Clinical pharmacokinetics of adefovir in human immunodeficiency virus type 1-infected patients.

The pharmacokinetics and bioavailability of adefovir [9-[2-(phosphonomethoxy)ethyl]adenine] were examined at two dose levels in three phase I/II studies in 28 human immunodeficiency type 1-infected patients. The concentrations of adefovir in serum following the intravenous infusion of 1.0 or 3.0 mg/kg of body weight were dose proportional and declined biexponentially, with an overall mean +/- standard deviation terminal half-life of 1.6 +/- 0.5 h (n = 28). Approximately 90% of the intravenous dose was recovered unchanged in the urine in 12 h, and more than 98% was recovered by 24 h postdosing. The overall mean +/- standard deviation total serum clearance of the drug (223 +/- 53 ml/h/kg; n = 25) approximated the renal clearance (205 +/- 78 ml/h/kg; n = 20), which was significantly higher (P < 0.01) than the baseline creatinine clearance in the same patients (88 +/- 18 ml/h/kg; n = 25). Since adefovir is essentially completely unbound in plasma or serum, these data indicate that active tubular secretion accounted for approximately 60% of the clearance of adefovir. The steady-state volume of distribution of adefovir (418 +/- 76 ml/kg; n = 28) suggests that the drug was distributed in total body water. Repeated daily dosing with adefovir at 1.0 mg/kg/day (n = 8) and 3.0 mg/kg/day (n = 4) for 22 days did not significantly alter the pharmacokinetics of the drug; there was no evidence of accumulation. The oral bioavailability of adefovir at a 3.0-mg/kg dose was < 12% (n = 5) on the basis of the concentrations in serum or 16.4% +/- 16.0% on the basis of urinary recovery. The subcutaneous bioavailability of adefovir at a 3.0-mg/kg dose was 102% +/- 8.3% (n = 5) on the basis of concentrations in serum or 84.8% +/- 28.5% on the basis of urinary recovery. These data are consistent with preclinical observations in various species.     

Clinical Pharmacokinetics of 1-[((S)-2-Hydroxy-2-Oxo-1,4,2-Dioxaphosphorinan-5-yl)methyl]cytosine in Human Immunodeficiency Virus-Infected Patients

The pharmacokinetics and bioavailability of 1-[((S)-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl]cytosine (cyclic HPMPC) were examined at four doses in 22 patients with human immunodeficiency virus infection. Two groups of six patients received a single dose of cyclic HPMPC at 1.5 or 3.0 mg/kg of body weight by each of the oral and intravenous routes in a random order with a 2-week washout period between administrations. Additional patients received single intravenous doses of cyclic HPMPC at 5.0 mg/kg (n = 6) or 7.5 mg/kg (n = 4). Serial serum and urine samples were collected at intervals over 24 h after dosing. The concentrations of cyclic HPMPC and cidofovir in serum and urine samples were determined by validated reverse-phase ion-pairing high-performance liquid chromatography methods with derivatization and fluorescence detection. After intravenous administration of cyclic HPMPC, concentrations of cyclic HPMPC declined in a biexponential manner, with a mean ± standard deviation half-life of 1.09 ± 0.12 h (n = 22). The pharmacokinetics of cyclic HPMPC were independent of dose over the dose range of 1.5 to 7.5 mg/kg. The total clearance of cyclic HPMPC from serum and the volume of distribution of intravenous cyclic HPMPC were 198 ± 39.6 ml/h/kg and 338 ± 65.1 ml/kg, respectively (n = 22). The renal clearance of cyclic HPMPC (132 ± 27.3 ml/h/kg; n = 22) exceeded the creatinine clearance (86.2 ± 16.3 ml/h/kg), indicating active tubular secretion. The cyclic HPMPC excreted in urine in 24 h accounted for 71.3% ± 16.0% of the administered dose. Cidofovir was formed from cyclic HPMPC in vivo with a time to the maximum concentration in serum of 1.64 ± 0.23 h (n = 22). Cidofovir levels declined in an apparent monoexponential manner, with a mean terminal half-life of 3.98 ± 1.26 h (n = 22). The cidofovir excreted in urine in 24 h accounted for 9.40% ± 2.33% of the administered cyclic HPMPC dose. Exposure to cidofovir after intravenous administration of cyclic HPMPC was dose proportional and was 14.9% of that from an equivalent dose of cidofovir. The present study suggests that intravenous cyclic HPMPC also has a lower potential for nephrotoxicity in humans compared to that of intravenous cidofovir. The oral bioavailabilities of cyclic HPMPC were 1.76% ± 1.48% and 3.10% ± 1.16% with the administration of doses of 1.5 and 3.0 mg/kg, respectively (n = 6 per dose). The maximum concentrations of cyclic HPMPC in serum were 0.036 ± 0.021 and 0.082 ± 0.038 μg/ml after the oral administration of doses of 1.5 and 3.0 mg/kg, respectively. Cidofovir reached quantifiable levels in the serum of only one patient for each of the 1.5- and 3.0-mg/kg oral cyclic HPMPC doses.     

Combined action of chloramphenicol and ampicillin on chloramphenicol-resistant Haemophilus influenzae.

Previous studies have demonstrated high, concentration-dependent serum protein binding of cefonicid. To determine the in vivo pharmacokinetic significance of these observations, the pharmacokinetics of both total and unbound (non-protein-bound) cefonicid was studied in six volunteers after a single intravenous dose of 30 mg/kg. Saturable serum protein binding was observed in vivo; the mean +/- standard deviation free fraction of cefonicid was 17.6 +/- 6.1% immediately after administration and declined to a constant value of approximately 2% as total serum concentrations fell below 100 micrograms/ml. This nonlinear binding was associated with a pronounced decline in unbound serum cefonicid concentrations during the first 3 h after administration, with low or undetectable unbound drug concentrations by 12 h. Renal clearance of total cefonicid averaged 21.1 ml/min per kg and did not vary with time; in contrast, the mean +/- standard deviation unbound cefonicid renal clearance increased from 5.7 +/- 2.1 to 10.8 +/- 1.6 ml/min per kg with time (P less than 0.02). This study may partially explain the poor results obtained with single daily dosing of cefonicid in endocarditis. Dosage regimens of certain antimicrobial agents with high, saturable serum protein binding and extensive renal tubular secretion may be most appropriately designed based on unbound drug pharmacokinetics.     

Amoxicillin pharmacokinetics in preterm infants with gestational ages of less than 32 weeks.

The multiple-dose pharmacokinetics of amoxicillin (AM [administered twice daily in a 25-mg/kg of body weight intravenous dose]) in 17 preterm infants (11 males; gestational age, 29 +/- 1.9 weeks; birth weight, 1,175 +/- 278 g) were evaluated on day 3 of life. Blood samples were collected from an arterial catheter at 0, 0.5, 1, 2, 4, 8, and 12 h after the intravenous dose. A high-performance liquid chromatography method was used to determine AM concentrations in serum. AM pharmacokinetics followed a one-compartment open model. The glomerular filtration rates of all patients were simultaneously studied by means of the 24-h continuous inulin infusion technique. The elimination half-life, apparent volume of distribution, and total body clearance of AM (mean +/- standard deviation) were 6.7 +/- 1.7 h, 584 +/- 173 ml, and 62.4 +/- 23.3 ml/h, respectively. The mean (+/- standard deviation) AM peak and trough levels were 53.6 +/- 9.1 and 16.0 +/- 4.9 mg/liter, respectively. All infants had a serum trough level above 5 mg/liter. The total body clearance and apparent volume of distribution of AM and the clearance of inulin increased significantly with increasing gestational age. The total body clearance of AM (1.0 +/- 0.4 ml/min) and the clearance of inulin (1.0 +/- 0.3 ml/min) were similar. The total body clearance of AM increased significantly with increasing clearance of inulin. We conclude that an AM dose of 25 mg/kg every 12 h given to preterm infants in the first week of life with gestational ages of less than 32 weeks results in serum levels well above the MIC for major microorganisms involved in neonatal infections.     

Pharmacokinetics of single dose intravenous vancomycin in CAPD peritonitis

The pharmacokinetics of single dose intravenous vancomycin (25 mg/kg) were studied in six patients with peritonitis complicating continuous ambulatory peritoneal dialysis. The volume of distribution after equilibration was 1.1 +/- 0.1 l/kg (mean +/- standard error) with a serum elimination half-life of 115 +/- 6 h. The peritoneal clearance was 1.4 +/- 0.5 ml/min and the serum clearance was 7.2 +/- 0.3 ml/min. Mean peak serum levels of 56.8 +/- 4.7 mg/l were detected. Initial mean overnight dialysate level was 12.3 +/- 0.8 mg/l. Vancomycin dialysate levels of 8 mg/l were achieved for a mean of 3.0 days and levels of 4 mg/l for a mean of 6.2 days. Single dose intravenous vancomycin may, therefore, have therapeutic value in selected patients.     

Effects of probenecid on the pharmacokinetics and elimination of acyclovir in humans.

The effects of probenecid on the pharmacokinetics and renal clearance of acyclovir were studied in humans. Acyclovir (5 mg/kg) was given as a 1-h infusion to three volunteers with normal renal function both before and after oral administration of probenecid (1 g). The kinetics were well described by a two-compartment open model with zero-order infusion. The mean acyclovir concentrations at all time points after 1.0 h from the end of acyclovir infusion following probenecid administration were statistically higher than the corresponding mean acyclovir concentrations following the acyclovir infusion without probenecid administration. In the absence of probenecid, the renal clearance (248 +/- 80 ml/min per 1.73 m2) accounted for 83% of the total clearance (300 +/- 69 ml/min per 1.73 m2) and was almost threefold greater than the estimated creatinine clearance (90 +/- 48 ml/min per 1.73 m2). After probenecid administration, there was a 32% decline in renal clearance (248 to 168 ml/min per 1.73 m2; P less than or equal to 0.05), a 40% increase in the area under the curve (91.3 to 127.6 nmol.h/ml; P less than 0.05), and an 18% increase in the terminal plasma half-life (2.3 to 2.7 h; P less than 0.01). Although statistically significant, these effects due to the influence of probenecid probably have only limited clinical importance. In this study we confirmed that acyclovir is eliminated predominantly by renal clearance, both by glomerular filtration and tubular secretion; our results suggested that at least part of the tubular secretion is inhibited by probenecid.     

Effect of meningitis and probenecid on the penetration of vancomycin into cerebrospinal fluid in rabbits.

This study examined the effects of experimental pneumococcal meningitis and probenecid administration on the penetration of parenterally administered vancomycin into cerebrospinal fluid in rabbits. Bacterial killing was also examined in infected animals. Meningitis was induced by intracisternal inoculation of Streptococcus pneumoniae. Vancomycin was administered in a loading dose followed by a continuous intravenous infusion for 6 h. Serum and cerebrospinal fluid samples were obtained at 0, 2, 4, and 6 h for antibiotic assays and quantitative cultures. Meningitis significantly enhanced the penetration of vancomycin into cerebrospinal fluid, but probenecid administration had no effect. In normal rabbits, at 6 h the mean percent penetration (cerebrospinal fluid concentration/serum concentration x 100%) +/- the standard deviation was 1.9 +/- 0.9% in the nonprobenecid group (n = 10) and 1.9 +/- 1.1% in the probenecid group (n = 9). In rabbits with experimental pneumococcal meningitis, the mean percent penetration at 6 h was 3.9 +/- 2.6% in the nonprobenecid group (n = 11) and 4.3 +/- 2.1% in the probenecid group (n = 9). Mean bacterial titers in the cerebrospinal fluid of infected animals decreased by more than 3.0 log 10 colony-forming units per ml in both the nonprobenecid and the probenecid groups.     

Pharmacokinetics of a fluoronaphthyridone, trovafloxacin (CP 99,219), in infants and children following administration of a single intravenous dose of alatrofloxacin

The pharmacokinetics of trovafloxacin following administration of a single intravenous dose of alatrofloxacin, equivalent to 4 mg of trovafloxacin per kg of body weight, were determined in 6 infants (ages 3 to 12 months) and 14 children (ages, 2 to 12 years). There was rapid conversion of alatrofloxacin to trovafloxacin, with an average +/- standard deviation (SD) peak trovafloxacin concentration determined at the end of the infusion of 4.3 +/- 1.4 microg/ml. The primary pharmacokinetic parameters (average +/- SD) analyzed were volume of distribution at steady state (1.6 +/- 0.6 liters/kg), clearance (151 +/- 82 ml/h/kg), and half-life (9.8 +/- 2.9 h). The drug was well tolerated by all children. There were no age-related differences in any of the pharmacokinetic parameters studied. Less than 5% of the administered dose was excreted in the urine over 24 h. On the basis of the mean area under the concentration-time curve of 30.5 +/- 10.1 microg. h/ml and the susceptibility (< or =0.5 microg/ml) of common pediatric bacterial pathogens to trovafloxacin, dosing of 4 mg/kg/day once or twice daily should be appropriate.     

Pharmacokinetics of michellamine B, a naphthylisoquinoline alkaloid with in vitro activity against human immunodeficiency virus types 1 and 2, in the mouse and dog.

Michellamine B (MB) is a naturally occurring naphthylisoquinoline alkaloid of novel chemical structure with activity against human immunodeficiency virus (HIV) types 1 and 2 in vitro. In conjunction with its preclinical evaluation, the plasma pharmacokinetics of MB was characterized in mice and dogs treated by intravenous infusions of 1- and 15-min durations, respectively. At doses ranging from 1 to 9 mg/kg of body weight, the drug exhibited apparent first-order kinetics in both species, affording triexponential plasma concentration-time profiles. Treatment with doses of 5 to 9 mg/kg provided peak plasma levels within the range that completely inhibits the cytopathic effects of HIV upon cultured human lymphoblastoid cells (50 to 100 micrograms/ml) without evidence of toxicity. MB had a biological half-life of 2.8 +/- 0.8 h in mice, with a mean residence time of 2.1 +/- 0.3 h, and a total plasma clearance of 2.4 +/- 0.5 ml/min/kg (mean +/- standard deviation; n = 3); however, the terminal-phase contribution to the area under the plasma profile from time zero to infinity was 44.6% +/- 12.9%. In contrast, the terminal phase was the primary determinant of drug disposition in dogs, accounting for 74.1% +/- 2.8% (n = 3) of the area under the curve. Furthermore, the systemic duration of MB was significantly longer in the dogs than in mice, as indicated by mean values of the apparent half-life (11.6 +/- 1.2 h), mean residence time (12.3 +/- 1.8 h), and clearance (0.50 +/- 0.08 ml/min/kg). However, there were no statistical difference between its apparent volume of distribution in the mice (0.60 +/- 0.08 liters/kg) and dogs (0.50 +/- 0.07 liters/kg). A single dog was also treated with a total dose of 97 mg/kg given as a 72-h constant-rate intravenous infusion, since prolonged systemic exposure to potentially therapeutic drug concentrations will very likely be required for clinical anti-HIV effects. Within 4 h after starting the infusion, the plasma MB concentration exceeded 18 micrograms/ml, it reported 50% effective concentration against HIV in vitro, and subsequently increased to 41 micrograms/ml at the end of the infusion. There were no clinical or pathological indications of toxicity. Whereas the total plasma clearance (0.48 ml/min/kg) was within the range observed for dogs treated by 15-min infusion, extension of the postinfusion sampling period from 24 h to 4 days facilitated better definition of the terminal exponential phase, yielding a value of 25.6 h for the biological half-life of MB. The amount of drug excreted by dogs unchanged in the urine ranged from 3.7 to 11.1% of the administered dose. Thus, the major pathways by which the drug is eliminated from the body remain to be identified. On the basis of these findings, continued development of MB as a novel lead compound for the treatment of HIV infection is warranted.     

Pharmacokinetics and pharmacodynamics of imipenem during continuous renal replacement therapy in critically ill patients

The pharmacokinetics of imipenem were studied in adult intensive care unit (ICU) patients during continuous venovenous hemofiltration (CVVH; n=6 patients) or hemodiafiltration (CVVHDF; n=6 patients). Patients (mean+/-standard deviation age, 50.9+/-15.9 years; weight, 98.5+/-15.9 kg) received imipenem at 0.5 g every 8 to 12 h (total daily doses of 1 to 1.5 g/day) by intravenous infusion over 30 min. Pre- and postmembrane blood (plasma) and corresponding ultrafiltrate or dialysate samples were collected 1, 2, 4, and 8 or 12 h (depending on dosing interval) after completion of the drug infusion. Drug concentrations were measured using validated high-performance liquid chromatography methods. Mean systemic clearance (CL(S)) and elimination half-life (t1/2) of imipenem were 145+/-18 ml/min and 2.7+/-1.3 h during CVVH versus 178+/-18 ml/min and 2.6+/-1.6 h during CVVHDF, respectively. Imipenem clearance was substantially increased during both CVVH and CVVHDF, with membrane clearance representing 25% and 32% of CL(S), respectively. The results of this study indicate that CVVH and CVVHDF contribute to imipenem clearance to a greater degree than previously reported. Imipenem doses of 1.0 g/day appear to achieve concentrations adequate to treat most common gram-negative pathogens (MIC up to 2 microg/ml) during CVVH or CVVHDF, but doses of 2.0 g/day or more may be required to adequately treat and prevent resistance in pathogens with higher MICs (MIC=4 to 8 microg/ml). Higher doses should only be used after consideration of potential central nervous system toxicities or other risks of therapy in these severely ill patients.     

Pharmacokinetics of vancomycin in patients undergoing continuous ambulatory peritoneal dialysis.

The pharmacokinetics of vancomycin were studied in four patients on continuous ambulatory peritoneal dialysis. After a single intravenous infusion of 10 mg/kg of total body weight, multiple blood, urine, and dialysate samples were collected during a 72-h evaluation period. The steady-state volume of distribution was 0.73 +/- 0.07 (mean +/- standard deviation) liters/kg with a beta half-life of 90.2 +/- 24.2 h. The continuous ambulatory peritoneal dialysis clearance of vancomycin was 1.35 +/- 0.35 ml/min, and the serum clearance was 6.4 +/- 1.1 ml/min. Peritoneal dialysate concentrations of vancomycin were rapidly attained after the intravenous infusion and averaged 2.2 +/- 0.7 mg/liter throughout the 72-h observation period. A loading dose of 23 mg/kg followed by a maintenance dose of 17 mg/kg every 7 days should attain and maintain therapeutic serum and dialysate concentrations. More frequent dosing may be necessary for less susceptible organisms.     

Clinical pharmacology of torasemide, a new loop diuretic

Torasemide is a new loop diuretic that potentially may have renal tubular effects from both the blood and urinary sides of the nephron. We assessed its pharmacokinetics and pharmacodynamics in eight normal subjects administering intravenous doses of 5, 10, and 20 mg compared with 40 mg furosemide. We assessed the effect of probenecid on response to the 20 mg dose. A dose intermediate to the 10 and 20 mg doses appeared equally natriuretic to 40 mg furosemide. Although total clearance was the same with all doses (about 0.45 ml/min/kg), renal clearance and the fraction of unchanged drug appearing in the urine decreased with higher doses raising the question of saturable renal secretion. Urinary dose-response curves showed torasemide to be five times as potent as furosemide. Probenecid pretreatment decreased both urine volume (P = 0.0016) and sodium excretion (P = 0.0003), implying that delivery of drug to the urinary side of the nephron is the major determinant of response.     

Pharmacokinetics of cefodizime in normal individuals and in patients with renal failure

The pharmacokinetics of cefodizime (HR 221) were studied in 6 healthy male individuals and 12 male patients with various degrees of chronic renal failure following intravenous bolus injection of 1 g of the drug. Serum pharmacokinetics were described by an open two-compartment kinetic model. The serum levels of cefodizime exceeded the MIC90 for Enterobacteriaceae, Haemophilus influenzae and Neisseria gonorrhoeae for more than 12 h in healthy individuals and 24 h in renal failure patients. The half-life of elimination was significantly prolonged (p less than 0.001) from 2.7 +/- 0.2 h in healthy volunteers to 7.7 +/- 1.5 h in renal failure patients. The total systemic clearance decreased significantly (p less than 0.001) from 43.3 +/- 5.8 ml/h/kg in healthy volunteers to 23.2 +/- 5.6 ml/h/kg in renal failure patients. A linear correlation (r = 0.9; p less than 0.001) was found between creatinine clearance and the total systemic clearance of cefodizime. The AUC0-infinity in patients with renal failure was more than double the value in healthy volunteers. An equation to calculate the 1-gram dose interval of cefodizime in patients with compromised renal function is provided.     

Effect of probenecid on the pharmacokinetics of cefmenoxime.

In this study, we were concerned with the effect of probenecid on the pharmacokinetics of 1,000 mg of cefmenoxime administered over a 30-min period by intravenous infusion. Each of a total of 10 subjects received cefmenoxime twice, once with and once without adjunctive probenecid. The data were fit by iterative nonlinear regression procedures to a two-compartment open pharmacokinetic model, with elimination from the central compartment. The mean calculated peak concentration, area under the curve from zero to infinity, and half-life without probenecid were 78.1 micrograms/ml, 77.2 micrograms . h/ml, and 1.14 h, respectively. When cefmenoxime was administered with probenecid, these values were 86.7 micrograms/ml, 158.2 micrograms . h/ml, and 1.78 h, respectively. Averages of about 55 and 46% of the administered doses were recovered in urine samples collected at 0 through 24 h for doses administered without and with probenecid, respectively. The mean corrected renal drug clearance was 159 and 66 ml/min without and with probenecid, respectively. Statistical significance (P less than 0.05) was demonstrated for the differences in beta half-life, (K/net), calculated peak concentration, area under the curve from 0 to infinity, and renal clearance, but not for K21, K12, volume of distribution, or alpha-phase distribution rate constant. The results of this study indicate that tubular secretion is the predominant mechanism of clearance for cefmenoxime and that probenecid alters the pharmacokinetics of the compound by competitively inhibiting its tubular secretion without affecting either the rate or the extent of its distribution.     

Single-dose pharmacokinetics of intravenous itraconazole and hydroxypropyl-beta-cyclodextrin in infants, children, and adolescents

This investigation was designed to evaluate the single-dose pharmacokinetics of itraconazole, hydroxyitraconazole, and hydroxypropyl-beta-cyclodextrin (HP-beta-CD) after intravenous administration to children at risk for fungal infection. Thirty-three children aged 7 months to 17 years received a single dose of itraconazole (2.5 mg/kg in 0.1-g/kg HP-beta-CD) administered over 1 h by intravenous infusion. Plasma samples for the determination of the analytes of interest were drawn over 120 h and analyzed by high-pressure liquid chromatography, and the pharmacokinetics were determined by traditional noncompartmental analysis. Consistent with the role of CYP3A4 in the biotransformation of itraconazole, a substantial degree of variability was observed in the pharmacokinetics of this drug after IV administration. The maximum plasma concentrations (C(max)) for itraconazole, hydroxyitraconazole, and HP-beta-CD averaged 1,015 +/- 692 ng/ml, 293 +/- 133 ng/ml, and 329 +/- 200 mug/ml, respectively. The total body exposures (area under the concentration-time curve from 0 to 24 h) for itraconazole, hydroxyitraconazole, and HP-beta-CD averaged 4,922 +/- 6,784 ng.h/ml, 3,811 +/- 2,794 ng.h/ml, and 641.5 +/- 265.0 mug.h/ml, respectively, with no significant age dependence observed among the children evaluated. Similarly, there was no relationship between age and total body clearance (702.8 +/- 499.4 ml/h/kg); however, weak associations between age and the itraconazole distribution volume (r(2) = 0.18, P = 0.02), C(max) (r(2) = 0.14, P = 0.045), and terminal elimination rate (r(2) = 0.26, P < 0.01) were noted. Itraconazole infusion appeared to be well tolerated in this population with a single adverse event (stinging at the site of infusion) deemed to be related to study drug administration. Based on the findings of this investigation, it appears that intravenous itraconazole can be administered to infants beyond 6 months, children, and adolescents using a weight-normalized approach to dosing.     

PHARMACOKINETICS OF INTRAVENOUS CAFFEINE IN CRITICALLY ILL PATIENTS

The pharmacokinetics of intravenous caffeine used to measure liver function were evaluated in 20 critically ill patients. Each patient received a single dose of 3.0 mg/kg of caffeine benzoate as a 30-min i.v. infusion. Caffeine serum concentrations were analysed by an enzyme-multiplied immunoassay technique (EMIT). Caffeine pharmacokinetics fitted an open one-compartment model. The mean value for the half-life (t1/2) was 9.46 +/- 4.32 h, the volume of distribution was 0.55 +/- 0.13 l/kg, and the plasma clearance (Cl) was 0.85 +/- 0.44 ml/min/kg. The pharmacokinetics parameters of caffeine in critically ill patients compared with normal volunteers were characterized by a reduction in plasma clearance and prolongation in plasma half-life, whereas the volume of distribution remained unchanged.     

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 of ceftazidime in normal and uremic subjects.

The pharmacokinetics of ceftazidime, administered as a single intravenous dose of 15 mg/kg given in a bolus injection over 3 min, were investigated in 5 normal subjects and in 19 uremic patients. The subjects studied were divided into five groups according to values for endogenous creatinine clearance (CLCR): group I, five subjects with CLCR greater than 80 ml/min; group II, five patients with CLCR = 30 to 80 ml/min; group III, six patients with CLCR = 10 to 30 ml/min; group IV, four patients with CLCR = 2 to 10 ml/min; and group V, four anuric patients on hemodialysis. A two-compartment open model was used to calculate the pharmacokinetic parameters. In normal subjects, the mean apparent elimination half-life was 1.57 +/- 0.13 h. The central distribution volume and the apparent volume of distribution were 0.127 +/- 0.023 and 0.230 +/- 0.015 liter/kg, respectively. Of the injected dose, 83.6 +/- 3.6% was eliminated in the urine as parent drug within 24 h. The terminal half-life increased with impairment of renal function to about 25 h in severely uremic patients. Impairment of function did not significantly modify the half-life at alpha phase, central distribution volume, or apparent distribution volume. A 6- to 8-h hemodialysis procedure reduced concentrations of ceftazidime in plasma by approximately 88%, and the elimination half-life was 2.8 +/- 0.2 h. There was no evidence of accumulation of ceftazidime in four patients with severe and chronic impairment of function who received doses of 0.5 to 1.0 g every 24 h for 10 days.     

Pharmacokinetics of cefetamet (Ro 15-8074) and cefetamet pivoxil (Ro 15-8075) after intravenous and oral doses in humans.

This report summarizes the results of three pharmacokinetic studies of cefetamet and cefetamet pivoxil conducted in normal adult male volunteers. In the first study the pharmacokinetics of cefetamet were evaluated after intravenous infusion of doses ranging from 133 to 2,650 mg. Over this dose range, the pharmacokinetics were linear. A dose-proportional increase in the area under the curve from zero to infinity was observed, whereas total clearance (140.3 +/- 23.6 ml/min), renal clearance (130.3 +/- 18.2 ml/min), volume of distribution at steady state (0.288 +/- 0.023 liter/kg), fraction excreted unchanged in the urine (94 +/- 11%), and elimination half-life (2.07 +/- 0.18 h) were independent of dose. In a second study the absolute bioavailability of single 1,500-mg doses of a tablet formulation of the pivaloyloxymethylester of cefetamet was evaluated under conditions of fasting and after a standard breakfast. Administration with food increased the extent of absorption (from 31 +/- 7 to 44 +/- 4%) while decreasing the rate of absorption (time to maximum concentration of drug in plasma increased from 3.0 +/- 0.6 to 4.8 +/- 0.4 h). The third study consisted of multiple oral administration of 1,000 mg of a similar oral tablet formulation twice daily for 10 days. This regimen was preceded and followed by intravenous administration of a 500-mg bolus dose of cefetamet. Oral doses were administered with breakfast and dinner. The absolute bioavailability of the tablet formulation was assessed after the first dose and after both the morning and the evening doses on day 10 of oral therapy. The compound was consistently absorbed to the extent of approximately 50% with no significant differences observed between the morning and evening doses on day 10.     

Steady-state kinetics of proguanil and its active metabolite, cycloguanil, in man

The pharmacokinetics of proguanil and its active metabolite, cycloguanil, were determined at steady-state in 6 healthy male volunteers after daily administration of 2 Paludrine tablets (200 mg proguanil hydrochloride). A maximum plasma proguanil concentration of 130.3 +/- 16.0 ng/ml (mean +/- SD) was reached at 3.8 +/- 1.3 h while a maximum cycloguanil concentration of 52.0 +/- 15.2 ng/ml was obtained at 5.3 +/- 1.0 h after dosing. The elimination half-lives of proguanil and cycloguanil were 14.5 +/- 3.0 h and 11.7 +/- 3.1 h, respectively. The plasma clearance of proguanil was 1.43 +/- 0.33 l/h/kg and the apparent volume of distribution was 30.7 +/- 12.3 l/kg. Renal clearance of proguanil (0.33 +/- 0.19 l/h/kg) was about 23% of the plasma clearance and 35.6 +/- 9.6% of the oral dose was recovered as proguanil and cycloguanil.