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.

Phase I clinical and pharmacological study of suppression of human antimouse antibody response to monoclonal antibody L6 by deoxyspergualin.

Development of human antimouse antibody (HAMA) is a major limiting factor in the application of murine mAb for clinical use. A novel immunomodulatory drug, deoxyspergualin (DSG), has shown potential to suppress antimouse antibody response in preclinical model systems. We conducted a Phase I trial to determine the effect of DSG on HAMA response to murine mAb L6 administered to patients with advanced cancers (in previous trials, this antibody elicited HAMA in two-thirds of the treated patients). L6 mAb was administered at a fixed dose of 200 mg/m2 on days 1-5. DSG was administered at doses of 50 mg/m2 [dose level (dl) 1] or 150 mg/m2 (dls II and III) on days 1-7. Treatment courses were repeated every 6 weeks (dls I and II) or every 3 weeks (dl III). HAMAs were quantitated by a commercially available ELISA assay (ImmuSTRIP; anti-isotypic antibodies) and a radiometric assay (antiisotypic and anti-idiotypic antibodies). Pharmacokinetics of L6 and DSG was also studied in all consenting patients. Among 24 evaluable patients, 2 patients developed detectable HAMAs using the ELISA (one each at dls I and II) after a median follow-up of 122 days (P = 0.0001 as compared to historical controls). Even in the two patients who developed HAMA, the HAMA levels were quite low (160 and 181 ng/ml; historical experience, 70-38,744 ng/ml). The radiometric assay detected anti-L6 antibodies in 13 patients (4, 6, and 3 at dls I-III, respectively) after a median of 82 days. The median highest anti-L6 antibody level was 129 ng/ml (range, 21-2150). The highest anti-L6 antibody level at dl III was only 44 ng/ml. The results suggest suppression of anti-idiotypic response also. No clinical antitumor activity was observed, and no significant changes in T4/T8 subsets or immunoglobulins occurred (suggesting a lack of generalized immunosuppression). We conclude that DSG can suppress HAMA response to L6. A starting dose of 150 mg/m2/day is recommended for Phase II trials to confirm this observation.

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.

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.

Antimicrobial pharmacodynamics.

The ultimate goal of antimicrobial therapy is to provide the best possible outcomes for patients. For this to occur, the clinician should be cognizant of many clinical, microbiologic, pharmacologic, and epidemiologic data as well as fundamental pharmacodynamic concepts. An understanding of pharmacodynamic principles is essential; it forms the scientific basis for the design of dosing strategies that maximize clinical efficacy and minimize toxicity. In the 1990s, data accumulated from in vitro models of infection, animal models of infection, healthy volunteer studies, and clinical trials that have expanded knowledge on how drugs best kill microorganisms. This knowledge has enabled clinicians to establish the best modes of antibiotic administration to maximize the killing of microorganisms and to optimize clinical outcomes.

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.

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.

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.

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.

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.

Randomized, placebo-controlled single-ascending-dose study to evaluate the safety, tolerability and pharmacokinetics of the HIV nucleoside reverse transcriptase inhibitor, BMS-986001, in healthy subjects.

The objectives of this study were to evaluate the safety, tolerability and pharmacokinetics (PK) of BMS-986001 as a single oral dose in healthy male subjects. Sixty-four healthy male subjects were randomized to receive a single dose of BMS-986001 or placebo in this single-blind, placebo-controlled, sequential ascending-dose study. There were eight treatment groups (10, 30, 100, 300, 600, and 900 mg fed; and 100 and 300 mg fasted) of eight subjects each (BMS-986001 n = 6/placebo n = 2). BMS-986001 was well tolerated, with no serious adverse events (AEs), deaths, or discontinuations due to AEs reported. AEs were experienced by 14.6% of subjects receiving BMS-986001; however, these did not appear to be dose related and were not considered to be related to study drug. BMS-986001 was rapidly absorbed and exhibited a linear dose-exposure relationship across the dose range studied. PK appeared similar whether administered with or without food. Administration of BMS-986001 as a single dose was generally safe and well tolerated. A linear dose-exposure relationship was seen across all doses studied, with no apparent food effect. Further clinical development is warranted.

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.

Inhibition of carbamazepine metabolism by cimetidine.

The effect of cimetidine on the single dose pharmacokinetics of carbamazepine was examined in nine male Sprague-Dawley rats after the administration of a 25 mg/kg iv dose of carbamazepine. Five rats received a concomitant 50 mg/kg iv dose of cimetidine. Concomitant cimetidine administration produced a decrease in carbamazepine clearance (liters/hr/kg) (0.68 +/- 0.037 vs. 0.41 +/- 0.091; p less than 0.002) which was accompanied by an increase in carbamazepine half-life (hr) (1.1 +/- 0.16 vs. 2.0 +/- 0.37; p less than 0.003). No cimetidine-induced alterations in the volume of distribution at steady-state (liters/kg) occurred (1.1 +/- 0.14 vs. 1.2 +/- 0.04; NS). A reduction in the partial area under the plasma concentration-time curve for carbamazepine-10, 11-epoxide (mg X hr/liter) (28 +/- 2.5 vs. 18 +/- 3.7; p less than 0.002) with cimetidine treatment suggests that a portion of the reduction in carbamazepine clearance may be the result of cimetidine-induced inhibition of epoxide formation. The effect of cimetidine on epoxide formation was further substantiated using an in vitro rat liver homogenate preparation where inhibition of epoxide formation by cimetidine occurred in a dose-dependent fashion.

Experimental impact of assay-dependent differences in plasma indocyanine green concentration determinations.

The purposes of the present investigation were (i) to directly compare in man, indocyanine green (ICG) plasma concentrations analyzed by high performance liquid chromatography (HPLC) vs. spectrophotometry; (ii) to evaluate whether the pharmacokinetic parameters generated for ICG from a clinical study are assay-dependent; (iii) to examine whether the method of pharmacokinetic analysis affects the magnitude of any assay-related differences observed in ICG's pharmacokinetic parameters; and (iv) to evaluate whether assay methodology and/or method of pharmacokinetic analysis affect the conclusions derived from a clinical study employing ICG as a marker for hepatic blood flow (HBF). Plasma samples obtained from a clinical study designed to assess the effects of cimetidine and posture on HBF were analyzed by spectrophotometry and HPLC. The spectrophotometric method overestimated ICG plasma concentrations when compared to HPLC. This finding is consistent with the observations of others suggesting the presence of a chemical impurity in the commercial ICG preparation. Data generated by the spectrophotometric method produced lower ICG clearance and HBF estimates and a longer ICG half-life regardless of the method of pharmacokinetic analysis. The method of pharmacokinetic data analysis had no effect on any pharmacokinetic parameter. The experimental conclusions derived from the clinical study were not affected by either analytical methodology or method of data analysis.

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.