to 80 mg/kg of microspheres with and without dexamethasone. At each dose, microspheres containing dexamethasone had a longer duration of block than microspheres without dexamethasone. From 8 to 80 mg/kg, the mean duration of block with bupivacaine-dexamethasone microspheres increased from 4 to 13 days. Plasma concentrations of bupivacaine remained 10-fold below the convulsive EC50 concentration for sheep. Chest wall histology showed a significant granulomatous reaction around bupivacaine microspheres but not around bupivacaine-dexamethasone microspheres. CONCLUSIONS: A single administration of bupivacaine-dexamethasone microspheres produces an effective chest wall analgesia of several days' duration. This may prove useful clinically for thoracic surgery or trauma.

A pharmacokinetic/pharmacodynamic study of controlled-release oxycodone.

A single-dose, analytically blinded, randomized, crossover study was conducted in 22 healthy male volunteers to compare the bioavailability of one 20 mg with two 10 mg controlled-release (CR) oxycodone tablets. In addition, pharmacodynamic effects were assessed using both objective and subjective measures for up to 48 hr after dosing. The two treatments were bioequivalent, with comparable rates (Cmax of one 20 mg tablet was 109% of two 10 mg tablets; 90% confidence limits: 98.4%-120%) and extents (AUC0-infinity: 107%; 100%-114%) of absorption. In addition, no significant differences between tablets were found for mean values of Tmax, T/12abs, or T/12elim. Correlations between plasma oxycodone concentrations and most pharmacodynamic measures were significant. The strongest correlations were observed for pupil size (r = -0.53) and subjects' assessment of drug effect (r = 0.53), with changes in plasma concentration accounting for more than 25% of the observed changes in these variables. This study demonstrated bioequivalence of two 10 mg and one 20 mg CR oxycodone tablet, with significant correlation between plasma oxycodone concentrations and pharmacodynamic effects in normal volunteers.

Differential effects of food on the bioavailability of controlled-release oxycodone tablets and immediate-release oxycodone solution.

The effects of a high-fat meal on the bioavailability of oxycodone hydrochloride, administered as a recently developed 40 mg controlled-release (CR) tablet or a 20 mg immediate-release (IR) solution, were evaluated in a randomized crossover study in 22 normal male and female subjects. Serial blood samples were collected for 36 h after dosing and analyzed for oxycodone by a validated method using gas chromatography/mass spectrometry. There was no significant food effect with CR oxycodone as judged by 90% confidence interval (CI) analysis of AUC0-infinity and Cmax values under fed and fasted conditions. For the IR solution, both oxycodone bioavailability and peak plasma oxycodone concentration were significantly altered by consumption of the high-fat meal, with the mean value for AUC0-infinity increasing to 120% (CI = 109-132%) and the mean value for Cmax decreasing to 82% (CI = 47-91%) of values observed in the fasted condition. Adverse events reported for both formulations were mostly mild to moderate in severity and typical of those observed with opioids.

Pharmacokinetic-pharmacodynamic relationships of controlled-release oxycodone.

Plasma concentrations of oxycodone, oxymorphone, and noroxycodone were determined after administration of 20 mg oral controlled-release oxycodone tablets to four subject groups: young (aged 21 to 45 years) men, elderly (aged 65 to 79 years) men, young women, and elderly women. Area under the oxycodone and noroxycodone concentration-time curve (AUC) values were comparable among the four groups. Compared with oxycodone, the oxymorphone AUC values were small, with significant differences between subject groups. AUC values were also calculated for the pharmacodynamic variable "drug effect," scored on a 100 mm visual analog scale. The two groups with the highest oxycodone AUC values (young and elderly women) had the lowest oxymorphone AUC values and the greatest drug effect AUC values. The two groups with the lowest oxycodone AUC values (young and elderly men) had the highest oxymorphone AUC values and the lowest drug effect AUC values. These results support oxycodone, and not oxymorphone, as being primarily responsible for pharmacodynamic and analgesic effects.

Steady-state bioavailability of controlled-release oxycodone in normal subjects.

The steady-state bioavailability of a controlled-release (CR) oxycodone tablet was compared with that of an immediate-release (IR) oxycodone solution in a randomized, analytically masked, multiple-dose, crossover study in 24 normal subjects. Each subject received either one 10-mg CR oxycodone tablet every 12 hours for 4 days or 5 mL of a 1-mg/1 mL IR oxycodone solution every 6 hours for 4 days. Steady state was achieved after approximately 1 day of dosing. The mean (+/- SD) maximum plasma oxycodone concentrations for CR oxycodone and IR oxycodone were 15.1 +/- 4.7 ng/mL and 15.6 +/- 4.4 ng/mL, respectively. The time to maximum concentration (Tmax) was approximately twice as long for CR oxycodone (3.2 +/- 2.2 hours) as for IR oxycodone (1.4 +/- 0.7 hours) (P = 0.005). The area under the plasma concentration-time curve from 0 to 12 hours at steady state was 103.6 +/- 40.0 ng.h/mL for CR oxycodone and 99.0 +/- 35.8 ng.h/mL for IR oxycodone. Except for Tmax, there were no significant differences in pharmacokinetic parameters between treatments. Approximately twice as many adverse experiences, several of longer duration than noted with CR oxycodone, were reported with IR oxycodone. The bioavailability of the CR tablet was equal to that of the IR solution; however, the rate of oxycodone absorption from the CR tablet was slower than that from the IR solution, as shown by the Tmax value. The use of CR oxycodone will allow selection of the most clinically appropriate nonopioid analgesic, as well as independent titration and dosing, thereby enhancing therapeutic flexibility.

Nephrotoxicity of pravadoline maleate (WIN 48098-6) in dogs: evidence of maleic acid-induced acute tubular necrosis.

Single oral administration of pravadoline maleate (WIN 48098-6), the maleic acid salt of WIN 48098, induced acute tubular necrosis (ATN) in male and female beagle dogs at dosages > or = 40 mg/kg (WIN 48098 base (31 mg/kg) and maleic acid (9 mg/kg)). Subsequent oral studies were conducted with equimolar dosages of maleic acid and WIN 48098-7, the ethanesulfonate salt of WIN 48098, to determine the nephrotoxic moiety of WIN 48098-6. ATN was observed for dogs given only maleic acid at single oral dosages > or = 9 mg/kg. This result provided evidence that maleic acid was responsible for the nephrotoxicity observed in dogs given single oral dosages of WIN 48098-6. The induction of maleic acid-related nephrotoxicity in dogs may confound the interpretation of toxicologic studies of maleic acid salts of basic pharmaceutics, if the dosage of test article results in the delivery of dosages of maleic acid > or = 9 mg/kg. Furthermore, the results of these studies underscore the importance of establishing maximum no-observed-effect dosages and target organ toxicity profiles for acids and bases that are commonly used in the development of salts of pharmaceutics.

Subchronic oral and intravenous (i.v.) safety evaluation and pharmacokinetics in rats and dogs of ipazilide fumarate (Win 54, 177-4), an antiarrhythmic agent.

Ipazilide fumarate (Win 54, 177-4) is a chemically novel antiarrhythmic agent that prolongs ventricular refractoriness and possesses antiectopic activity. Subchronic (29 days) nonclinical safety evaluation of ipazilide was conducted following oral and iv administration in Sprague-Dawley rats (20-320 mg/kg oral and 1.25-10 mg/kg iv) and 14 and 28 days in beagle dogs (3-30 mg/kg oral and 2.5-20 mg/kg iv). The pharmacokinetic parameters of ipazilide indicate that ipazilide is absorbed (tmax less than or equal to 1 hr) in fasted rats and dogs following single and repeated oral administrations. The apparent elimination half-life in the two species is approximately 1 hr (except in rats at a dosage of 320 mg/kg), suggesting rapid clearance. Increases in liver weights (rats 320 mg/kg) accompanied by the observation of centrilobular hypertrophy of hepatocytes were considered an expression of an adaptive metabolic response of the liver to ipazilide and may be associated with the induction of microsomal enzymes. Duodenal villous atrophy and epithelial hyperplasia (rats, 80 and 320 mg/kg) were interpreted to represent an irritant response to the drug. Local irritation was also observed at the injection site in rats and dogs. Dogs tolerated the oral and the iv administration of ipazilide at dosages of up to 30 and 20 mg/kg, respectively. Despite emesis (oral dogs), which was reduced in frequency following repeated treatment over several weeks, plasma levels in treated dogs (i.e., Cmax 4-5 micrograms/ml) were approximately twice that required to convert spontaneous arrhythmias in the conscious dog model 24 hr after myocardial infarction.(ABSTRACT TRUNCATED AT 250 WORDS)

Determination of a novel steroidal androgen receptor antagonist (Win 49596) in human plasma using solid-phase extraction and high-performance liquid chromatography with ultraviolet detection.

A rapid, sensitive and selective method was developed for the determination of a novel steroidal androgen receptor antagonist (Win 49596, I) in human plasma. The procedure involved extraction from plasma using a solid-phase phenyl support and elution directly onto a reversed-phase C8 column using a mobile phase consisting of 0.2 mol/l sodium acetate buffer at pH 7-acetonitrile (45:55, v/v). Drug was monitored by ultraviolet detection at a wavelength of 238 nm. Linear responses were observed for standards over the range 0.01-5.0 micrograms/ml. The minimum quantifiable level was 0.02 microgram/ml, using a 0.5-ml plasma sample. The precision was 5.5% and the accuracy ranged from -9.4% to 0.23%. The analytical method has been used to quantify I in plasma from dogs and rats and is projected for use with human plasma from clinical trials.

Effect of the acetylator phenotype on amrinone pharmacokinetics.

Ten healthy male subjects were phenotyped with isoniazid for their acetylator status and then received intravenous amrinone at a dose of 75 mg during a period of 10 minutes. Blood samples were drawn at specified times during a 24-hour period after dosing. Plasma concentrations of amrinone were determined by a specific HPLC method. The plasma concentration data were fitted to a biexponential model by nonlinear regression. The mean apparent first-order elimination t1/2 for amrinone in the slow acetylators was 4.4 hours, whereas it was 2.0 hours in the fast acetylators (P less than 0.05). There was little difference in the volume of distribution at steady state. Clearance was lower in the slow acetylators, 16.6 L/hr, than in the fast acetylators, 37.2 L/hr (P less than 0.05). The AUC was higher for the slow acetylators, 4.96 micrograms X hr X ml-1, than for the fast acetylators, 2.20 micrograms X hr X ml-1 (P less than 0.01). Concentrations of amrinone and its N-acetyl metabolite in the urine from each volunteer were determined. The ratio of N-acetylamrinone to amrinone was calculated and, as expected, the fast acetylators had a higher ratio than did the slow acetylators (P less than 0.01).

Use of WIN 51711 to prevent echovirus type 9-induced paralysis in suckling mice.

The systemic efficacy of the antipicornavirus agent WIN 51711 was assessed in suckling mice infected with echovirus type 9 (Barty strain). Single, daily intraperitoneal doses of WIN 51711 as low as 10 mg/kg significantly (P less than .01) slowed the rate of onset of echovirus-induced paralysis and reduced the number of paralyzed animals. Intraperitoneal administration beginning 2 hr before infection or 48 hr after infection was equally effective in preventing paralysis. Oral administration of WIN 51711 twice daily beginning 72 hr after infection was the most-effective dosage regimen, with doses as low as 3 mg/kg preventing paralysis in 75% of the animals. Titers of virus in asymptomatic mice on day 6 after infection were reduced by up to 4.75 log pfu in WIN 51711-medicated mice when compared with placebo. Maximal concentrations of WIN 51711 in adult mice after oral medication with a 100 mg/kg dose were 24.3, 21.5, 10.4, 9.8, 6.9, and 4.1 micrograms/g in heart, kidney, brain, liver, serum (micrograms/ml), and muscle, respectively at 0.5-1.0 hr after medication.

Pharmacokinetics of the bipyridines amrinone and milrinone.

The pharmacokinetics of milrinone were studied in sequential ascending doses in New York Heart Association Class III and IV patients receiving oral and intravenous medication. The parameters determined after parenteral administration were estimated by fitting the plasma concentration data to an open two-compartment body model. After oral medication, regression-independent parameters were determined. After either oral or parenteral administration of milrinone, plasma levels were dose dependent and the drug had an apparent first-order terminal elimination half-life of approximately 2 hr. The apparent volume of distribution was approximately 400 to 500 ml/kg, and total body clearance was approximately 130 ml/kg/hr. These values obtained in patients receiving milrinone were compared with those obtained for milrinone in volunteers, as well as those noted with the other inotropic bipyridine, amrinone. Milrinone's elimination from the blood stream patients was slower that that in normal healthy subjects and faster than amrinone's elimination in patients with congestive heart failure. Milrinone's pharmacokinetic parameters in these patients were unchanged after approximately 30 days of continuous oral medication.

Analysis of amifloxacin in plasma and urine by high-pressure liquid chromatography and intravenous pharmacokinetics in rhesus monkeys.

An analytical method for the quantitation of amifloxacin, 6-fluoro-1,4-dihydro-1-(methylamino)-7-(4-methyl-1-piperazinyl)-4-oxo-3- quinolinecarboxylic acid, in plasma and urine has been developed. The method involves extraction with chloroform, back-extraction into 0.1 M sodium hydroxide, and subsequent analysis by reverse-phase high-pressure liquid chromatography with UV detection. The precision of the assay calculated as the overall standard deviation was +/- 4.9% in plasma and +/- 1.1% in urine. The range of mean percent differences from the nominal values was used as an estimate of accuracy and was 93.6 to 103% of the nominal values in plasma and 95.2 to 107% of the nominal values in urine. The minimum quantifiable levels were 0.032 micrograms/ml in plasma and 2.7 micrograms/ml in urine. The methods were employed in a pharmacokinetic analysis of amifloxacin after intravenous administration to rhesus monkeys. The decline in drug plasma levels was described by a biexponential process with mean rates of 8.4 h-1 and 0.32 h-1 with corresponding half-lives of ca. 5 min and 2.2 h. Amifloxacin was rapidly excreted, with ca. 53% of the dose appearing in the urine within 48 h after medication. The mean renal clearance +/- standard deviation was 4.4 +/- 1.0 ml X kg-1 X min-1 and is compatible with passive glomerular filtration in this species.

Metabolism and disposition of amifloxacin in laboratory animals.

Sprague-Dawley rats received [14C]amifloxacin mesylate either orally or intravenously at 20 mg (base equivalent) per kg. Blood radioactivity peaked at 0.5 h after oral administration and was equivalent to 7.54 micrograms/ml for males and 6.73 micrograms/ml for females. After intravenous administration to rats, 52.5% of the dose was recovered in the urine of males and 45.3% in the urine of females within 72 h. The corresponding values after oral administration were 50.8% for males and 37.2% for females. The remainder of the dose was recovered in the feces. After intravenous administration of [14C]amifloxacin mesylate at 10 mg (base equivalent) per kg to female rhesus monkeys, 80.3% of the radioactivity was excreted in the urine at 24 h. The apparent first-order terminal elimination half-life of intact amifloxacin in plasma was 2.3 h; radioactivity in plasma was eliminated more slowly. Male rats excreted 26.2% of the dose in the urine as amifloxacin and 17.8% as the piperazinyl-N-oxide derivative of amifloxacin after intravenous administration. The corresponding amounts for female rats were 29.0% as amifloxacin and 7.8% as the piperazinyl-N-oxide metabolite. Similar excretion profiles were observed after oral administration. After intravenous administration, female monkeys excreted 54.5% of the dose in the urine as amifloxacin, 12.9% as the piperazinyl-N-desmethyl metabolite, and 5.6% as the piperazinyl-N-oxide during the first 12 h. In contrast, there was no evidence of the piperazinyl-N-desmethyl metabolite in rats.

Relative bioavailability and pharmacokinetics: a combination of pentazocine and acetaminophen.

The relative bioavailability and pharmacokinetics of a combination product containing pentazocine and acetaminophen were studied in 20 healthy human males. Each subject, in a single-dose three-way crossover design, received two different preparations containing 50 mg of pentazocine (as base) and 1300 mg of acetaminophen either as capsule-shaped tablets or as a solution. Plasma concentrations of pentazocine and acetaminophen were determined from 0.25 to 12 h following oral administration. The plasma data for both compounds in the tablet formulation were described by an open one-compartment body model with first-order absorption. The average (+/- SD) bioavailability of the tablet relative to that of the solution was 85.0 +/- 31.1 and 88.6 +/- 13.1% for pentazocine and acetaminophen, respectively. The apparent first-order regression-dependent elimination rate constants for pentazocine from the tablet and solution preparations were 0.19 +/- 0.08 and 0.20 +/- 0.06 h-1, respectively, while the rate constants for acetaminophen were 0.26 +/- 0.03 and 0.25 +/- 0.03 h-1 for the tablet and solution preparations, respectively. These rate constants correspond to terminal elimination half-lives of approximately 3.6 h for pentazocine and approximately 2.7 h for acetaminophen.