Pharmacometrics and the transition to model-based development.

As the transition to model-based drug development continues, pharmacometric analysis will have an increasingly important role across the entire life cycle of drug discovery, development, regulatory approval, and commercialization. For this reason, pharmacometrics can--and should--have an integrating function in the transformation to model-based development. This essay describes an approach for formalizing the pharmacometrics process using the disciplines encompassed by enterprise engineering.

Effect of garenoxacin on eubacteria in the normal intestinal microflora when administered concomitantly with digoxin.

Garenoxacin is a new des-F(6)-quinolone with a broad antimicrobial spectrum. It has been reported that antibiotics may raise digoxin concentrations in the plasma of patients who are taking these agents concurrently, possibly due to the effect on the digoxin-metabolizing intestinal microflora. Sixteen healthy subjects were given a loading dose of digoxin (0.25 mg orally, q 6 h) on Day 1 followed by once-daily doses of 0.25 mg on Days 2 through 14. The subjects also received garenoxacin 600 mg orally, q 24 h, on Days 8 through 14. The number of enterococci, bacilli, corynebacteria, enterobacteria, bifidobacteria, lactobacilli, clostridia and bacteroides decreased whereas the number of eubacteria increased in the intestinal microflora. Eubacterium lentum strains increased during the administration of garenoxacin and returned towards normal levels within 14 days after the last dose of garenoxacin. The fecal concentrations of garenoxacin varied between 14.0-310.0 mg/kg. The minimum inhibitory concentrations of garenoxacin against the isolated E. lentum strains were >64 mg/L. There was no degradation of digoxin by the E. lentum strains.

Multiple-dose safety and pharmacokinetics of oral garenoxacin in healthy subjects.

Garenoxacin (T-3811ME, BMS-284756) is a novel des-F(6) quinolone that has been shown to be effective in vitro against a wide range of clinically important pathogens, including gram-positive and gram-negative aerobes and anaerobes. This study was conducted to evaluate the safety and tolerability of multiple oral doses (100 to 1200 mg/day) of garenoxacin in healthy subjects and to determine its multiple-dose pharmacokinetics. Forty healthy male and female subjects (18 to 45 years of age) were enrolled in this randomized, double-blind, placebo-controlled, sequential, multiple- and ascending-dose study. Each subject received a once-daily oral dose of garenoxacin (100, 200, 400, 800, or 1200 mg) or a placebo for 14 days. Blood and urine samples were collected for measurements of garenoxacin by validated liquid chromatography with dual mass spectrometry, and plasma garenoxacin concentration-time data were analyzed by noncompartmental methods. The effects of garenoxacin on Helicobacter pylori, psychometric test performance, and electrocardiograms were assessed, as was drug safety. Over the 14 days of dosing, geometric mean peak concentrations of garenoxacin in plasma (C(max)) at the 100- and 1200-mg doses were within the ranges of 1.2 to 1.6 and 16.3 to 24 microg/ml, respectively. The corresponding values for the geometric mean area under the concentration-time curve over the dosing interval (AUC(tau)) for garenoxacin in plasma at the 100- and 1200-mg doses were within the ranges of 11.5 to 15.7 and 180 to 307 microg. h/ml, respectively. Increases in systemic exposure to garenoxacin in terms of AUC and C(max) were approximately dose proportional over the 100- to 400-mg dose range but demonstrated increases that were somewhat greater than the dose increments at the 800- and 1200-mg doses. Median values for the time to achieve C(max) were in the range of 1.13 to 2.50 h for all doses. The mean elimination half-life for garenoxacin in plasma appeared to be independent of dose and ranged from 13.3 to 17.8 h (day 14). Approximately 30 to 50% of an administered garenoxacin dose was excreted unchanged in the urine. At doses of 100 to 400 mg, steady-state concentrations of garenoxacin in plasma appeared to be attained by the fourth dose. Multiple oral doses of garenoxacin were well tolerated and did not demonstrate clinically significant effects on QT(c) or psychometric test results. Garenoxacin administered alone for 14 days at doses of >or=400 mg demonstrated activity against H. pylori. These results suggest that multiple once-daily oral doses of garenoxacin of up to 1200 mg are safe and well tolerated and that the pharmacokinetics of garenoxacin support once-daily administration.

Ecological impact of the des-F(6)-quinolone, BMS-284756, on the normal intestinal microflora.

OBJECTIVE: BMS-284756 (T-3811ME) is a novel des-F(6)-quinolone effective against a broad spectrum of aerobic and anaerobic pathogens. The aim of this study was to investigate the ecological effect of BMS-284756 on the intestinal microflora. METHODS: Forty healthy subjects participated in the trial. Eight subjects were assigned to each of five dose panels (100, 200, 400, 800 and 1200 mg BMS-284756) and received daily oral dosing with either BMS-284756 (n = 6) or placebo (n = 2) for 14 days. Fecal samples were collected before (days -2 and -1), during (days 7 and 14), and after (days 21, 28, and 45) completion of the administration period. RESULTS: In subjects receiving 100 or 200 mg BMS-284756, no significant changes in the intestinal aerobic and anaerobic microflora occurred. The number of enterococci, bacilli, corynebacteria, bifidobacteria, lactobacilli, clostridia and bacteroides decreased in subjects receiving 400 or 800 mg BMS-284756, whereas the number of eubacteria increased. Subjects who received 1200 mg BMS-284756 had significant changes in the microflora: enterococci, bacilli, corynebacteria, enterobacteria, bifidobacteria, lactobacilli, clostridia and bacteroides were suppressed, whereas eubacteria and yeasts were increased. Regardless of dose, the microflora returned to normal levels at day 28 (2 weeks after the administration of BMS-284756 was discontinued). Fecal concentrations of BMS-284756 increased with the higher doses, from 35.7 mg/kg (100 mg) to 262.8 mg/kg (1200 mg). These ecological findings should be considered if 800- or 1200-mg doses of BMS-284756 are to be used for longer periods than 14 days. CONCLUSION: The ecological impact of BMS-284756 is selective, with results similar to those described for other quinolones.

Pharmacodynamics of fluoroquinolones against Streptococcus pneumoniae in patients with community-acquired respiratory tract infections.

Fluoroquinolone antibiotic agents have demonstrated efficacy in the treatment of respiratory tract infections. This analysis was designed to examine the relationship between drug exposure, as measured by the free-drug area under the concentration-time curve at 24 h (AUC(24))/MIC ratio, and clinical and microbiological responses in patients with community-acquired respiratory tract infections involving Streptococcus pneumoniae. The study population included 58 adult patients (34 males, 24 females) who were enrolled in either of two phase III, randomized, multicenter, double-blind studies of levofloxacin versus gatifloxacin for the treatment of community-acquired pneumonia or acute exacerbation of chronic bronchitis. Clearance equations from previously published population pharmacokinetic models were used in conjunction with dose and adjusted for protein binding to estimate individual patient free-drug AUC(24)s. In vitro susceptibility was determined in a central laboratory by broth microdilution in accordance with NCCLS guidelines. Pharmacodynamic analyses were performed on data from all evaluable patients with documented S. pneumoniae infection using univariate and multivariable logistic regression; pharmacodynamic breakpoints were estimated using Classification and Regression Tree analysis. A statistically significant (P = 0.013) relationship between microbiological response and the free-drug AUC(24)/MIC ratio was detected. At a free-drug AUC(24)/MIC ratio of <33.7, the probability of a microbiological response was 64%, and at a free-drug AUC(24)/MIC ratio of >33.7, it was 100% (P < 0.01). These findings may provide a minimum target free-drug AUC(24)/MIC ratio for the treatment of infections involving S. pneumoniae with fluoroquinolone antibiotics and provide a paradigm for the selection of fluoroquinolones to be brought forward from drug discovery into clinical development and dose selection for clinical trials. Further, when target free-drug AUC(24)/MIC ratios are used in conjunction with stochastic modeling techniques, these findings may be used to support susceptibility breakpoints for fluoroquinolone antibiotics and S. pneumoniae.

The use of Monte Carlo simulation to examine pharmacodynamic variance of drugs: fluoroquinolone pharmacodynamics against Streptococcus pneumoniae.

BACKGROUND: For fluoroquinolones, AUC:MIC ratios correlate with maximal bacterial eradication in in vitro models of infection and favorable cure rates in humans with respiratory tract infection. Inter-subject pharmacokinetic and MIC variability may impact the probability of attaining optimal AUC:MIC ratios and hence favorable clinical outcome. METHODS: Monte Carlo simulation was utilized to estimate the probability of attaining AUC:MIC ratios of 30, 40, 50, 60, 70, 80, 90, 100, 110 and 120 using AUC values from patients treated with either gatifloxacin or levofloxacin and microbiologic activity against S. pneumoniae observed in 1997 SENTRY Antimicrobial Surveillance Program. RESULTS: The probability curves for 5000 patient simulations were plotted. The median AUC:MIC ratios were 120 for gatifloxacin and 50.5 for levofloxacin. The probability of attaining AUC:MIC ratios of 30, 50, 70 and 100 for gatifloxacin were 94%, 86%, 78% and 62%, and for levofloxacin were 80%, 51%, 31% and 17%, respectively. CONCLUSION: Gatifloxacin has a higher probability of achieving target AUC:MIC ratios than levofloxacin. Monte Carlo simulation, using patient-based AUC and MIC distributions, may have implications for selection of optimal antibiotics for the empiric treatment of infections. Moreover, Monte Carlo simulation may have utility in the determination of MIC breakpoints.

Clinical pharmacology of gatifloxacin, a new fluoroquinolone.

Gatifloxacin is an advanced-generation, 8-methoxy fluoroquinolone that is active against a broad spectrum of pathogens, including antibiotic-resistant Streptococcus pneumoniae. The drug has high oral bioavailability (96%), and, therefore, oral and intravenous formulations are bioequivalent and interchangeable. Gatifloxacin has a large volume of distribution ( approximately 1.8 L/kg), low protein binding ( approximately 20%), and broad tissue distribution and is primarily excreted unchanged in the urine (>80%). Gatifloxacin can be administered without dose modification in patients with hepatic impairment, in women, and in the elderly. In vitro experiments and clinical studies indicate that gatifloxacin does not interact with drugs metabolized by the cytochrome P450 enzyme family. At therapeutically relevant doses, gatifloxacin's pharmacodynamically linked parameters (the ratio of maximum serum concentration to minimum inhibitory concentration and the ratio of the area under the curve to minimum inhibitory concentration) are similar to or better than those of other fluoroquinolones. Clinical studies show that gatifloxacin has limited potential to prolong the QT interval on the electrocardiogram and lacks the potential to cause photosensitivity reactions, to alter oral glucose tolerance, or to cause crystalluria.

Pharmacokinetics of single-dose oral stavudine in subjects with renal impairment and in subjects requiring hemodialysis.

Two open-label studies assessed the pharmacokinetics of single orally administered doses of 40 mg of stavudine in subjects with renal impairment. In one study (study I), 15 subjects with selected degrees of renal impairment, but not requiring hemodialysis, were stratified into three groups of five subjects each according to creatinine clearance (CL(CR)) normalized by body surface area (ml/min/1.73 m(2)): mild (CL(CR), 60 to 80), moderate (30 to 50), and severe (/= 90) were also enrolled. The stavudine area under the curve from 0 h to infinity (AUC(0-infinity)) increased nonlinearly with declining renal function: 1,864, 2,215, 3,609, and 5,928 ng. h/ml for normal renal function and for mild, moderate, and severe renal impairment, respectively (P = 0.0001 between renal impairment groups). The following stavudine dosage recommendations for renal impairment were proposed for subjects weighing >/=60 kg: CL(CR) of >50 ml/min/1.73 m(2), 40 mg every 12 h; CL(CR) of 21 to 50 ml/min/1. 73 m(2), 20 mg every 12 h; and CL(CR) of 10 to 20 ml/min/1.73 m(2), 20 mg every 24 h. For subjects weighing <60 kg, the proposed doses were 30, 15, and 15 mg, respectively, with the same dosing intervals specified above. In a second study (study II), 12 subjects with end-stage renal disease requiring hemodialysis three times a week were enrolled in a randomized, open-label crossover study (dialysis 2 h after dosing and lasting 4 h or dosing without dialysis). There were no statistically significant differences for AUC(0-infinity), AUC(2-6), time to maximum concentration of drug in serum, half-life, or apparent oral clearance when the two treatment dosage regimens were compared. As a result of study II, the recommended dosing rate for subjects requiring hemodialysis was the same as that proposed for those with severe renal impairment not requiring hemodialysis; however, dosing was recommended to follow hemodialysis and to occur at the same time each day.

A dose-escalation study of the safety, tolerability, and pharmacokinetics of intravenous gatifloxacin in healthy adult men.

STUDY OBJECTIVES: To examine single- and multiple-dose safety, tolerability, and pharmacokinetics of gatifloxacin administered as daily 1-hour intravenous infusions for 14 days, and to determine the effect of gatifloxacin on glucose tolerance, pancreatic beta-cell function, and electrocardiogram (ECG). DESIGN: Randomized, double-blind, placebo-controlled, ascending-dose study. SETTING: Bristol-Myers Squibb, Clinical Pharmacology Unit, Princeton, New Jersey, USA. PATIENTS: Forty healthy male subjects, eight in each of five groups, were enrolled to receive sequential doses of gatifloxacin: 200 mg (10 mg/ml), 200 mg (1 mg/ml), and 400, 600, and 800 mg (2 mg/ml); six subjects per group received active drug and two received placebo. INTERVENTIONS: A single dose of the drug was administered as an intravenous infusion over 1 hour. After a 72-hour washout period, the drug was administered once/day for 14 days by 1-hour intravenous infusion. Physical examinations, ECGs, spirometry, and clinical laboratory tests, including glucose tolerance test (GTT) and assessment of glucose homeostasis, were performed before treatment and on selected dosing days. A safety evaluation was performed before escalating doses. No intrasubject dose escalation was permitted. MEASUREMENTS AND MAIN RESULTS: The pharmacokinetics of gatifloxacin were dose linear and time independent after intravenous administration over the range of 200-800 mg. After daily repeated administration, a predictable, modest accumulation was observed; steady state was reached by the third dose. Approximately 80% of the dose was recovered as unchanged drug in urine. Mean changes (before the first dose to the last dose) after oral GTT and in fasting serum glucose, insulin, and C-peptide concentrations were comparable among the gatifloxacin and placebo treatment groups. A mild, transient decrease in serum glucose was associated with the end of the 1-hour infusion of gatifloxacin. No clinically important changes in QTc interval or spirometry occurred. The most frequent treatment-related adverse effects were local intravenous site reactions, which were associated with dose and/or concentration of intravenous solution. CONCLUSION: Gatifloxacin was safe and well tolerated at intravenous doses of up to 800 mg/day for 14 days. Gatifloxacin pharmacokinetics were linear and time independent.

Interchangeability of 400-mg intravenous and oral gatifloxacin in healthy adults.

STUDY OBJECTIVE: To evaluate the interchangeability of 400-mg intravenous and oral doses of gatifloxacin. DESIGN: Randomized, open-label, crossover study. SETTING: GFI Pharmaceutical Services, Inc., Evansville, Indiana, USA. SUBJECTS: Twenty-four healthy men and women (12 of each gender), aged 18-42 years. INTERVENTIONS: Subjects received single doses of gatifloxacin 400 mg either by intravenous infusion over 1 hour or a 400-mg tablet orally with 240 ml of water, each dose separated by a 1-week washout. Plasma concentrations of gatifloxacin were determined by a validated high-performance liquid chromatography; pharmacokinetic parameters were calculated using noncompartmental methods. Distributions of pharmacokinetic parameter values were summarized by route of administration and gender. Effects of treatment on pharmacokinetic parameter values of gatifloxacin were assessed by an analysis of variance model suitable for a two-way, two-treatment, crossover design. Clinical evaluations were performed to assess drug safety and tolerability. MEASUREMENTS AND MAIN RESULTS: Intravenous and oral gatifloxacin were considered interchangeable because both routes were bioequivalent with respect to area under the curve (AUC; 90% confidence interval for the ratio of geometric means contained within 0.8-1.25). The plasma concentration-time profile after intravenous administration was similar and comparable in extent of exposure (AUC0-infinity) with that for the oral route when equal doses were administered to men and women. The absolute bioavailability of gatifloxacin after oral administration was 96%, consistent with bioequivalence of the 400-mg intravenous and oral doses. The drug was well tolerated; the frequency of adverse events was comparable after intravenous and oral administration. CONCLUSION: Intravenous and tablet formulations of gatifloxacin are bioequivalent and therefore interchangeable. This permits greater flexibility in choosing oral or parenteral therapy, with the possibility of avoiding hospitalization based on knowledge that oral administration will deliver therapeutic exposure to the drug, or abbreviating hospital stay due to ease of switching from intravenous to oral therapy.

Age and gender effects on the pharmacokinetics of gatifloxacin.

STUDY OBJECTIVE: To compare the pharmacokinetics and safety of gatifloxacin in elderly (> or = 65 yrs) and young (18-45 yrs) men and women. DESIGN: Open-label, parallel-group, single-dose study. SETTING: GFI Pharmaceutical Services Inc., Evansville, Indiana, USA. SUBJECTS: Forty-eight healthy subjects in four groups of 12 each. INTERVENTIONS: Subjects received single oral doses of gatifloxacin 400 mg. Serial blood and urine samples were collected for 96 hours after dosing to determine drug concentrations. MEASUREMENTS AND MAIN RESULTS: Age and gender had moderate effects on the pharmacokinetics of gatifloxacin. Elderly women had a 21% higher geometric mean peak plasma concentration (Cmax) and a 32% higher area under the plasma concentration-time curve (AUC0-infinity) than young women. Adjustment for creatinine clearance had only a slight effect on Cmax but reduced the estimated effect of age on AUC0-infinity in women from a 32% increase to a 15% increase. Gender effects on pharmacokinetic values were noted among elderly subjects only. Geometric means for Cmax and AUC0-infinity were 21% and 33% higher, respectively, for elderly women and elderly men. Adjustment for body weight reduced these differences to 11% and 20%, respectively. CONCLUSION: The effects of age on gatifloxacin pharmacokinetic values were largely attributed to declining renal function, whereas those of gender were largely attributed to differences in body weight. These modest age- and gender-related differences do not warrant dosage adjustment.

Safety and pharmacokinetics of a single oral dose of gatifloxacin in patients with moderate to severe hepatic impairment.

STUDY OBJECTIVES: To assess the safety and pharmacokinetics of oral gatifloxacin 400 mg in subjects with and without hepatic impairment, and the need to modify doses in patients with hepatic dysfunction. DESIGN: Single-dose, nonrandomized, open-label, parallel-group study. SETTING: Clinical Research Center, New Orleans, Louisiana. PATIENTS: Eight subjects with grade B or C hepatic dysfunction (Child-Pugh classification) and eight age-, weight-, and gender-matched subjects with normal hepatic function. INTERVENTIONS: After a single oral dose of gatifloxacin 400 mg, blood and urine samples were collected at specified times or intervals over 48 hours to determine drug concentrations. MEASUREMENTS AND MAIN RESULTS: All 16 subjects (7 with grade B and 1 with grade C hepatic impairment, 8 with normal hepatic function) completed the study. Peak plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC0-infinity) for gatifloxacin were 32% and 22% higher, respectively, in subjects with hepatic impairment. Except for Cmax, the ratio of means for AUC satisfied the specified criterion (0.67-1.50) for lack of effect. There were no statistically significant differences in any other pharmacokinetic values except apparent oral clearance (ClT/F). All treatment-emergent adverse events were mild or moderate in intensity and resolved before subjects were discharged from the study. CONCLUSION: Modest increases in Cmax and AUC0-infinity are not anticipated to have a negative effect on the outcome of therapy in hepatically impaired subjects, nor are they anticipated to result in adverse drug reactions. Patients with moderate to severe (Child-Pugh grade B or C) hepatic dysfunction do not require gatifloxacin dose adjustments. In addition, the similarity in half-life (t1/2) for the groups (8.9 hrs for hepatically impaired subjects, 9.3 hrs for controls) suggests that no difference would be anticipated in the extent of drug accumulation after multiple doses. The overall safety and tolerability of a single oral dose of gatifloxacin 400 mg were excellent in both healthy subjects and those with hepatic impairment.

Effect of multiple-dose gatifloxacin or ciprofloxacin on glucose homeostasis and insulin production in patients with noninsulin-dependent diabetes mellitus maintained with diet and exercise.

STUDY OBJECTIVES: To compare the effects of gatifloxacin and ciprofloxacin on glucose homeostasis, including glucose tolerance test (GTT), pancreatic beta-cell function, and insulin production and secretion in patients with noninsulin-dependent (type 2) diabetes mellitus (NIDDM) maintained with diet and exercise; and to evaluate the pharmacokinetics, safety, and tolerability of gatifloxacin. DESIGN: Randomized, double-blind, placebo-controlled, multiple-dose study. SETTING: GFI Pharmaceutical Services, Inc., Evansville, Indiana; Chicago Center for Clinical Research, Chicago, Illinois; and New Orleans Center for Clinical Research, New Orleans, Louisiana, USA. PATIENTS: Forty-eight men and women with NIDDM. INTERVENTIONS: Patients were assigned sequentially at enrollment to receive gatifloxacin 400 mg/day orally, ciprofloxacin 500 mg twice/day orally, or placebo for 10 days. Oral GTTs were performed on specific days throughout the study, as well as measurements of serum glucose, serum insulin, and C-peptide levels. Physical examinations, electrocardiograms, spirometry, and clinical laboratory tests were performed before dosing and on selected dosing days. MEASUREMENTS AND MAIN RESULTS: Gatifloxacin had no significant effect on glucose tolerance and pancreatic beta-cell function, as shown by oral GTT results and insulin and C-peptide levels. Fasting glucose levels 0-6 hours after gatifloxacin administration on days 1 and 10 showed a downward trend, but it was not significant compared with placebo; results were similar with ciprofloxacin. Gatifloxacin also lacked a long-term effect on fasting insulin levels, but this was not shown for a short-term effect, suggesting a modest, transient effect on insulin release. On the other hand, ciprofloxacin had no short-term effect but produced a more sustained effect on insulin release and production. The pharmacokinetics of gatifloxacin in patients with NIDDM were similar to those in healthy subjects. Overall, subjects tolerated treatment well. All reported drug-related adverse events were mild to moderate in intensity. The frequency of adverse events was similar in gatifloxacin- and ciprofloxacin-treated patients, and only slightly higher than in placebo-treated patients. CONCLUSION: Gatifloxacin was well tolerated in patients with NIDDM controlled by diet and exercise. It had no significant effect on glucose homeostasis, beta-cell function, or long-term fasting serum glucose levels, but it did cause a brief increase in serum insulin levels.

Open-label, nonrandomized study of the effects of gatifloxacin on the pharmacokinetics of midazolam in healthy male volunteers.

STUDY OBJECTIVE: To confirm findings from an in vitro study that showed gatifloxacin did not substantially inhibit cytochrome P450 (CYP) 3A4 model substrate metabolism. DESIGN: Open-label, nonrandomized trial. SETTING: Clinical pharmacology unit. SUBJECTS: Fourteen healthy adult men. INTERVENTION: Using midazolam probe methodology, the clearance of midazolam in the presence of multiple-dose gatifloxacin was evaluated. MEASUREMENTS AND MAIN RESULTS: Typical steady-state concentrations of gatifloxacin 400 mg once/day had no effect on midazolam clearance, and gatifloxacin pharmacokinetics were unaffected by midazolam. All doses of both agents were well tolerated. CONCLUSION: Data from this in vivo trial support in vitro experience with gatifloxacin and suggest that interactions are unlikely between gatifloxacin and drugs that are metabolized by CYP3A.

Pharmacokinetics and safety of a single dose of stavudine (d4T) in patients with severe hepatic impairment.

This open-label study enrolled five subjects with biopsy-proven cirrhosis and moderate to severe hepatic impairment (Child-Pugh classification grade B or C) and five age- and gender-matched controls. All subjects received a single 40-mg oral dose of stavudine (d4T). Stavudine pharmacokinetics in subjects with hepatic impairment were similar to those in age- and gender-matched control subjects and were not substantially different from those previously observed in human immunodeficiency virus-infected patients. Based on these findings, stavudine use does not require modification of the dose or dosing interval for patients with liver disease.

The pharmacokinetics and pharmacodynamics of fosinopril in haemodialysis patients.

The pharmacokinetics and pharmacodynamics of fosinoprilat, the diacid of fosinopril sodium (a new angiotensin-converting enzyme (ACE) inhibitor), were investigated in six haemodialysis patients. Intravenous 14C-fosinoprilat (7.5 mg), oral 14C-fosinopril sodium (10 mg) and oral fosinopril sodium (10 mg) were administered in an open-label, randomized study. Mean maximum concentration (Cmax), clearance (CL), volume of distribution at steady-state (Vss), mean residence time (MRTiv), and t1/2 values after IV administration of 14C-fosinoprilat were 2,042 micrograms.ml-1, 11.3 ml.min-1, 11.0 l, 16.3 h and 28.3 h, respectively. Following oral administration of 14C-fosinopril, mean Cmax, time to maximum plasma concentration (tmax), and fosinoprilat bioavailability values were 197 ng.ml-1, 5.2 h and 29.2%. Para-hydroxy fosinoprilat and fosinoprilat glucuronide comprised approximately 15% and 2% of radioactivity recovered in faeces. Four hours of haemodialysis only cleared approximately 1.5% of the administered dose. The maximum effect (Emax) model was fitted to the percentage inhibition of serum ACE activity vs. fosinoprilat concentration data in three patients. Emax ranged from 95.3 to 102.5%, and IC50 (the fosinoprilat concentration required to produce 50% of Emax) ranged from 2.6 to 4.2 ng.ml-1. Pharmacokinetic variables of the patients were similar to those in patients with moderate to severe renal dysfunction. Dosage modifications or supplemental dosing following dialysis are unnecessary.

Comparative safety, tolerance, and pharmacokinetics of amphotericin B lipid complex and amphotericin B desoxycholate in healthy male volunteers.

Amphotericin B lipid complex (ABLC), a lipid complex formulation of amphotericin B, and amphotericin B desoxycholate (AB) were compared for safety, tolerance, and pharmacokinetics in two groups of eight healthy male volunteers. After a 1-mg test dose, study drug was infused at 0.1, 0.25, and 0.5 mg/kg; the 0.5-mg/kg dose was not given to subjects receiving AB. ABLC caused few acute adverse effects except for mild somnolence (drowsiness) in six volunteers. In addition, three of eight ABLC recipient had asymptomatic, transient serum transaminase elevations that resolved spontaneously. The AB recipients experienced more acute side effects, but only one had a mild shaking chill: three of eight also experienced sleepiness. No significant changes in vital signs, electrocardiogram, oximetry, pulmonary function, or clinical status were observed in either group. Due to its increased estimate volume of distribution and estimated clearance. ABLC yielded decreased amphotericin B levels and area under the serum concentration versus time curve relative to AB.

The relationship of salicylate lipophilicity to rectal insulin absorption enhancement and relative lymphatic uptake.

The sodium salts of the 3,5-dichloro, 3,5-dibromo-, 3,5-diiodo-, and 5-methoxy- analogs of salicylic acid have been evaluated as enhancers of rectal insulin absorption. A relationship was found between adjuvant potency and relative lipophilicity. Maximal adjuvant activity was obtained with 0.1 M 3,5-dichlorosalicylate. Higher concentrations (0.15 M) of 3,5-diiodosalicylate produced a decline in adjuvant activity, which may be associated with extraction of specific cellular proteins. This may indicate the existence of an optimal salicylate lipophilicity for adjuvant efficacy. Relative adjuvant activity was found to be related to the lymph:plasma absorption ratio of [125I]insulin. Lymphatic uptake of insulin was not related to lymph flow rate.