Multiple-Dose Pharmacokinetics of Ceftibuten in Healthy Adults and Geriatric Volunteers

The steady-state pharmacokinetics of ceftibuten, an orally active cephalosporin were investigated in 12 healthy male volunteers (19--38 years) and in 12 geriatric volunteers (65--76 years). Each received one 200-mg ceftibuten capsule every 12 h on days 1--3 and one capsule in the morning on day 4. Plasma and urine samples were collected at various times on days 1--4 and assayed by high-pressure liquid chromatographic method for ceftibuten and ceftibuten-trans, a conversion product. The T(max) for ceftibuten and ceftibuten-trans occurred at about 2 and 3 h, respectively, in both populations. The C(max) and AUC((0--12 h)) ranged from 10.8 to 12.4 &mgr;g ml(minus sign1) and from 47.5 to 55.1 &mgr;g h ml(minus sign1), respectively, for normal volunteers compared to 12.9--17.5 &mgr;g ml(minus sign1) and 62.3--87.1 &mgr;g h ml(minus sign1), respectively, for geriatric volunteers. The respective values for ceftibuten-trans in normal and geriatric volunteers were 1.3 and 1.3 &mgr;g ml(minus sign1), respectively, and 6.9--8.2 and 5.9--9.8 &mgr;g h ml(minus sign1). At steady state, the C(max) and AUC((0--12 h)) of ceftibuten-trans were about 10--11% and 13--16% those of ceftibuten in normal volunteers and about 8--9% and 9--11% those of ceftibuten, respectively, in geriatric volunteers. The accumulation factor of ceftibuten in normal volunteers was 1.1 as compared to 1.3 in geriatric volunteers. The terminal phase half-life was 2.5 h in healthy volunteers and 3.2 h in geriatric volunteers. Urinary excretion appeared to be the major route of elimination in both populations accounting for more than 90% of the dose recovered in the urine during the dosing interval. The results of this study demonstrate that ceftibuten, 200 mg given twice a day, is safe and well tolerated, is well absorbed, and that steady-state is achieved on days 3 and 4. There is some accumulation in the elderly, but dosage regimen based on age is not warranted.     

Effect of Food on the Pharmacokinetics and Pharmacodynamics of Torsemide

The effect of food on the bioavailability, pharmacokinetics, and pharmacodynamics of oral torsemide was examined in a group of 14 healthy male volunteers. Administration of torsemide with a standard high-fat, high-carbohydrate breakfast resulted in a decrease in absorption rate (fed: C(max) 988 plus minus 269 ng ml(minus sign1), T(max) 1.50 plus minus 0.64 h; fasting: C(max) 1466 plus minus 202 ng ml(minus sign1), T(max) 0.89 plus minus 0.37 h) but no change in the extent of absorption (fed: AUC 3424 plus minus 841 h ng ml(minus sign1); fasting: AUC 3357 plus minus 859 h ng ml(minus sign1)) or the amount of drug excreted unchanged (fed: % dose 23.5 plus minus 4.3; fasting: % dose 23.7 plus minus 6.2). Elimination half-life and renal clearance were unchanged. These minor alterations in the pharmacokinetics of the drug were not reflected by a change in either the pharmacodynamic relationship between urinary sodium and drug excretion rates or the cumulative amount of electrolytes and urine excreted. The diuretic effect of torsemide will be consistent regardless of drug administration relative to food intake.     

Effect of Gender and Menopausal Status on the Pharmacokinetics of Tirilazad Mesylate in Healthy Subjects

The pharmacokinetics of tirilazad were assessed in men ages 40--60 years, women <40 years of age, premenopausal women ages 40--60, and postmenopausal ages 40--60. Eight subjects in each group received single 3.0 mg kg(minus sign1) intravenous infusions of tirilazad mesylate over 10 min. Plasma concentrations of tirilazad and U-89678, an active metabolite, were measured by high-performance liquid chromatography. Tirilazad administration was well tolerated in all groups. Mean tirilazad clearance was 59.6% higher in young women compared to the middle-aged men (35.6 plus minus 8.04 L h(minus sign1) vs. 22.3 plus minus 8.40 L h(minus sign1)). Mean tirilazad clearance in middle-aged women was 30.7% higher than in middle-aged men. Mean clearance in postmenopausal women (26.1 plus minus 4.21 L h(minus sign1)) was not significantly different than that in middle-aged men, but clearance corrected for body weight was significantly different between the men and postmenopausal women. Clearance in premenopausal middle-aged women (32.2 plus minus 7.60 L h(minus sign1)) was not significantly different from that in young women and was 44% greater than that in middle-aged men. Mean AUC(0minus signinfty infinity) and C(max) values for U-89678 were significantly higher in men than in all of the female groups. Among the women, values for U-89678 AUC(0minus signinfty infinity) were lowest in young women (467 plus minus 345 ng h ml(minus sign1), 8.8% of male value) and highest in postmenopausal women (1565 plus minus 1382 ng h ml(minus sign1), 29.4% of male value). The absolute values for U-89678 AUC(0minus signinfty infinity) must be interpreted with caution, as limited assay sensitivity and low plasma concentrations in the latter portion of the concentration-time profile in women precluded accurate determination of the terminal half-life and AUC(0minus signinfty infinity). Regardless, these results show that women, particularly premenopausal women, have lower concentrations of U-89678, an active metabolite of tirilazad, than are achieved in men. The gender differences in tirilazad and U-89678 pharmacokinetics are of sufficient magnitude that they may impact the clinical response of male and female patients to tirilazad treatment.     

Tobramycin Serum Concentrations After Aerosol and Oral Administration in Cystic Fibrosis

We sought to describe tobramycin absorption after aerosol administration to cystic fibrosis (CF) subjects. Serum tobramycin concentrations were determined by modification of the radioimmuno-assay (RIA) technique, lowering the limit of detection from 1.0 &mgr;g ml(minus sign1) to 0.05 &mgr;g ml(minus sign1). In 37 studies, after aerosol delivery of 666 plus minus 195 mg to the airway of 24 patients, in which 222 samples were assayed, only 1 serum sample contained tobramycin at a concentration greater than 1.0 &mgr;g ml(minus sign1). Twenty-six of the 37 studies permitted estimation of pharmacokinetic parameters of tobramycin. The serum clearance of tobramycin following aerosol adminstration is 39.13 plus minus 0.393 L h(minus sign1) (mean plus minus standard error of the mean), with an elimination half-life of 3.072 plus minus 0.194 h. The half-life was significantly longer than that found after intravenous adminstration. The elimination rate constant (K(e)) was calculated to be 0.234 plus minus 0.002 h(minus sign1). Estimated total-body clearance in which systemic absorption was determined from sputum and urinary recovery of tobramycin was 0.094 plus minus 0.002 1 hr(minus sign1) kg(minus sign1). We also studied tobramycin absorption in six CF subjects after ingestion of a 80-mg m(minus sign2) dose, to gain insight into the tobramycin levels observed after swallowing an aerosol. Four out of the six subjects had measurable serum tobramycin concentration after ingestion. The serum concentration-time curve mirrored what was seen after aerosol administration. We concluded that tobramycin has poor systemic absorption in CF subjects after aerosol administration. Tobramycin in serum after aerosol administration is in part due to the gastrointestinal absorption of swallowed drug, as well as absorption from lower respiratory tract.     

Human Pharmacokinetics of the Neuroprotective Agent NBQX

We studied the pharmacokinetics of the glutamate antagonist NBQX (6-nitro-7-sulphamoylbenzo[f]quinoxaline-2,3-dione) in 16 normal male volunteers aged 18--37 years in a double-blind, placebo-controlled design. Intravenous infusions of 0.0075 and 0.03 mg kg(minus sign1) over 30 min were given to six subjects at each dose level (parallel groups). Two subjects at each dose level received placebo. The drug was well tolerated and no clinically significant alterations of cardivascular or renal function or in biochemical and hematological parameters were observed. Mean values of C(max) were 41 and 177 ng ml(minus sign1) at the two-dose levels. Compartmental pharmacokinetic analysis yielded a plasma half-life of 0.75 h, a total plasma clearance of 0.222 L h(minus sign1) kg(minus sign1) and a volume of distribution at steady state of 0.153 L kg(minus sign1). The renal clearance was 0.130 L h(minus sign1) kg(minus sign1) implying tubular secretion of the drug.     

Bioequivalence of Two Recombinant Human Growth Hormones in Healthy Male Volunteers after Subcutaneous Administration

The bioequivalence of recombinant human growth hormone (rhGH) (somatropin) and its N-methionyl variant (Met-hGH) [Protropin((R)) (somatrem for injection)] was determined in 42 healthy male volunteers (n = 21 per treatment) who were randomized to receive either protein by subcutaneous administration of 0.1 mg kg(minus sign1). Serum samples were collected over 24 h after the injection, and the concentration of human growth hormone (hGH) were determined by an immunoradiometric assay. Bioequivalence of the two proteins was assessed by determining whether the 90% confidence limits for the ratio of geometric means using logarithmically transformed AUC and C(max) parameters (log(10)AUC(0--24), log(10)AUC(0--infty infinity), and log(10)C(max)) were within the 80--125% range. The bioequivalence of the two treatments was also tested by calculating a bioequivalance index (xi(2)) that measured the difference between the two mean concentration-time profiles. The 90% confidence intervals for the ratios of the geometric means for AUC were within the prescribed 80--125% range for bioequivalence. The upper limit of the 90% confidence interval for the ratio of the geometric means for C(max) fell slightly outside the 125% criterion even though the geometric mean itself, 106.6%, was very close to the ideal of 100%. There was a larger standard error associated with C(max) than with the AUCs, and this marginally larger confidence limit for C(max) resulted more from the variance among the subject than to the difference in the means. In fact, the bioequivalence index, xi(2), was 0.075, indicating that the mean curves after rhGH and Met-hGH are essentially superimposable.     

Discrepancy between Bioavailability and Hypotensive Effect of Oral and Sublingual Nifedipine

Nifedipine, 10-mg capsules, were given orally and sublingually to six healthy volunteers according to a randomized crossover design. Nifedipine plasma levels, blood pressure, and heart rate were determined at several times after medication. C(max) was higher (134 plus minus 17 vs. 93 plus minus 2 ng ml(minus sign1), mean plus minus SD, P < 0.01) and occurred earlier (0.5 vs. 1 h) with oral than with sublingual nifedipine. However, there was no significant difference in AUC (268 plus minus 56 vs. 288 plus minus 35 ng h ml(minus sign1)) nor in t(1/2) (1.8 plus minus 0.2 vs. 1.9 plus minus 0.3 h), indicating that sublingual administration decreased the rate but not the extent of nifedipine absorption. Notwithstanding the difference in C(max), both routes yielded a similar reduction in diastolic blood pressure of 13 plus minus 1 mm Hg. Heart rate increase, which reflects the activation of homeostatic mechanisms, was greater with oral than with sublingual nifedipine, that is, 18 plus minus 1 vs. 13 plus minus 1 beats min(minus sign1), P < 0.01. It is concluded that slower absorption after sublingual administration increases nifedipine hypotensive efficiency by producing less counteracting homeostatic responses than the more rapidly absorbed oral nifedipine.     

Pharmacokinetics and safety of oral posaconazole in neutropenic stem cell transplant recipients

The pharmacokinetics of posaconazole oral suspension in neutropenic patients undergoing high-dose chemotherapy and stem cell transplantation were evaluated, and the association of plasma posaconazole exposure with the presence and severity of oral mucositis was explored in this nonrandomized, open-label, parallel-group, multiple-dose pharmacokinetic study. Thirty patients were enrolled and received one of three regimens (group I, 200 mg once daily; group II, 400 mg once daily; group III, 200 mg four times daily) for the duration of neutropenia. The mean total exposure for day 1, as shown by the area under the concentration-time curve from 0 to 24 h (AUC(0-24)), was 1.96 mg . h/liter in group I and was 51% higher in group II and in group III. Increases in AUC(0-24) and maximum plasma concentration (C(max)) in groups II and III were dose related. The AUC(0-24) and C(max) values on day 1 were similar between groups II and III. There was interpatient variability of up to 68% in the pharmacokinetic values for our study population. Steady state was attained by days 5 to 6. Average steady-state plasma posaconazole trough values were 192, 219, and 414 ng/ml in groups I, II, and III, respectively. The AUC(0-24) and apparent oral clearance increased by increasing dose and dosing frequency. Mucositis appeared to reduce exposure but did not significantly affect mean total posaconazole exposure (AUC and C(max)) at steady state (P = 0.1483). Moreover, this reduction could be overcome by increasing the total dose and dosing frequency. Posaconazole was safe and well tolerated.     

Lack of Pharmacokinetic Interaction between Aspirin and Warfarin

An open-label, randomized, two-phase crossover study was conducted on 36 healthy male volunteers to identify the effects of coadministration of aspirin (acetylsalicylic acid; ASA) and crystalline warfarin sodium (Coumadin((R))) on the elimination and disposition kinetics of ASA, salicylic acid (SA) and R- and S-warfarin enantiomers. Twenty-four subjects were administered single doses of 325 mg of ASA alone and in combination with 10 mg of crystalline warfarin sodium with a 1-week washout between ASA doses. ASA and SA pharmacokinetic parameters were determined after each dose. Twelve subjects were administered single doses of 10 mg of crystalline warfarin sodium alone and in combination with 325 mg of ASA with a 4-week washout between warfarin doses. R- and S-warfarin enantiomer pharmacokinetic parameters were determined after each dose. Pharmacokinetic parameters were compared using analysis of variance and 90% confidence intervals. ASA and SA AUCs (the area under the plasma concentration versus time curve from time zero to time infinity) respectively were 3.28 plus minus 0.80 and 66.99 plus minus 11.73 &mgr;g h ml(minus sign1) (ASA alone), and 3.22 plus minus 0.61 and 69.48 plus minus 15.79 &mgr;g h ml(minus sign1) (ASA with warfarin). R-warfarin and S-warfarin AUCs respectively were 33.9 plus minus 9.3 and 23.9 plus minus 16.0 &mgr;g h ml(minus sign1) (warfarin alone) and 33.6 plus minus 10.2 and 22.6 plus minus 14.7 &mgr;g h ml(minus sign1) (warfarin with ASA). The only pharmacokinetic parameter which was statistically significantly different when the combination was administered was the S-warfarin elimination rate constant (p < 0.05), but the difference (9.2% increase in the presence of ASA) was small and no significant difference was found in S-warfarin clearance. It is concluded that there is no pharmacokinetic interaction when a single dose of ASA 325 mg is coadministered with a single dose of crystalline warfarin sodium 10 mg.     

Single- and Multiple-Dose Pharmacokinetics of Reduced Metabolite (MDL 74,156) following Oral Administration of Dolasetron Mesylate to Normal Male Subjects

Dolasetron, a 5-hydroxytryptamine(3) receptor antagonist, is under investigation for prevention of nausea and vomiting due to chemotherapy. The keto-reduced metabolite of dolasetron has been identified in human plasma and is likely responsible for the antiemetic activity. This study evaluated single and multiple dose pharmacokinetics of the reduced metabolite following oral administration of dolasetron mesylate in healthy male subjects. Five groups (six active/two placebo each) of subjects received either oral doses of dolasetron mesylate ranging from 25 to 200 mg or placebo on day 1 and every 12 h on days 2 through 9. Because plasma dolasetron concentrations were low and sporadic, pharmacokinetics of the parent compound could not be determined. The reduced metabolite appeared rapidly in the plasma and reached a maximal plasma concentration in about 1 h. The maximal plasma concentrations and areas under plasma concentration--time curves were proportional to the dose. The mean apparent oral clearance ranged from 9.89 to 23.10 ml min(minus sign1) kg(minus sign1). The half-life ranged from 5.20 to 10.80 h. Mean renal clearance and fraction of dose excreted in urine were 0.97 to 3.97 ml min(minus sign1) kg(minus sign1) and 7.47 to 31.9%, respectively. The pharmacokinetics of reduced metabolite appears to be dose independent after single and multiple dosing.     

Steady-state pharmacokinetics of lamivudine in human immunodeficiency virus-infected patients with end-stage renal disease receiving chronic dialysis

The steady-state pharmacokinetics of lamivudine were evaluated in 11 subjects with human immunodeficiency virus infection and end-stage renal disease, 9 of whom were receiving hemodialysis and 2 of whom were receiving chronic ambulatory peritoneal dialysis (CAPD). All subjects received 150 mg of lamivudine daily for at least 2 weeks prior to sampling for determination of the pharmacokinetics of lamivudine over a 24-h period on 2 consecutive days. On the first day, subjects received 150 mg of oral lamivudine and underwent dialysis (hemodialysis or CAPD). On the second day, subjects received another 150 mg of oral lamivudine but dialysis was not performed. For the subjects undergoing hemodialysis, the geometric mean predose serum lamivudine concentration was 1.14 microg/ml (95% confidence interval [CI], 0.83 to 1.58 microg/ml), the geometric mean maximum concentration in serum (C(max)) was 3.77 microg/ml (95% CI, 3.01 to 4.71 microg/ml), and the geometric mean area under the serum concentration-time curve from time zero to 24 h (AUC(0-24)) was 49.8 microg. h/ml (95% CI 39.1 to 63.6 microg. h/ml). Hemodialysis removed approximately 28 mg of lamivudine but had no significant effect on C(max) or AUC(0-24). In the absence of hemodialysis, the geometric mean lamivudine terminal elimination half-life was 17.2 h (95% CI, 10.5 to 28.1 h), whereas the geometric mean intradialysis half-life of lamivudine was 5.3 h (95% CI, 3.4 to 8.2 h). The pharmacokinetics of lamivudine in subjects undergoing CAPD were similar to those in subjects undergoing hemodialysis. CAPD removed 24 mg of lamivudine over a 24-h period but had no effect on C(max) or AUC(0-24). Pharmacokinetic modeling suggests that a lamivudine dose of 25 mg daily in hemodialysis subjects would provide serum exposure similar to that provided by a dose of 150 mg twice daily in patients with normal renal function.     

Food Enhances Bioavailability of the New Antiarrhythmic Agent Tiracizine by Affecting its Hepatic First-Pass Metabolism: Evidence by Serum and Urine Metabolite Kinetics

The serum and urine kinetics of tiracizine, a new class I antiarrhythmic agent, and three of its metabolites were assessed in eight healthy extensive metabolizers after a single oral administration of 100 mg tiracizine in fasted state and after a standard breakfast. Additionally, ECG changes caused by tiracizine were compared between the two states. With food, the mean A(0minus signinfty infinity) value of the parent compound was significantly increased (560.7 versus 419.0 ng h ml(minus sign1)). The amount excreted unchanged in urine (percentage of the dose) rose significantly (2.43% versus 1.78%). However, mean AUC(0--32 h) and C(max) as well as urinary excretion of the 3-amino-5-methylamino-acetyliminodibenzyl metabolite were decreased (1152.8 versus 1328.0 ng h ml(minus sign1), 43.6 versus 56.1 ng ml(minus sign1), and 8.59 versus 11.95%, respectively). Total urine recovery (sum of individual tiracizine and metabolite excretion) tended to decrease (31.1% versus 36.1%). Serum and urine metabolite kinetics indicate that food-induced enhancement of tiracizine bioavailability is caused by an alteration in hepatic first-pass metabolism. Reduced N-demethylation is considered to be the limiting step. Tiracizine-induced PQ and QRS prolongations in the ECG tended to be more pronounced with food. Due to the serum concentration dependence of these ECG alterations, food intake might alter the antiarrhythmic efficacy of tiracizine at higher doses. Therefore, patients should be advised to take tiracizine in a constant relationship to food to assure consistent bioavailability.     

The Effect of Urinary pH and Flow Rate on the Renal Elimination of Zopolrestat and Zopolrestat Glucuronide in Humans

Zopolrestat is an aldose reductase inhibitor that may be useful in the treatment of diabetic complications by reducing flux through the polyol pathway. The plasma half-life of zopolrestat in man is approximately 30 h, and approximately 45% of an orally administered 1000-mg dose is eliminated in the urine as unchanged drug. Because active secretion accounts for much of the renal clearance for zopolrestat, a carboxylic acid with a pK(a) of 5.46, the effect of urinary pH and flow rate on renal clearance of drug was investigated in a series of studies. Renal clearance of zopolrestat following oral administration of 200 mg was determined in normal male volunteers under basal conditions and after treatment with NH(4)Cl and NaHCO(3) to alter urinary pH. Plasma concentrations of zopolrestat were similar under basal and NaHCO(3) treatment but were approximately twofold higher under NH(4)Cl treatment. However, the half-life of zopolrestat under NH(4)Cl treatment (29.5 h) was similar to the half-life of zopolrestat in untreated subjects. Renal clearance decreased by a factor of 2.54 for each unit decrease in urinary pH. In a second study, there was no effect of urine flow rate on renal clearance following an oral dose of 400 mg. Renal elimination of zopolrestat and zopolrestat glucuronide was also examined in volunteers with normal urine flow dosed at either 600 or 1000 mg/day. Whereas renal clearance of zopolrestat decreased with decreasing urinary pH, renal elimination of zopolrestat glucuronide was not affected by pH.     

Initial Studies on the Effect of Inhaled Misoprostol in a Guinea Pig Model of Allergic Bronchoconstriction

Inhaled E series prostaglandins (PGEs) have been shown to modulate responses to both allergic and nonallergic provocation. Little is known about the effect of inhaled misoprostol on the airway and whether its antiasthmatic activity would be similar to other PGEs. In the present study, nebulized solutions of misoprostol and PGE(2) (0.3--300 &mgr;g ml(minus sign1)) effectively blocked the acute bronchospasm due to inhaled antigen challenge in actively sensitized guinea pigs. A 300-&mgr;g ml(minus sign1) solution nebulized for 10 s (about 0.25 ml), 5 min prior to challenge, provided nearly complete inhibition with significant reductions seen at 30 and 3 &mgr;g ml(minus sign1) in certain experiments. Misoprostol treatment resulted in a significant reduction in the number of eosinophils present in bronchoalveolar lavage 24 h after antigen challenge. This combination of effects suggests that inhaled misoprostol may be effective in the treatment of the acute and chronic symptoms of asthma.     

Misoprostol and Prednisone Treatment of Lupus Nephritis

Fourteen patients were enrolled in a placebo-controlled double-blind randomized trial of 8 weeks of treatment for active lupus nephritis. Seven patients received prednisone at a dose of 1 mg kg(minus sign1) day(minus sign1) plus misoprostol at a dose of 200 &mgr;g P.O. Q.I.D.; 7 patients received prednisone plus placebo. The patients included 12 females, 2 males; 3 African-Americans, 3 Asians, 5 Hispanics, and 3 Caucasians. There were no serious side effects associated with prednisone or misoprostol treatment during the 8-week study period. Laboratory measures obtained at baseline, 4, 8, and 12 weeks included complete blood count (CBC), ESR, C reactive protein (CRP), serum creatinine, creatinine clearance, 24-h urine protein excretion, C3, C4, and anti-double stranded DNA (anti-dsDNA). Statistical analysis was conducted assessing change in measures over time in the entire study group by paired t-tests. The effect of treatment on change over time was examined by analysis of covariance. Log transformation of the variables was performed prior to statistical analysis. For the entire study group, the mean levels of ESR, CRP, 24-h protein excretion, C3, C4, and anti-dsDNA were improved at 4, 8, and 12 weeks. The mean ESR at baseline was 70 plus minus 8 compared to 42 plus minus 8 at 12 weeks (p < 0.01). The mean CRP at baseline was 0.6 plus minus 0.2 compared to 0.2 plus minus 0.1 at 12 weeks (p < 0.01). The 24-h protein excretion was 4367 plus minus 769 mg at baseline compared to 2512 plus minus 709 mg at 12 weeks (p = 0.02). The mean C3 at baseline was 40 plus minus 4 mg dl(minus sign1) compared to 60 plus minus 4 mg dl(minus sign1) at 12 weeks (p < 0.01). The mean C4 at baseline was 14 plus minus 1 mg dl(minus sign1) compared to 23 plus minus 2 mg dl(minus sign1) at 12 weeks (p < 0.01). The mean anti-dsDNA at baseline was 4268 plus minus 1780 compared to 316 plus minus 111 at 12 weeks (p < 0.001). The baseline serum creatinine (1.12 plus minus.15 mg dl(minus sign1)) and creatinine clearance (82 plus minus 15 ml min(minus sign1)) were not significantly changed at 12 weeks (1.10 plus minus 0.2 mg dl(minus sign1) and 80 plus minus 17 ml min(minus sign1), respectively). Comparing the misoprostol treatment group to the placebo group, there were no statistically significant differences for ESR, CRP, creatinine, creatinine clearance, 24-h protein excretion, C3, C4, or anti-dsDNA at any time points. However, comparing the misoprostol treatment group at 4 weeks to the placebo group, a more rapid decrease in anti-dsDNA (reduction of 3297 plus minus 2374) was observed in the misoprostol treatment group versus 304 plus minus 409 in the placebo group), as well as lower mean anti-dsDNA levels (464 plus minus 140) in the misoprostol treatment group versus 4118 plus minus 3834 in the placebo group). Also, the C3 and C4 levels at 12 weeks in the misoprostol treatment group (67 plus minus 5 and 27 plus minus 3 mg dl(minus sign1), respectively) were greater than levels in the placebo group (52 plus minus 4 and 19 plus minus 3 mg dl(minus sign1), respectively). The data demonstrate that oral prednisone is effective in reducing proteinuria and improving the biological markers of disease activity (i.e., ESR, CRP, C3, C4, and anti-dsDNA) following short-term treatment of active lupus nephritis. Additionally, the more rapid change in anti-dsDNA levels and superior normalization of complement levels in the treatment group, although not statistically significant, are consistent with a biologic effect of misoprostol on lymphocyte function and the production of a pathogenic autoantibodies.     

Lack of pharmacokinetic interaction between gemifloxacin and digoxin in healthy elderly volunteers

Gemifloxacin is a novel fluoroquinolone with a broad spectrum of antibacterial activity. The objective of this double-blind, randomized, placebo-controlled, 2-way crossover study was to demonstrate the lack of a pharmacokinetic interaction between gemifloxacin and digoxin. During two 14-day treatment periods, healthy elderly volunteers received digoxin (0.25 mg, once daily) co-administered on days 8-14 with either gemifloxacin (320 mg, p.o., once daily) or placebo. On day 14 of each period, blood samples and urine were collected for 24 h post dose and analysed for digoxin levels by radioimmunoassay. Steady-state digoxin pharmacokinetics were not affected by multiple dosing with gemifloxacin. There was no significant difference in digoxin values for the area under the plasma concentration-time curve over the dosing interval 0-24 h (AUC((0-24))) or the trough plasma concentration (C24) after co-administration with either gemifloxacin or placebo. Geometric means for AUC((0-24)) and C24 were 18.1 and 17.8 ng x h/ml and 0.597 and 0.566 ng/ml, respectively. The point estimates (90% confidence intervals) for AUC((0-24)) and C24 (digoxin + gemifloxacin):(digoxin + placebo) were 1.01 (0.93, 1.10) and 1.05 (0.95, 1.16), respectively, entirely within the equivalence range (0.80, 1.25). There were no marked differences between co-administration regimens for maximum observed plasma concentration (C(max)) or renal clearance values. Gemifloxacin was well tolerated during co-administration with digoxin, and the incidence of adverse events was similar to that seen with placebo. There were no clinically relevant changes in vital signs, electrocardiogram readings or laboratory parameters. In conclusion, this study demonstrates that gemifloxacin may be co-administered with digoxin without the need for digoxin dose adjustment. Copyright Copyright 1999 S.Karger AG, Basel.     

Pharmacokinetics and safety of ascending single doses of DZ-2640, a new oral carbapenem antibiotic, administered to healthy Japanese subjects

DZ-2640 is the ester-type oral carbapenem prodrug of an active parent compound, DU-6681. The pharmacokinetics and safety of DU-6681 were investigated in six studies after oral administration of a single dose of DZ-2640 to healthy male Japanese volunteers at doses of 25, 50, 100, 200, and 400 mg (as the equivalents of DU-6681) in the fasted state. The same volunteers received the drug at a dose of 100 mg in the fasted and fed states to examine the effect of food intake on the bioavailability of DZ-2640. The concentrations of DU-6681 in plasma and urine were determined by a validated high-performance liquid chromatography method and a bioassay. A good correlation between both methods was seen, indicating an absence of major active metabolites. The mean maximum concentrations of DU-6681 in plasma (C(max)) ranged from 0.263 microgram/ml (25-mg dose) to 2.489 microgram/ml (400-mg dose) and were reached within 1.5 h following drug administration. After reaching the C(max), plasma DU-6681 concentrations declined in a monophasic manner, with a half-life of 0.47 to 0.89 h. The area under the concentration-time curve (AUC) and C(max) increased almost linearly with the dose up to the 200-mg dose. The AUC and C(max) increased less than proportionally after administration of the 400-mg dose, suggesting a reduction in drug absorption. The plasma protein binding of DU-6681 was in the range of 23.3 to 25.6%. The cumulative urinary recoveries (0 to 24 h) were in the range of 31.9 to 44.9%. The AUC was slightly but statistically significantly reduced by food intake. However, the C(max), half-life, and recovery in urine were not affected by food intake. The renal clearance (402 to 510 ml/min) was much greater than the mean glomerular filtration rate (ca. 120 ml/min), which indicated active tubular secretion of the drug. A mild transient and moderate diarrhea was observed in two of six volunteers in the study with a single dose of 25 mg. Mild soft stools were observed in two of six volunteers who received a 400-mg dose of the drug.     

Pharmacokinetic assessment of oral ganciclovir in lung transplant recipients with cystic fibrosis

Oral ganciclovir has been used as prophylaxis and therapy against cytomegalovirus in patients with HIV infection and following organ transplantation. Oral ganciclovir has clear practical advantages over intravenous ganciclovir but has a relatively low bioavailability and this may be problematic in at-risk patients with malabsorption. The bioavailability and therefore therapeutic potential of oral ganciclovir in cystic fibrosis (CF) patients post-lung transplant (LT) might be expected to be inadequate given the high incidence of malabsorption in these patients. An 8 h pharmacokinetic study was performed in 12 CF patients 160 +/- 122 days post-transplant who had been taking 1 g oral ganciclovir tds for 3 days with food (plus normal enzyme supplements). Mean (range) serum creatinine was 150 Imol/L (70-280). Blood was sampled at 0.5, 1, 2, 3, 4, 6 and 8 h post-final dose. Plasma was stored at -20 degrees C and later analysed by highperformance liquid chromatography. Mean peak concentration (C(max)) was 4.8 mg/L (0. 96-12.8), mean minimum concentration (C(min)) was 3.6 mg/L (0.78-11. 7) and mean area under the curve (AUC) was 35.4 mg.8 h/L (8-99). C(max), C(min) and AUC correlated significantly with one another (P < 0.001) as well as with serum creatinine and creatinine clearance (P < 0.01). When corrected for alterations in renal function, plasma oral ganciclovir levels are as predicted for other transplant populations. Three days of oral ganciclovir results in therapeutically useful plasma drug levels in the CF LT population, despite a background of general malabsorption. C(max), C(min) and AUC are highly correlated, allowing for the possibility of steady-state drug monitoring to confirm that the recommended dosing algorithm produces appropriate plasma levels.     

Pharmacokinetics of ciprofloxacin and its penetration into bronchial secretions of mechanically ventilated patients with chronic obstructive pulmonary disease

We evaluated the pharmacokinetic profile of ciprofloxacin and its penetration into bronchial secretions of critically ill patients with chronic obstructive pulmonary disease (COPD). Twenty-five mechanically ventilated patients with severe COPD who were suffering from an acute, infectious exacerbation were included in this prospective, open-label study. All subjects received a 1-hour intravenous infusion of 400 mg ciprofloxacin every 8 h. Serial blood and bronchial secretion samples were obtained at steady state, and concentrations were determined using high-performance liquid chromatography. The pharmacodynamic parameters that are associated with the efficacy of fluoroquinolones against Gram-negative pathogens were also calculated. The mean peak (maximum) concentration (C(max)) and trough (minimum) concentration in plasma were 5.37 ± 1.57 and 1 ± 0.53 mg/liter, respectively. Mean values for volume of distribution, clearance, half-life, and area under the curve from 0 to 24 h (AUC(0-24)) were 169.87 ± 84.11 liters, 26.96 ± 8.86 liters/h, 5.35 ± 2.21 h, and 47.41 ± 17.02 mg · h/liter, respectively. In bronchial secretions, a mean C(max) of 3.08 ± 1.21 mg/liter was achieved in 3.12 ± 1.01 h, and the penetration ratio was 1.16 ± 0.59. The target of AUC(0-24)/MIC of ≥125 was attained in all patients, in the majority of them (76%), and in none at MICs of 0.125, 0.25, and 1 μg/ml, respectively. Slightly better results were obtained for the ratio C(max)/MIC of ≥10. In conclusion, ciprofloxacin demonstrates excellent penetration into bronchial secretions. There is wide interindividual variability in its pharmacokinetic parameters in critically ill COPD patients and inadequate pharmacodynamic exposure against bacteria with MICs of ≥0.5 μg/ml.