Safety and pharmacokinetics of rimantadine small-particle aerosol.

The safety and pharmacokinetics of rimantadine administered by small-particle aerosol were assessed in healthy adults and adults with acute influenza virus infection. Aerosolized rimantadine delivered at a concentration of 40 micrograms/liter of air was associated with nasal burning and irritation in normal volunteers. A concentration of 20 micrograms/liter of air was well tolerated for up to 12 h by normal volunteers and was not associated with any changes in pulmonary function, as measured by routine spirometry, plethysmography, or diffusion capacity of carbon monoxide. Mean peak levels of drug in serum were approximately 10-fold lower after 12 h of aerosol administration than they were after oral administration of 200 mg (29.7 versus 255 ng/ml, respectively), while mean nasal wash levels were approximately 100-fold higher (6,650 versus 66.6 ng/ml, respectively). Elimination half-lives were similar after both aerosol and oral administration (24.1 and 25.2 h, respectively), and rimantadine urinary excretion was less than 1% per 24 h in both groups. Twenty micrograms of aerosolized rimantadine per liter of air given 12 h daily for 3 days to nine adults with acute influenza virus infection was well tolerated. Levels in plasma after 12 h of aerosol inhalation were similar to those in normal volunteers, but were higher at the end of the third treatment than they were at the end of the first treatment (88.3 versus 47.9 ng/ml, respectively). Thus, rimantadine delivered via small-particle aerosol at a dose of 20 micrograms/liter of air was well tolerated in normal volunteers and in those with acute influenza and was associated with high local concentrations.     

Pharmacological properties of a new antimalarial bisthiazolium salt, T3, and a corresponding prodrug, TE3

A new approach to malarial chemotherapy based on quaternary ammonium that targets membrane biogenesis during intraerythrocytic Plasmodium falciparum development has recently been developed. To increase the bioavailability, nonionic chemically modified prodrugs were synthesized. In this paper, the pharmacological properties of a bisthiazolium salt (T3) and its bioprecursor (TE3) were studied. Their antimalarial activities were determined in vitro against the growth of P. falciparum and in vivo against the growth of P. vinckei in mice. Pharmacokinetic evaluations were performed after T3 (1.3 and 3 mg/kg of body weight administered intravenously; 6.4 mg/kg administered intraperitoneally) and TE3 (1.5 and 3 mg/kg administered intravenously; 12 mg/kg administered orally) administrations to rats. After intraperitoneal administration, very low doses offer protection in a murine model of malaria (50% efficient dose [ED50] of 0.2 to 0.25 mg/kg). After oral administration, the ED50 values were 13 and 5 mg/kg for T3 and TE3, respectively. Both compounds exerted antimalarial activity in the low nanomolar range. After TE3 administration, rapid prodrug-drug conversion occurred; the mean values of the pharmacokinetic parameters for T3 were as follows: total clearance, 1 liter/h/kg; steady-state volume of distribution, 14.8 liters/kg; and elimination half-life, 12 h. After intravenous administration, T3 plasma concentrations increased in proportion to the dose. The absolute bioavailability was 72% after intraperitoneal administration (T3); it was 15% after oral administration (TE3). T3 plasma concentrations (8 nM) 24 h following oral administration of TE3 were higher than the 50% inhibitory concentrations for the most chloroquine-resistant strains of P. falciparum (6.3 nM).     

Multiple-dose pharmacokinetics of rimantadine in elderly adults.

To assess the possible effect of aging on rimantadine hydrochloride pharmacokinetics, single- and multiple-dose kinetics were determined in 18 healthy adults with ages between 51 and 79 years. Subjects ingested single 100-mg oral doses of rimantadine after an overnight fast, followed after 5 days by a dosage of 100 mg twice a day for 9.5 days. No differences were observed among the age-stratified groups in measured or derived pharmacokinetic parameters. Peak concentrations in plasma (mean +/- standard deviation) following the single- and multiple-dose regimens, respectively, were 89 +/- 25 and 417 +/- 129 ng/ml for subjects who were 50 to 60 years of age (group 1), 92 +/- 24 and 401 +/- 84 ng/ml for those 61 to 70 years of age (group 2), and 100 +/- 14 and 538 +/- 51 for those 71 to 79 years of age (group 3). The elimination half-life in plasma following multiple doses averaged 33.5 h for group 1, 32.5 h for group 2, and 38.6 h for group 3. Steady-state concentrations in nasal mucus developed by day 5 of dosing (1.5-fold higher than concentrations in plasma), and rimantadine remained detectable in secretions for 5 days after the last dose in 65% of subjects. Stepwise regression analysis suggested that changes in maximum concentration in plasma and area under the concentration-time curve at steady state may be related to creatinine clearance. The results indicate that no important differences in rimantadine multiple-dose pharmacokinetics exist among healthy elderly adults with ages between 51 and 79 years.     

Pharmacokinetics of the oral triazole antimycotic vibunazole in animals

Methods of assay of the oral triazole antimycotic vibunazole (BAY n 7133) in body fluids by GLC, HPTLC and by a microbiological assay are described and compared. Bioassay data of vibunazole concentrations in mice and rats are lower than those of the chemical methods, probably due to a species-dependent difference in protein binding. The pharmacokinetics of vibunazole was studied after administration to mice, rats, rabbits, beagle dogs and rhesus monkeys. Peak concentrations of 14 to 16 mg/l were found in plasma of mice after oral administration of 25 mg/kg as an aqueous suspension. After the first oral dose the mean plasma half-life was 4.8 h. After the fifth dose, plasma levels were lower and declined with a half-life of 1.2 h which may indicate enzyme induction. Signs of enzyme induction after multiple oral doses were also seen in beagle dogs but not in rhesus monkeys. After intravenous administration to one beagle dog, vibunazole plasma half-life was 1.8 h. The absolute bioavailability of oral vibunazole in the dog was estimated to be about 70%.     

Differences in side effects of amantadine hydrochloride and rimantadine hydrochloride relate to differences in pharmacokinetics.

In a double-blind, placebo-controlled study, the comparative toxicities and blood concentrations of amantadine hydrochloride and rimantadine hydrochloride were determined. Healthy, working adults ingested either 200 (n = 52) or 300 mg (n = 196) per day in divided doses for 4.5 days. Mean plasma drug concentrations at 4 h after the first dose were lower in rimantadine recipients given 100- (140 versus 300 ng/ml for rimantadine and amantadine, respectively; P less than 10(-5)) or 200-mg doses (310 versus 633 ng/ml; P less than 10(-5)). The plasma drug concentrations after the first dose correlated significantly with total symptom sources for both amantadine and rimantadine, but the plasma levels of toxic and nontoxic subjects overlapped extensively. At 300-mg/day dosage amantadine was associated more often with adverse central nervous system symptoms (33% of amantadine versus 9% of rimantadine recipients; P less than 0.001) and sleep disturbance (39 versus 13%; P less than 0.001), but not gastrointestinal symptoms (19.5 versus 16.0%). However, no differences between the drugs were noted in symptom frequency or scores in volunteers with similar plasma concentrations. Amantadine and rimantadine differ in their pharmacokinetics but not in their potential for side effects at comparable plasma concentrations.     

Absorption and tissue distribution of a novel carboxymethyldextran after oral administration

The aim of this study was to investigate the development of an oral dextran derivative OTR4120. Pharmacokinetics (PK) parameters of OTR4120 were determined after treatment with intravenous injection (i.v.) at dose 5 mg/kg, intraperitoneal injection (i.p.) at dose 50 mg/kg or oral administration at dose 70 mg/kg. To study distribution at dose 70 mg/kg after oral administration, OTR4120 was given by gavage to mice. In ex vivo experiments, SDS-PAGE showed that plasma of mice treated orally at dose 70 mg/kg induced the formation of covalently linked complexes between antithrombin III and thrombin. OTR4120 were absorbed and metabolized following oral administration. OTR4120 given i.v., i.p. and oral had relatively small volume of distribution 0.95 L/kg and 4.68 L/kg respectively, plasma clearance was 45, 520 and 514 ml/h per kg after i.v., i.p. or oral administration respectively. Short elimination half-life was 80 min after i.p. administration and 383 min after oral administration. OTR4120 was distributed in the spleen and kidney and accumulated there over a long period, whereas the OTR4120 levels in liver were negligible a 24 hours after oral administration. Food do not change the oral bioavailability of OTR4120 in mice, AUC, C_max and T_max of OTR4120 were not significantly different when mice received the oral dose with food compared with under fasting conditions. This work presents another therapeutic agents administration way using dextran delivery system.     

Single-dose pharmacokinetics of a pleconaril (VP63843) oral solution in children and adolescents. Pediatric Pharmacology Research Unit Network

Pleconaril is an orally active, broad-spectrum antipicornaviral agent which demonstrates excellent penetration into the central nervous system, liver, and nasal epithelium. In view of the potential pediatric use of pleconaril, we conducted a single-dose, open-label study to characterize the pharmacokinetics of this antiviral agent in pediatric patients. Following an 8- to 10-h period of fasting, 18 children ranging in age from 2 to 12 years (7.5 +/- 3.1 years) received a single 5-mg/kg of body weight oral dose of pleconaril solution administered with a breakfast of age-appropriate composition. Repeated blood samples (n = 10) were obtained over 24 h postdose, and pleconaril was quantified from plasma by gas chromatography. Plasma drug concentration-time data for each subject were fitted to the curve by using a nonlinear, weighted (weight = 1/Ycalc) least-squares algorithm, and model-dependent pharmacokinetic parameters were determined from the polyexponential parameter estimates. Pleconaril was well tolerated by all subjects. A one-compartment open-model with first-order absorption best described the plasma pleconaril concentration-time profile in 13 of the subjects over a 24-h postdose period. Pleconaril pharmacokinetic parameters (means +/- standard deviations) for these 13 patients were as follows. The maximum concentration of the drug in serum (Cmax) was 1,272.5 +/- 622.1 ng/ml. The time to Cmax was 4.1 +/- 1.5 h, and the lag time was 0.75 +/- 0.56 h. The apparent absorption rate constant was 0.75 +/- 0.48 1/h, and the elimination rate constant was 0.16 +/- 0.07 1/h. The area under the concentration-time curve from 0 to 24 h was 8,131.15 +/- 3,411.82 ng.h/ml. The apparent total plasma clearance was 0.81 +/- 0.86 liters/h/kg, and the apparent steady-state volume of distribution was 4.68 +/- 2.02 liters/kg. The mean elimination half-life of pleconaril was 5.7 h. The mean plasma pleconaril concentrations at both 12 h (250.4 +/- 148.2 ng/ml) and 24 h (137.9 +/- 92.2 ng/ml) after the single 5-mg/kg oral dose in children were higher than that from in vitro studies reported to inhibit > 90% of nonpolio enterovirus serotypes (i.e., 70 ng/ml). Thus, our data support the evaluation of a 5-mg/kg twice-daily oral dose of pleconaril for therapeutic trials in pediatric patients with enteroviral infections.     

Pharmacokinetics of amdinocillin in healthy adults.

The pharmacokinetics of amdinocillin (mecillinam) were determined in 10 healthy volunteers. Single doses of 10 and 15 mg/kg of body weight were administered intravenously and intramuscularly in a crossover study. Plasma concentrations of amdinocillin were determined by microbiological assay. Mean peak plasma concentrations were 49 and 87 micrograms/ml after intravenous doses of 10 and 15 mg/kg, respectively. The terminal half-life value of 0.89 h was similar for both doses. After intramuscular injections, the mean concentration of drug in plasma was 26.2 micrograms/ml for the 10-mg/kg dose and 29.6 micrograms/ml for the 15-mg/kg dose, with terminal half-lives of 0.96 and 0.86 h, respectively. The mean apparent volumes of distribution at steady state were 18 and 16 liters/100 kg for the intravenous doses of 10 and 15 mg/kg, respectively. Drug concentrations in plasma at 4 h were above the minimal inhibitory concentrations for gram-negative organisms categorized as susceptible to this drug.     

Preclinical pharmacokinetics and distribution to tissue of AG1343, an inhibitor of human immunodeficiency virus type 1 protease.

AG1343, a potent inhibitor of human immunodeficiency virus type 1 (HIV-1) protease (Ki = 2 nM), was designed by protein structure-based drug design techniques. AG1343 has potent antiviral activity (95% effective dose = 0.04 microgram/ml) against a number of HIV-1 strains in acute and chronic models of infection. As part of its preclinical development, the oral bioavailability of AG1343 in rats, dogs, monkeys, and marmosets was determined and its tissue distribution in rats was evaluated. There were no major interspecies differences in AG1343 pharmacokinetics. Following intravenous administration, the elimination half-life of AG1343 ranged from 1 to 1.4 hr. The total volume of distribution (2 to 7 liters/kg) exceeded the volume of total body water, indicating extensive tissue distribution. Systemic clearance of AG1343 (1 to 4 liters/kg) in the different species corresponded to hepatic blood flow, suggesting possible hepatic involvement in the elimination of AG1343. Following oral administration, peak levels in plasma ranged from 0.34 microgram/ml after treatment with 10 mg/kg of body weight in the dog to 1.7 micrograms/ml after dosing with 50 mg/kg in the rat. Because of the slow absorption of AG1343, plasma concentrations of AG1343 exceeding that required for 95% inhibition of HIV-1 replication were maintained for up to 7 h after a single oral dose in all species evaluated. Average oral bioavailability of AG1343 ranged from 17% in the marmoset to 47% in the dog. Studies of distribution to tissue in the rat after oral administration of 14C-AG1343 established extensive distribution with concentrations in most tissues exceeding that found in plasma. Of particular significance were high levels of AG1343 equivalent in mesenteric lymph nodes (32.05 micrograms/g) and spleen tissue (9.33 micrograms/g). The major excretory route for AG1343 was via feces, with 100% of the dose recovered by 48 h. Results from these studies demonstrate that AG1343 is orally bioavailable and that levels in plasma in the therapeutic range are achievable and are maintained for prolonged periods in the animal models tested. On the basis of these and other findings, AG1343 was developed for further testing in human subjects.     

Pharmacokinetics of rimantadine hydrochloride in patients with chronic liver disease

Six patients with chronic liver disease and six sex-, age (+/- 5 years)-, and weight (+/- 5 kg)-matched healthy control subjects received a single dose of two 100 mg tablets rimantadine HCl. Eight additional patients with chronic liver disease who were not matched to healthy subjects received a single dose of two 100 mg tablets of rimantadine HCl. Blood and urine samples were collected and rimantadine concentrations were determined by a GCMS method. The values for maximum plasma concentration, AUC, elimination half-life, and renal clearance were not significantly different between patients and control subjects, independent of the statistical analyses (parametric and nonparametric) used. The mean apparent elimination half-life, volume of distribution, and total clearance in the matched patients with liver disease were 32 hours, 24 L/kg, and 676 ml/min, respectively. Renal clearance and the amount excreted in the urine unchanged were 63 ml/min and 10%, respectively. In conclusion, rimantadine pharmacokinetics were not appreciably altered in patients with less severe chronic liver disease.     

Phase I dose escalation study to evaluate the safety and pharmacokinetic profile of tefibazumab in subjects with end-stage renal disease requiring hemodialysis

Two cohorts of four subjects requiring hemodialysis received tefibazumab (10 or 20 mg/kg). The mean elimination half-life was between 17 and 18 days, the average volume of distribution was 7.3 liters, and the average clearance was 12 ml/h for both dose groups. At a dose of 20 mg/kg of body weight, plasma levels were 88 microg/ml at 21 days.     

Pharmacokinetics of cefonicid, a new broad-spectrum cephalosporin.

This study determined the pharmacokinetic disposition of cefonicid. A single dose of 7.5 mg/kg of body weight was administered to five healthy volunteers as a 5-min intravenous infusion. Multiple plasma and urine samples were collected for 48 h. Peak plasma concentrations ranged from 95 to 156 micrograms/ml and fell slowly (mean plasma half-life, 4.4 +/- 0.8 h), so that levels after 12 h were in the range of 6 to 12 micrograms/ml. Urinary concentrations were high but variable and ranged from 100 to 1,000 micrograms/ml for the first 12 h after the dose and averaged 84 micrograms/ml between 12 and 24 h. Plasma and renal clearances were 0.32 +/- 0.06 and 0.29 +/- 0.05 ml/min per kg, respectively. An average of 88 +/- 6% of the dose was excreted unchanged in the urine over 48 h. The mean steady-state volume of distribution was found to be 0.11 +/- 0.01 liters/kg.     

Zalcitabine Population Pharmacokinetics: Application of Radioimmunoassay

Zalcitabine population pharmacokinetics were evaluated in 44 human immunodeficiency virus-infected patients (39 males and 5 females) in our immunodeficiency clinic. Eighty-one blood samples were collected during routine clinic visits for the measurement of plasma zalcitabine concentrations by radioimmunoassay (1.84 ± 1.24 samples/patient; range, 1 to 6 samples/patient). These data, along with dosing information, age (38.6 ± 7.13 years), sex, weight (79.1 ± 15.0 kg), and estimated creatinine clearance (89.1 ± 21.5 ml/min), were entered into NONMEM to obtain population estimates for zalcitabine pharmacokinetic parameters (4). The standard curve of the radioimmunoassay ranged from 0.5 to 50.0 ng/ml. The observed concentrations of zalcitabine in plasma ranged from 2.01 to 8.57 ng/ml following the administration of doses of either 0.375 or 0.75 mg. A one-compartment model best fit the data. The addition of patient covariates did not improve the basic fit of the model to the data. Oral clearance was determined to be 14.8 liters/h (0.19 liter/h/kg; coefficient of variation [CV] = 23.8%), while the volume of distribution was estimated to be 87.6 liters (1.18 liters/kg; CV = 54.0%). We were also able to obtain individual estimates of oral clearance (range, 8.05 to 19.8 liters/h; 0.11 to 0.30 liter/h/kg) and volume of distribution (range, 49.2 to 161 liters; 0.43 to 1.92 liters/kg) of zalcitabine in these patients with the POSTHOC option in NONMEM. Our value for oral clearance agrees well with other estimates of oral clearance from traditional pharmacokinetic studies of zalcitabine and suggests that population methods may be a reasonable alternative to these traditional approaches for obtaining information on the disposition of zalcitabine.     

Pharmacokinetics of rifabutin.

We investigated the pharmacokinetics of rifabutin in 15 male patients as part of a phase I trial of the treatment of early symptomatic human immunodeficiency virus infection. Six or more patients were studied at each of four different oral dosage levels: 300, 600, 900, and 1,200 mg/day. Twelve studies were also conducted with tracer doses of intravenous radiolabeled [14C]rifabutin. Blood and urine samples were collected for at least 72 h after the first (day 1) and last (day 28) doses of rifabutin and analyzed by high-pressure liquid chromatography. The plasma concentration data were best described by a two-compartment open model with a terminal half-life of 36 h. Rifabutin was rapidly absorbed, reaching a peak concentration about 2 to 3 h after an oral dose. Peak and trough concentrations for the 1,200-mg dose were 907 and 194 ng/ml, respectively. Total body clearance was 10 to 18 liters/h. Oral bioavailability was 12 to 20%. The drug was moderately bound to plasma proteins with a free fraction of 29 +/- 2% (mean +/- standard deviation). About 10% of an administered intravenous dose of rifabutin is excreted into the urine unchanged. Renal clearance was 1.5 +/- 0.2 liters/h. The volume of distribution was large (8 to 9 liters/kg), suggesting extensive distribution into the tissues. The area under the curve for the last dose was smaller than that of the first dose, suggesting possible induction of drug-metabolizing enzymes.     

Human intravenous pharmacokinetics and absolute oral bioavailability of cefatrizine.

Cefatrizine was administered intravenously and orally at dose levels of 250, 500, and 1,000 mg to normal male volunteers in a crossover study. Intravenous pharmacokinetics were dose linear over this range; mean peak plasma concentrations at the end of 30-min infusions were, respectively, 18, 37, and 75 micrograms/ml, total body clearance was 218 ml/min per 1.73 m2, renal clearance was 176 ml/min per 1.73 m2, and mean retention time in the body was 1.11 h. Cumulative urinary excretion of intact cefatrizine was 80% of the dose, and half-lives ranged from 1 to 1.4 h. Steady-state volume of distribution was 0.22 liters/kg. On oral administration, the absolute bioavailabilities of cefatrizine were 75% at 250 and 500 mg and 50% at 1,000 mg. The mean peak plasma concentrations and peak times were, respectively, 4.9, 8.6, and 10.2 micrograms/ml at 1.4, 1.6, and 2.0 h, mean residence times were 2.4, 2.6, and 3.1 h, and mean absorption times were 1.3, 1.6, and 1.9 h. Oral renal clearance and half-life values corresponded well to the intravenous values. Cumulative urinary excretion of intact cefatrizine (as percentage of dose) was 60 at 250 mg, 56 at 500 mg, and 42 at 1,000 mg. It is hypothesized that the lack of oral dose linearity between the 500- and 1,000-mg doses is due to a component of cefatrizine absorption by a saturable transport process. Relative absorption at the high dose would be sufficiently slow that an absorption "window" would be passed before maximum bioavailability could be attained. It is not expected that the observed bioavailability decrease at doses exceeding 500 mg will have any therapeutic significance, since clinical studies are establishing efficacy for a recommended unit dosage regimen of 500 mg.     

Sequential, single-dose pharmacokinetic evaluation of meropenem in hospitalized infants and children.

Meropenem is a new carbapenem antibiotic which possesses a broad spectrum of antibacterial activity against many of the pathogens responsible for pediatric bacterial infections. In order to define meropenem dosing guidelines for children, an escalating, single-dose, pharmacokinetic study at 10, 20, and 40 mg/kg of body weight was performed. A total of 73 infants and children in four age groups were enrolled in the study: 2 to 5 months, 6 to 23 months, 2 to 5 years, and 6 to 12 years. The first patients enrolled were those in the oldest age group, who received the lowest dose. Subsequent enrollment was determined by decreasing age and increasing dose. Complete studies were performed on 63 patients. No age- or dose-dependent effects on pharmacokinetic parameter estimates were noted. Mean pharmacokinetic parameter estimates were as follows: half-life, 1.13 +/- 0.15 h; volume of distribution at steady state, 0.43 +/- 0.06 liters/kg; mean residence time, 1.57 +/- 0.11 h; clearance, 5.63 +/- 0.75 ml/min/kg; and renal clearance, 2.53 +/- 0.50 ml/min/liters kg. Approximately 55% of the administered dose was recovered as unchanged drug in the urine during the 12 h after dosing. No significant side effects were reported in any patients. By using the derived pharmacokinetic parameter estimates, a dose of 20 mg/kg given every 8 h will maintain plasma meropenem concentrations above the MIC that inhibits 90% of strains tested for virtually all potentially susceptible bacterial pathogens.     

Open-label, dose escalation study of the safety and pharmacokinetic profile of tefibazumab in healthy volunteers

Tefibazumab (Aurexis) is a humanized monoclonal antibody being evaluated as adjunctive therapy for the treatment of Staphylococcus aureus infections. This open-label, dose escalation study evaluated the safety and pharmacokinetics of tefibazumab in 19 healthy volunteers aged 18 to 69 years. Each subject received a single administration of tefibazumab at a dose of 2, 5, 10, or 20 mg/kg of body weight infused over 15 min. Plasma samples for pharmacokinetic assessments were obtained before infusion as well as 1, 6, 12, and 24 h and 3, 4, 7, 21, 28, 42, and 56 days after dosing. Plasma concentrations of tefibazumab were detected 1 h after the end of the infusion, with a mean maximum concentration of drug in serum (C(max)) of 59, 127, 252, and 492 microg/ml following doses of 2, 5, 10, and 20 mg/kg, respectively. The median time to maximum concentration of drug in serum (T(max)) was 1.0 h for each dose. The mean elimination half-life (t(1/2)) was approximately 22 days. The volume of distribution (V) was 4.7, 6.7, 7.2, and 7.2 liters after doses of 2, 5, 10, and 20 mg/kg, respectively. Clearance (CL) was 6.0, 9.2, 10.2, and 9.9 ml/hr, respectively. At the highest dose, plasma levels of tefibazumab were >100 microg/ml for 21 days. On day 56, the mean plasma concentrations were 6.3, 10.0, 16.4, and 30.5 microg/ml for the 2, 5, 10, and 20 mg/kg doses, respectively. Tefibazumab exhibited linear kinetics across doses of 5, 10, and 20 mg/kg. No anti-tefibazumab antibodies were detected after dosing in any subject. There were no serious adverse events, and tefibazumab was well tolerated over the entire dose range.     

Pharmacokinetics, oral bioavailability, and metabolic disposition in rats of (-)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl] cytosine, a nucleoside analog active against human immunodeficiency virus and hepatitis B virus.

The pharmacokinetics and metabolism of the potent anti-human immunodeficiency virus and anti-hepatitis B virus compound, (-)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl] cytosine (FTC), were investigated in male CD rats. Plasma clearance of 10 mg of FTC per kg of body weight was biexponential in rats, with a half-life at alpha phase of 4.7 +/- 1.1 min (mean +/- standard deviation) and a half-life at beta phase of 44 +/- 8.8 min (n = 5). The total body clearance of FTC was 1.8 +/- 0.1 liters/h/kg, and the oral bioavailability was 90% +/- 8%. The volume of distribution at steady state (Vss) was 1.5 +/- 0.1 liters/kg. Increasing the dose to 100 mg/kg slowed clearance to 1.5 +/- 0.2 liters/kg/h, lowered the Vss to 1.2 +/- 0.2 liters/kg, and reduced the oral bioavailability to 65% +/- 15%. FTC in the brains of rats was initially less than 2% of the plasma concentration but increased to 6% by 2 h postdose. Probenecid elevated levels of FTC in plasma as well as in brains but did not alter the brain-to-plasma ratio. The urinary and fecal recoveries of unchanged FTC after a 10-mg/kg intravenous dose were 87% +/- 3% and 5% +/- 1.6%, respectively. After a 10-mg/kg oral dose, respective urinary and fecal recoveries were 70% +/- 2.5% and 25% +/- 1.6%. Two sulfoxides of FTC were observed in the urine, accounting for 0.4% +/- 0.03% and 2.7% +/- 0.2% of the intravenous dose and 0.4% +/- 0.06% and 2.5% +/- 0.3% of the oral dose. Also observed were 5-fluorocytosine, representing 0.4% +/- 0.06% of the intravenous dose and 0.4% +/- 0.07% of the oral dose, and FTC glucuronide, representing 0.7% +/- 0.2% of the oral dose and 0.4% +/- 0.2% of the intravenous dose. Neither deaminated FTC nor 5-fluorouracil was observed in the urine (less than 0.2% of dose). The high oral availability and minimal metabolism of FTC encourage its further preclinical development.     

Pharmacokinetics and safety of oral levofloxacin in human immunodeficiency virus-infected individuals receiving concomitant zidovudine.

This phase I, double-blind, randomized, placebo-controlled, parallel-design study was conducted to evaluate the safety and pharmacokinetics of levofloxacin in human immunodeficiency virus (HIV)-infected subjects concomitantly receiving a stable regimen of zidovudine (AZT). Sixteen HIV-infected males with CD4-cell counts ranging from 100 to 550 and not experiencing significant AZT intolerance were enrolled. Subjects received levofloxacin (350 mg of levofloxacin hemihydrate) or a placebo (eight subjects per treatment group) as a single oral dose on day 1, multiple doses every 8 h from days 3 to 9, and a single dose on day 10. On days 1 and 10, an AZT dose (100 mg) was administered concurrently with the study drug. In between these doses, AZT was administered according to the regimen used by the subject prior to entering the study up to a maximum of 500 mg/day. Plasma levofloxacin concentrations were monitored for 36 h after levofloxacin dosing on day 1, immediately prior to the morning doses on days 3 to 9, and for 72 h after dosing on day 10. Plasma AZT concentrations were monitored on day 0 for baseline (for 6 h after the AZT dose) and for 4 h after the AZT doses on days 1 and 10. Levofloxacin was rapidly absorbed (time to maximum plasma concentration, approximately 1.0 h) and extensively distributed in the body with an apparent volume of distribution of approximately 104 liters (approximately 1.34 liters/kg). Steady-state conditions on day 10 were confirmed. Pharmacokinetic profiles of levofloxacin from single doses and multiple (three-times-daily) doses were similar, with a moderate accumulation (observed day 10-to-day 1 ratio of the maximum plasma concentration, approximately 185% versus expected 169%; for the corresponding ratio of the area under the concentration-time curve from 0 to 8 h [AUC(0-8)], the values were observed 217% versus expected 169%) at steady state. Mean average steady-state peak plasma concentration, plasma levofloxacin concentration at the end of the dosing interval, AUC(0-8), terminal half-life, and total body clearance were 7.06 microg/ml, 3.62 microg/ml, 37.4 microg x h/ml, 7.2 h, and 9.4 liters/h (0.12 liters/h/kg), respectively. Pharmacokinetic profiles of levofloxacin in HIV-infected patients did not appear to be affected by the concomitant administration of AZT; nor were AZT pharmacokinetics altered by levofloxacin. Oral administration of 350 mg of levofloxacin hemihydrate every 8 h appeared to be well tolerated by the subjects. There were no apparent differences in adverse events between the two treatment groups. There were no clinically significant changes from baseline in any laboratory parameter or vital sign following treatments observed in this study. The study results suggest that there is no need for levofloxacin dosage adjustment in HIV-seropositive subjects who concomitantly receive AZT.     

Pharmacokinetic studies of CP-74,667, a new quinolone, in laboratory animals.

The pharmacokinetics of CP-74,667 (7-(8'-methyl-3',8'-diazabicyclo[3.2.1]oct-3'-yl)-1-cyclopropyl-6- fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid) were studied following oral or parenteral administration in mice, rats, rabbits, dogs, and cynomolgus monkeys. The mean peak levels of CP-74,667 in serum following a single oral dose of 20 mg/kg of body weight were similar in all species, with a range of 3.7 micrograms/ml in mice to 5.6 micrograms/ml in dogs. In contrast, elimination half-lives were species dependent, with mean values of 2.1, 1.8, 4.5, 7.8, and 13.1 h in mice, rats, rabbits, dogs, and monkeys, respectively. The oral bioavailability of CP-74,667 was 100% in dogs and monkeys, as determined by intravenous-oral crossover experiments. The maximum concentration of drug in serum and area under the concentration-time curve (AUC) of CP-74,667 in dogs were proportional to dose over the range of 5 to 40 mg/kg. Accumulation of drug in serum was observed following the administration of four once-a-day doses of 7.1 mg/kg in monkeys (mimicking a 500-mg human dose), with significant increases in half-life, maximum and minimum concentrations of drug in serum, and AUC. The good tissue penetration of CP-74,667 suggested by a volume of distribution in excess of 2 liters/kg in dogs and monkeys was confirmed by tissue distribution studies with the same species, which demonstrated tissue concentrations (except for those in brain tissue) greater than 1.45 times higher than corresponding levels in serum. The mean urinary recoveries of unchanged drug were 17.7% in rats, 7.8% in monkeys, and 4.9% in dogs. Metabolism studies in dogs, following intravenous dosing, indicated that renal excretion of CP-74,667-related materials accounted for 41.6% of the administered dose, while biliary recoveries accounted for 6.8%. The CP-74,667 N-oxide metabolite was the primary drug-related material eliminated via renal excretion (37.2% of dose). The pharmacokinetics of CP-74,667 describe a quinolone with complete oral absorption, linear pharmacokinetics, a long elimination half-life, and wide distribution into tissues.