Single-dose pharmacokinetics of imipenem-cilastatin in neonates.

The single-dose pharmacokinetics of imipenem (N-formimidoyl thienamycin), a beta-lactam antibiotic, used in combination with cilastatin, a renal dehydropeptidase I inhibitor, were evaluated in 10 neonates 1 to 8 days of age. The imipenem-cilastatin combination was given intravenously over a 15-min period at a dose of 15 or 25 mg/kg. Drug concentrations in serum, urine, and cerebrospinal fluid (when available) were determined by high-pressure liquid chromatography, and plasma disposition of the drugs was described by a two-compartment open model. The mean peak plasma levels of imipenem 30 min postinfusion were 55.4 and 27.2 micrograms/ml, and the mean t1/2 beta values were 2.1 and 1.8 h at doses of 25 and 15 mg/kg, respectively. The calculated volume of distribution was 0.41 liters/kg. In two patients from whom cerebrospinal fluid was obtained 1.5 h postinfusion, imipenem levels were 5.6 and 1.1 micrograms/ml at doses of 25 and 15 mg/kg, respectively, representing 10 and 4% of the 1-h serum levels. No side effects attributable to a single dose of imipenem-cilastatin were noted.     

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.     

Multiple-dose pharmacokinetics of ceftibuten in healthy volunteers.

The pharmacokinetics of ceftibuten, a new cephalosporin antibiotic, and its conversion product, ceftibutentrans, were studied in healthy male volunteers following daily oral administration of a 400-mg capsule for 7 days. Mean concentrations of ceftibuten in plasma obtained on day 5 were similar to those obtained on day 7. Analysis of variance indicated that the concentrations in plasma on days 5 and 7 were at steady state. The mean accumulation factor was 1.14 for day 5 and 1.13 for day 7. The half-life (2.4 h) was independent of the duration of drug administration, and the mean maximum concentration of drug in plasma was 18 to 19 micrograms/ml. Urinary excretion was the major elimination route for ceftibuten, by which 57 to 59% of the drug was excreted unchanged over a 24-h period. The amounts of ceftibuten-trans in plasma and urine were low.     

Multiple-dose pharmacokinetics of ceftazidime in cancer patients.

The pharmacokinetic parameters of ceftazidime were determined in 25 patients with neoplastic diseases. A group of 13 patients each received 1 g of ceftazidime over 15 min as a single intravenous dose. The mean peak drug concentration in serum was 77.4 micrograms/ml, and the serum half-life was 144 min. Urinary excretion at 12 h was 64.5%. These 13 patients also received 2 g of ceftazidime over 15 min at 8-h intervals for 7 or 8 days. The mean peak drug concentrations in serum were 103.6 micrograms/ml on day 1 and 87 micrograms/ml on day 7 or 8. A second group of 12 patients received 1 g of ceftazidime over 30 min, followed by 1 g over 2 h and every 4 h thereafter. The mean peak drug concentration in serum at 30 min was 57.5 micrograms/ml. Average peak and trough levels obtained on day 2 or 3 were 65 and 34.8 micrograms/ml, respectively, and remained in this range thereafter. The above-mentioned dose schedules produced high and adequate ceftazidime concentrations in serum.     

Multiple-dose pharmacokinetics of amdinocillin in healthy volunteers.

The pharmacokinetics of amdinocillin (mecillinam) after multiple intravenous doses to healthy subjects are described. Assay of plasma and urine samples was carried out with a sensitive and specific high-pressure liquid chromatographic technique. A dose of 10 mg/kg of body weight was administered every 4 h for six doses. No accumulation was noted. Mean peak plasma concentrations were approximately 50 micrograms/ml, and the plasma half-life was approximately 53 min. Total plasma clearance was 4.6 ml/min per kg after the first dose, which declined slightly to 4.1 ml/min per kg after the last dose. Renal clearance remained fairly constant at approximately 2.9 ml/min per kg, or twice the creatinine clearance. The fraction excreted unchanged totaled 63% during the 4-h interval after the first dose and was nearly 70% overall. The steady-state volume of distribution was calculated to be 0.26 liter/kg. Urinary concentrations of amdinocillin were far in excess of the usual inhibitory concentrations for susceptible pathogens and were as high as 3,000 micrograms/ml. Dose of amdinocillin every 4 h provide plasma and urine concentrations which should be effective for the treatment of infections.     

Multiple-dose pharmacokinetics of ciprofloxacin administered intravenously to normal volunteers.

We administered multiple doses of ciprofloxacin intravenously over 30 min every 12 h for 1 week to nine healthy volunteers. Three volunteers received a placebo (vehicle) intravenously. Doses of 100, 150, and 200 mg were evaluated with a 1-week wash-out period intervening between each dose level. Terminal excretion half-lives averaged 3.67 +/- 0.65, 3.60 +/- 0.26, and 4.00 +/- 0.69 h for the 100-, 150-, and 200-mg doses, respectively. Serum clearances were 30.1 +/- 3.4, 29.8 +/- 4.0, and 26.9 +/- 4.1 liters/h per 1.73 m2 for these doses. Urine concentrations remained in excess of the MIC for 90% of the relevant urinary tract pathogens for the full 12-h dosing interval at each dose. Renal clearance accounted for 56 to 71% of the serum clearance. However, because a microbiologic assay was used and biologically active, renally excreted metabolites were identified, the renal clearance determinations are likely to be in excess of the true values. The doses of ciprofloxacin administered intravenously were well tolerated, and the drug concentrations appeared adequate for the treatment of the vast majority of cases of nosocomially acquired sepsis and urinary tract infections. For patients with serious Pseudomonas infections and perhaps staphylococcal infections, either an 8-h dosing schedule or larger doses on a 12-h schedule should be considered.     

Multiple-dose pharmacokinetics and safety of rufloxacin in normal volunteers.

The pharmacokinetics and safety of rufloxacin were evaluated in a double-blind, placebo-controlled study. Two groups of 16 healthy volunteers were given a single oral loading dose of 400 or 600 mg of rufloxacin on day 1 of the study. A single daily maintenance dose of 200 or 300 mg was then administered for a further 9 days; in addition, four subjects in each group received placebos. Rufloxacin levels in plasma and urine were determined by high-performance liquid chromatography. Following the initial dose, the mean (+/- standard error of the mean) peak concentrations of rufloxacin in plasma were 3.35 +/- 0.12 micrograms/ml in the 400-mg group and 4.54 +/- 0.19 micrograms/ml in the 600-mg group. They were generally reached 2 to 3 h after dosing. At the end of treatment, maximum levels in plasma rose to 4.51 +/- 0.15 and 7.20 +/- 0.25 micrograms/ml in the 400-mg and 600-mg groups, with a mean extent of accumulation (fold) of 3.1 +/- 0.1 and 3.3 +/- 0.1. For the 400-mg and 600-mg groups, the elimination half-lives were 40.0 +/- 1.5 and 44.0 +/- 1.3 h, mean residence times were 57.8 +/- 2.2 and 63.7 +/- 1.8 h, apparent volumes of distribution were 132 +/- 4 and 139 +/- 5 liters, and apparent total body clearance were 39 +/- 1 and 44 +/- 4 ml/min, assuming complete bioavailability. Of the total dose administered, the percentages excreted in urine were 49.6 +/- 1.3 and 51.1 +/-2.1%, with renal clearances of 21 +/- 1 and 22 +/- 2 ml/min, for the 400-mg and 600-mg groups. On the whole, the treatments were well tolerated, but some minor adverse events (mainly headache, insomnia, or abdominal discomfort) were reported for 7 subjects on abnormalities were detected in the laboratory examinations or in ocular function tests. This study shows that a 200-mg daily oral dose of rufloxacin preceded by a loading dose of 400 mg are well tolerated and produce steady-state concentrations in plasma above the MIC for most susceptible pathogens.     

Multiple-dose pharmacokinetics of ritonavir in human immunodeficiency virus-infected subjects.

The multiple-dose pharmacokinetics of ritonavir were investigated in four groups of human immunodeficiency virus-positive male subjects (with 16 subjects per group) under nonfasting conditions; a 3:1 ritonavir:placebo ratio was used. Ritonavir was given at 200 (group I), 300 (group II), 400 (group III), or 500 (group IV) mg every 12 h for 2 weeks. The multiple-dose pharmacokinetics of ritonavir were moderately dose dependent, with the clearance for group IV (6.8 +/- 2.7 liters/h) being an average of 32% lower than that for group I (10.0 +/- 3.2 liters/h). First-pass metabolism should be minimal for ritonavir. The functional half-life, estimated from peak and trough concentrations, were similar among the dosage groups, averaging 3.1 and 5.7 h after the morning and evening doses, respectively. The area under the concentration-time curve at 24 h (AUC24) and apparent terminal-phase elimination rate constant remained relatively time invariant, but predose concentrations decreased 30 to 70% over time. Concentration-dependent autoinduction is the most likely mechanism for the time-dependent pharmacokinetics. The Km and initial maximum rate of metabolism (Vmax) values estimated from population pharmacokinetic modeling (nonlinear mixed-effects models) were 3.43 microg/ml and 46.9 mg/h, respectively. The group IV Vmax increased to 68 mg/h after 2 weeks. The maximum concentration of ritonavir in serum (Cmax) and AUC after the evening doses were an average of 30 to 40% lower than the values after the morning doses, while the concentration at 12 h was an average of 32% lower than the predose concentration, probably due to protracted absorption. Less than 2% of the dose was eliminated unchanged in the urine. Triglyceride levels increased from the levels at the baseline, and the levels were correlated with baseline triglyceride levels and AUC, Cmax, or predose concentrations.     

Serum bactericidal activities and comparative pharmacokinetics of meropenem and imipenem-cilastatin.

The pharmacokinetics and serum bactericidal activities (SBAs) of imipenem and meropenem were investigated in a randomized crossover study. Twelve healthy male volunteers received a constant 30-min infusion of either 1 g of imipenem plus 1 g of cilastatin or 1 g of meropenem. The concentrations of the drugs in serum and urine were determined by bioassay and high-pressure liquid chromatography. Pharmacokinetic parameters were based on an open two-compartment model and a noncompartmental technique. At the end of infusion, the mean concentrations of imipenem and meropenem measured in serum were 61.2 +/- 9.8 and 51.6 +/- 6.5 mg/liter, respectively; urinary recoveries were 48.6% +/- 8.2% and 60.0% +/- 6.5% of the dose in 12 h, respectively; and the areas under the concentration-time curve from time zero to infinity were 96.1 +/- 14.4 and 70.5 +/- 10.3 mg.h/liter, respectively (P < or = 0.02). Imipenem had a mean half-life of 66.7 +/- 10.4 min; that of meropenem was 64.4 +/- 6.9 min. The volumes of distribution at steady state of imipenem and meropenem were 15.3 +/- 3.3 and 18.6 +/- 3.0 liters/70 kg, respectively, and the mean renal clearances per 1.73 m2 were 85.6 +/- 17.6 and 144.6 +/- 26.0 ml/min, respectively. Both antibiotics were well tolerated in this single-dose administration study. The SBAs were measured by the microdilution method of Reller and Stratton (L. B. Reller and C. W. Stratton, J. Infect. Dis. 136:196-204, 1977) against 40 clinically isolated strains. Mean reciprocal bactericidal titers were measured 1 and 6 h after administration. After 1 and 6 h the median SBAs for imipenem and meropenem, were 409 and 34.9 and 97.9 and 5.8, respectively, against Staphylococcus aureus, 19.9 and 4.4 and 19.4 and 4.8, respectively, against Pseudomonas aeruginosa, 34.3 and 2.2 and 232 and 15.5, respectively, against Enterobacter cloacae, and 13.4 and 2.25 and 90.7 and 7.9, respectively, against Proteus mirabilis. Both drugs had rather short biological elimination half-lives and a predominantly renal route of elimination. Both carbapenems revealed high SBAs against clinically important pathogens at 1 h; meropenem had a higher SBA against E. cloacae and P. mirabilis, and the SBA of imipenem against S. aureus was greater than the SBA of meropenem.     

Multiple-dose pharmacokinetics of sparfloxacin and its influence on fecal flora.

In a randomized, double-blind, placebo-controlled, multiple-dose pharmacokinetic study, the safety and effect on intestinal flora of sparfloxacin (SPX) were determined in 12 healthy male volunteers (8 received SPX and 4 received a placebo). Following fasting and oral administration of 400 mg on day 1 and 200 mg on days 2 to 8, concentrations of the free drug in serum, urine, and feces were measured by high-performance liquid chromatography; serum and urine were also evaluated by a microbiological assay. All results, except those for renal excretion, exclude the glucuroconjugate metabolite. A mean peak concentration in serum (400-mg dose) of 0.56 +/- 0.13 mg/liter was measured 3.52 +/- 0.98 h after administration. Pharmacokinetic parameters (measured by high-performance liquid chromatography) were based on an open, one-compartment model and resulted in the following day 1 (calculated for the 200-mg dose), day 4 (recalculated for a single dose), and day 8 values (mean +/- standard deviation): area under the curve, 16.4 +/- 2.3 (day 1) and 18.3 +/- 5.1 (day 4) mg.h/liter; elimination half-life, 18.3 +/- 3.9 h; steady-state volume of distribution, 4.7 +/- 1.4 (day 1) and 4.3 +/- 1.2 (day 8) liters/kg; apparent total clearance, 201 +/- 31 (day 1) and 190 +/- 51 (day 4) ml/min; renal clearance, 19.1 +/- 5.8 (day 1) and 23.2 +/- 19.4 (day 4) ml/min. Recovery in urine on day 1 was 5.89% +/- 1.4% of the dose in 24 h for the parent compound and 18.4% +/- 6.8% for the SPX glucuronide.(ABSTRACT TRUNCATED AT 250 WORDS)     

Multiple-dose pharmacokinetics of cefonicid in patients with impaired renal function.

The pharmacokinetics of multiple-dose administration of cefonicid to patients with normal and impaired renal function were studied by using high-performance liquid chromatography to measure serial serum and urine concentrations. Eighteen patients received an initial dose of 15 mg/kg intravenously over 12 min plus two or three subsequent modified doses at intervals of 24 to 72 h, depending upon the degree of renal impairment. Six patients chronically requiring hemodialysis and 12 nondialysis subjects (creatinine clearance, 10 to 80 ml/min per 1.73 m2) were studied. The concentrations of cefonicid in serum after the initial dose were best described by an open two-compartment model. The elimination half-life of cefonicid ranged between 5.5 and 84.9 h. Mean peak and trough concentrations in serum for all patients were 178.2 +/- 29.3 micrograms/ml (plus or minus standard deviation) and 39.0 +/- 17.5 micrograms/ml, respectively. Trough concentrations were higher in patients requiring hemodialysis than in nondialysis subjects, but the difference was clinically insignificant. The renal clearance/plasma clearance ratio of cefonicid was linearly related to creatinine clearance and decreased with impaired renal function. Therefore, nonrenal mechanisms of elimination become more important as renal function declines. Since cefonicid concentrations were within the therapeutic range for nearly all dosing intervals, we conclude that the guidelines used for dosage reduction and interval prolongation in this study result in therapeutically adequate concentrations in serum and, at the same time, result in no significant drug accumulation.     

Multiple-dose pharmacokinetics and distribution in tissue of terbinafine and metabolites.

The pharmacokinetics of terbinafine and its inactive metabolites SDZ 86-621 (the N-demethyl form), SDZ 280-027 (the carboxybutyl form), and SDZ 280-047 (N-demethyl- carboxybutyl form) in plasma were characterized for 10 healthy male subjects receiving 250 mg of terbinafine orally once a day for 4 weeks and in the subsequent 8-week washout phase. Terbinafine concentrations were also measured in sebum, hair, nail, and stratum corneum samples. Concentrations of the parent compound and metabolites were determined by validated high-performance liquid chromatography methods. Terbinafine was rapidly absorbed, with peak concentrations in plasma of 1.70 +/- 0.77 micrograms/ml occurring 1.2 +/- 0.3 h postdose. Concentrations subsequently exhibited a triphasic decline, with a terminal deposition half-life of 16.5 +/- 2.8 days. Terbinafine accumulated approximately twofold over the 4-week dosing phase. The predominant metabolite in plasma samples was SDZ 280-027; specifically, the ratios of metabolite area under the curve to terbinafine area under the curve following the last dose were 1.25, 1.38, and 1.08 for metabolites SDZ 86-621, SDZ 280-027, and SDZ 280-047. Measurable concentrations of terbinafine were achieved in sebum and hair samples within the first week of administration and by week 3 in stratum corneum and nail samples. Fungicidal concentrations persisted in plasma and peripheral tissue samples for prolonged periods (weeks to months) after administration of the last dose. These pharmacokinetic properties are likely an underlying factor in the shorter treatment times and good clinical cure rates which have been reported for terbinafine in the therapy of onychomycoses and dermatomycoses.     

Multiple-dose pharmacokinetics of ceftazidime and its influence on fecal flora.

Eight healthy volunteers each received 2.0 g of ceftazidime by constant intravenous infusion over 20 min twice daily every 12 h for 8 days. Concentrations of ceftazidime in serum and urine were measured by a microbiological assay and by high-pressure liquid chromatography. Qualitative and quantitative studies on aerobic and anaerobic fecal flora were carried out before, during, and 2 weeks after the end of treatment. The mean (+/- standard deviation) maximum drug concentration in serum at the end of the 20-min infusion (day 1) was 185.5 +/- 28.5 micrograms/ml, decreasing to 0.8 +/- 0.4 microgram/ml after 12 h. The mean recovery of drug in urine at 12 h was 71.5 +/- 12.2%. Pharmacokinetic parameters calculated on the basis of a two-compartment model were as follows: elimination half-life, 110.5 +/- 15.2 min; volume of distribution at steady state, 21.2 +/- 2.6 liters/100 kg; volume of distribution by the area method, 26.2 +/- 4.0 liters/100 kg; area under the serum concentration-time curve, 293.3 +/- 47.8 micrograms X h/ml; total body clearance, 116.4 +/- 20.3 ml/min per 70 kg; renal clearance, 82.2 +/- 15.1 ml/min per 70 kg. The agar diffusion test and high-pressure liquid chromatographic analysis showed a good correlation of results. Metabolites of ceftazidime could not be detected by high-pressure liquid chromatography in serum or urine. No accumulation of ceftazidime could be observed during the 8-day study period. Mean maximum drug levels in serum were 185.5 to 214.5 micrograms/ml, and mean trough levels were 0.8 to 1.1 micrograms/ml (days 1 to 8). No severe side effects were noted. During ceftazidime treatment, anaerobes were left intact, whereas members of the family Enterobacteriaceae could be isolated from stool in only three of eight subjects. Two weeks after discontinuation of the drug, all stool specimens contained ampicillin- and cefazolin-resistant gram-negative rods.     

Multiple-dose pharmacokinetics and safety of oral amifloxacin in healthy volunteers.

The multiple-dose pharmacokinetics and safety of amifloxacin, a new fluoroquinolone antibacterial agent, were evaluated in healthy male volunteers. Amifloxacin was administered orally at 200, 400, or 600 mg every 12 h (q12h) and 400, 600, or 800 mg every 8 h (q8h) for 10 days. An additional dose was administered on day 11. Concentrations of amifloxacin in plasma and urine were measured on days 1, 5, and 11 by high-performance liquid chromatography. Steady-state amifloxacin concentrations were reached by day 5. Mean +/- standard deviation maximum observed amifloxacin concentrations in plasma were 2.52 +/- 1.12, 4.98 +/- 1.44, 5.40 +/- 2.02, 4.59 +/- 2.17, 6.53 +/- 2.44, and 8.01 +/- 3.00 micrograms/ml after the initial dose and 2.30 +/- 0.98, 5.41 +/- 0.74, 8.05 +/- 1.68, 6.87 +/- 2.81, 9.53 +/- 0.50, and 11.9 +/- 1.92 micrograms/ml on day 11 of the study for the 200-, 400-, and 600-mg q12h and 400-, 600-, and 800-mg q8h regimens, respectively. Amifloxacin was rapidly absorbed, as evidenced by the mean time to the maximum observed amifloxacin concentration of 0.98 h. Mean values for the terminal amifloxacin half-life in plasma ranged from 3.58 to 5.78 h. Mean amifloxacin concentrations in urine on day 11 in samples collected 0 to 2 h after dosing were 105, 417, 376, 336, 518, and 464 micrograms/ml for the 200-, 400-, and 600-mg q12h and 400-, 600-, and 800-mg q8h regimens, respectively. The mean amount of the dose excreted in the urine as amifloxacin was 53.9%. Amifloxacin was generally well tolerated, although there was a tendency for the subjects who received amifloxacin to experience more gastrointestinal, central nervous system, and cutaneous complaints than did those who received placebo. Clinically significant adverse reactions, including pruritus and transaminase elevations, occurred only at doses of 1,200 mg/day or above. Clinical and pharmacokinetic data suggest that orally administered amifloxacin may have utility in the treatment of urinary tract infections.     

Multiple-dose pharmacokinetics of cefprozil and its impact on intestinal flora of volunteers.

The pharmacokinetics of cefprozil were determined with 12 volunteers (8 received cefprozil and 4 received a placebo) after oral administration of 500 mg every 12 h over an 8-day period in a randomized, double-blind, placebo-controlled design. Concentrations in serum and urine were measured by high-pressure liquid chromatography and bioassay. The pharmacokinetic parameters were calculated on the basis of an open one-compartment model. The mean maximum concentration in serum on day 1 was 11.5 +/- 2.6 mg/liter, and the time to reach maximum concentration was 122.3 +/- 30 min after administration. Bioavailability parameters (area under the concentration-time curve from zero to infinity, maximum concentration of the drug in serum, and urinary recovery) indicated an excellent absorption. No accumulation over the 8-day period was registered. Cefprozil had a short biological elimination half-life of 58 +/- 10 min and a renal clearance of 210 +/- 51 ml/min, indicating high rates of renal excretion and tubular secretion. Analysis of the fecal flora showed an ecological impact of cefprozil on the intestinal microflora, such as a moderate decrease in enterobacteria and a slight increase in enterococci, staphylococci, and bacteroides during the study. The number of all bacterial species was already normalized 4 days after the administration period. The tolerance of cefprozil proved to be excellent; only a slight and reversible increase of liver enzymes (in two volunteers), mild cephalalgia, tiredness, and soft stool were registered during the 8-day period. Cefprozil had excellent absorption, no accumulation over an 8-day period, and only a limited impact on the intestinal microflora.     

Multiple-dose pharmacokinetics of rectally administered acetaminophen in term infants

OBJECTIVE: To investigate pharmacokinetics and pharmacodynamics of rectally administered acetaminophen (INN, paracetamol) in term neonates directly after birth. METHODS: In this prospective clinical trial, term neonates wtih painful conditions or who were undergoing painful procedures received multiple-dose acetaminophen. Serum concentrations were determined serially with an HPLC method, and pharmacokinetic analysis was performed. Pain assessment was performed by means of a validated pain score. RESULTS: Ten consecutive term neonates received four rectal doses of acetaminophen, 20 mg/kg body weight, every 6 hours. Mean peak serum concentrations (+/-SD) during multiple-dose administration were 10.79 +/- 6.39 mg/L, 15.34 +/- 5.21 mg/L, and 6.24 +/- 3.64 mg/L for the entire group, boys, and girls, respectively. There was a significant difference between the boys and the girls (P = .01). No serum concentrations associated with toxicity (>120 mg/L) were found. Median time to peak serum concentration was 1.5 hours after the first dose and 15 hours for multiple doses. Mean (+/-SD) half-life was 2.7 +/- 1.4 hours in eight patients. There was no correlation between dose and serum concentration or between pain score and serum concentration. There was a significant inverse relationship between the preceding pain score and peak serum concentrations. CONCLUSIONS: In term neonates, multiple rectal doses of acetaminophen, 20 mg/kg body weight, led to widely varying serum concentrations but did not result in therapeutic concentrations in all infants. Boys had higher peak concentrations. Because accumulation was not found, a dose of 30 mg/kg followed by doses of 20 mg/kg at 6- to 8-hour administration intervals are appropriate to reach therapeutic concentrations. A concentration-effect relationship could not be determined.     

Multiple-dose pharmacokinetics of concurrent oral ciprofloxacin and rifampin therapy in elderly patients.

The purpose of this clinical study was to investigate the influence of concomitant drug therapy with ciprofloxacin and rifampin on the individual pharmacokinetic profile of each agent in elderly patients. Twelve nursing home patients (age, 74 +/- 7 years), colonized with methicillin-resistant Staphylococcus aureus, were randomized to receive 14-day therapy with oral ciprofloxacin (750 mg every 12 h) (group A; n = 6) or ciprofloxacin (750 mg every 12 h) and oral rifampin (300 mg every 12 h) (group B; n = 6). Serial blood samples were obtained from 0 to 12 h following ciprofloxacin doses 1 and 13 and from 0 to 36 h after the last ciprofloxacin dose. No significant differences (P greater than 0.05) were found between or within groups in any pharmacokinetic parameter. The mean ciprofloxacin oral clearance values were 0.35 +/- 0.06, 0.41 +/- 0.15, and 0.38 +/- 0.11 liter/h per kg for doses 1, 13, and 28, respectively, in group A patients. The mean oral clearance values in group B patients for the respective doses were 0.53 +/- 0.36, 0.32 +/- 0.13, and 0.36 +/- 0.17 liter/h per kg. Likewise, no significant differences (P greater than 0.05) in rifampin pharmacokinetic parameters were found when compared with historical controls. These data suggest that ciprofloxacin and rifampin may be given concomitantly in standard clinical dosing regimens. The combination results in therapeutic levels of both drugs and appears to be safe for administration to elderly nursing home patients.