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C Gerbeau

Publications and source records attributed to C Gerbeau.

At least 19 recordsLinked to original sources
PubMed2001

Differential influence of azathioprine and mycophenolate mofetil on the disposition of basiliximab in renal transplant patients.

Pharmacokinetic sampling was performed in two multicenter trials in which basiliximab (anti-CD25 monoclonal antibody) was administered with triple immunosuppression consisting of cyclosporine microemulsion, corticosteroids, and either azathioprine or mycophenolate mofetil. Blood samples were collected over 12 wk post-transplant from 31 azathioprine-treated and 66 mycophenolate mofetil-treated patients. Empirical Bayes estimates of each patient's basiliximab disposition parameters were derived and the duration of CD25 saturation was estimated as the time over which serum concentrations exceeded 0.2 microg/mL as confirmed by flow cytometry measurements. Basiliximab clearance was 29+/-14 mL/h when coadministered with azathioprine and 18+/-8 mL/h with mycophenolate mofetil. Both were significantly lower compared with a clearance of 37+/-15 mL/h from a previous study of basiliximab with dual therapy (p<0.001). As a consequence of the lower clearance of basiliximab, the durations of CD25 saturation were prolonged in the presence of azathioprine (50+/-20 d; range, 13--84) and mycophenolate mofetil (59+/-17 d; range, 28--94) compared with dual therapy (36+/-14 d; range, 12--91). A total of 27 acute rejection episodes occurred during the first 6 months in the two studies. Durations of CD25 saturation were not different in these patients compared with those who remained rejection-free in each study. A single patient among 57 who were screened developed anti-idiotype antibodies to basiliximab. The average duration of CD25 saturation was prolonged by 39 and 64% in the presence of azathioprine and mycophenolate mofetil, respectively. This graded effect was also observed for basiliximab clearance and may be due in part to a differentially reduced humoral response to basiliximab. Nonetheless, the range of CD25 saturation durations and basiliximab clearances did not extend outside the range when basiliximab was used with dual therapy in the absence of these agents. Hence, no dosing adjustment is deemed necessary when basiliximab is used in triple immunosuppressive therapy including either azathioprine or mycophenolate mofetil.

Antibodies, Anti-Idiotypic↗
PubMed2001

Longitudinal assessment of everolimus in de novo renal transplant recipients over the first post-transplant year: pharmacokinetics, exposure-response relationships, and influence on cyclosporine.

OBJECTIVE: Our objective was to characterize the steady-state pharmacokinetics of everolimus and cyclosporine (INN, ciclosporin) when coadministered in de novo kidney allograft recipients during the first year after transplantation. METHOD: This study was a multicenter randomized double-blind study of 101 patients who were randomly assigned 1:1:1 to receive everolimus tablets at doses of 0.5 mg, 1 mg, or 2 mg twice daily with cyclosporine and prednisone. Blood sampling for the pharmacokinetics of everolimus and cyclosporine was performed on day 1, on weeks 1, 2, 3, and 4, and on months 2, 3, 6, 9, and 12. Everolimus dose-proportionality and stability over time were assessed in the context of linear regression and ANOVA models. Everolimus exposure-response relationships between area under the blood concentration-time curve (AUC) and changes in platelets, leukocytes, and lipids were explored with the median-effect model. Potential differences in cyclosporine dosing and pharmacokinetics at different levels of everolimus exposure were assessed in the context of ANOVA. RESULTS: Everolimus steady state was reached on or before day 7, with a median 3-fold accumulation of drug exposure compared with that after the first postoperative dose. Both steady-state maximum concentration and AUC were dose proportional over the full dose range when assessed on day 1, as well as for the full duration of the study at steady state. There was evidence for longitudinal stability in AUC of everolimus during the course of the study. The interindividual pharmacokinetic variability for AUC was 85.4% and intraindividual, interoccasion variability was 40.8%. Age (range, 17-69 years), weight (range, 49-106 kg), and sex (65 men and 36 women) were not significant contributors to variability. There was an increasing incidence of transient thrombocytopenia (< or =100 x 10(9)/L) with increasing everolimus AUC (P = .03). Cyclosporine doses, trough concentrations, and AUC exhibited similar temporal patterns during the course of the study regardless of the co-administered everolimus dose level (P = .13, .82, and .76, respectively). CONCLUSIONS: Everolimus exhibited dose-proportional, stable exposure during the first post-transplant year. For a 4-fold range of everolimus doses there were no differential effects on cyclosporine dosing or pharmacokinetics.

Administration, Oral↗
PubMed2001

A population pharmacokinetic screen to identify demographic-clinical covariates of basiliximab in liver transplantation.

BACKGROUND: Basiliximab is a high-affinity interleukin-2 receptor (CD25) chimeric monoclonal antibody used for immunoprophylaxis in organ transplantation. It was assessed in a randomized, double-blind, placebo-controlled efficacy trial in de novo liver allograft recipients who received 40 mg of basiliximab (20 mg on days 0 and 4) in addition to baseline immunosuppression with cyclosporine (INN, ciclosporin) microemulsion and corticosteroids. METHODS: Serial blood samples (8.3 +/- 1.4 per patient) were collected during 12 weeks after transplantation from 184 basiliximab-treated patients, and empirical Bayes estimates of each patient's disposition parameters were derived. Demographic-clinical covariates were explored with regression methods. RESULTS: Basiliximab clearance was 55 +/- 26 mL/h, the distribution volume was 9.7 +/- 4.2 L, and the half-life was 8.7 +/- 6.7 days. Patient weight, age, sex, ethnicity, history of alcoholism, hepatitis C seropositivity, and notable postoperative bleeding had no clinically relevant influences on basiliximab disposition; however, the cumulative volume of drained ascites fluid in the first week was positively correlated with clearance. Receptor-saturating basiliximab concentrations (> or =0.1 microg/mL) were maintained for 38 +/- 16 days, and this was negatively correlated with the cumulative volume of drained ascites fluid in week 1. Patients who experienced an acute rejection episode did not clear basiliximab at a faster rate than their rejection-free peers nor did they maintain CD25-saturating concentrations for a shorter period. CONCLUSIONS: Although the standard dose regimen of 20 mg of basiliximab on days 0 and 4 after transplantation appears to be appropriate for the majority of patients with liver transplants, a supplemental dose at the end of the first week may be considered for those with substantial (>10 L) postoperative ascites fluid drainage.

Antibodies, Anti-Idiotypic↗
PubMed2001

Removal of basiliximab by plasmapheresis.

Basiliximab is a chimeric monoclonal antibody directed against the alpha chain of interleukin-2 (IL-2) receptors. Given its expected volume of distribution (plasma volume), therapeutic plasmapheresis may be expected to lower serum Basiliximab levels. A 20-mg dose of Basiliximab was given before plasmapheresis. Blood and pheresis fluid samples were obtained to monitor Basiliximab levels. A total of three blood samples were drawn: the first was obtained 4 hours before, the second sample immediately before commencement, and the third 2 hours after cessation of plasmapheresis. A fourth sample was obtained from the removed plasma. There was an appreciable reduction in Basiliximab concentration levels after plasmapheresis. From the change in serum concentration after plasmapheresis, approximately 64.6% of circulating Basiliximab was removed. Plasmapheresis removes substantial amounts of Basiliximab. Therefore, supplemental Basiliximab should be given after plasmapheresis to maintain the desired duration of IL-2R saturation.

Antibodies, Monoclonal↗
PubMed1999

Population pharmacokinetics and exposure-response relationships for basiliximab in kidney transplantation. The U.S. Simulect Renal Transplant Study Group.

BACKGROUND: Basiliximab is an interleukin-2 receptor (CD25) chimeric monoclonal antibody used for acute rejection prophylaxis in renal transplants. In the context of a randomized, double-blind efficacy trial, its population pharmacokinetics and potential exposure-response relationships were explored in de novo kidney allograft recipients receiving 40 mg basiliximab (20 mg on days 0 and 4) in addition to baseline immunosuppressive therapy with cyclosporine microemulsion and corticosteroids. METHODS: Serial blood samples (8.2+/-1.3 per patient) were collected over 12 weeks after transplant from 169 basiliximab-treated patients, and empirical Bayes estimates of each patient's disposition parameters were derived. The duration of CD25 saturation was estimated as the time over which serum basiliximab concentrations exceeded 0.2 microg/ml. The relationships between pharmacokinetic parameters and demographic-clinical covariates were explored by regression methods and unpaired t-tests. RESULTS: Basiliximab clearance was 36.7+/-15.2 ml/hr, distribution volume 8.0+/-2.4 L, and half life 7.4+/-3.0 days. Patient weight (range, 44-131 kg) and age (range, 20-69 yrs) each contributed < or =6% to the variability in clearance and volume. Gender, ethnic group, and the presence of proteinuria had no clinically relevant influences on basiliximab disposition. Receptor-saturating basiliximab concentrations were maintained for 36+/-14 days (range, 12-91). There was no apparent relationship between the incidence or day of onset of acute rejection episodes during CD25 saturation and basiliximab concentration (range, 0.2-5.0 microg/ml). In patients who experienced a rejection episode after basiliximab was eliminated from serum (n=33), basiliximab had not been cleared faster than in their rejection-free peers (P=0.322) nor had CD25 been saturated for a shorter period of time (33+/-13 days vs. 37+/-14 days for rejection-free patients, P=0.162). CONCLUSIONS: There were no demographic or clinical subpopulations not adequately treated with the standard basiliximab dosing regimen. Over the range of CD25 suppression durations observed in this study, extended periods of receptor blockade did not seem to confer an immunoprophylactic advantage compared with shorter periods of receptor suppression.

Adult↗
PubMed1999

Constructing a prediction interval for time to reach a threshold concentration based on a population pharmacokinetic analysis: an application to basiliximab in renal transplantation.

Basiliximab is an immunosuppressant chimeric monoclonal antibody directed to the human interleukin-2 receptor alpha-chain used for prevention of acute rejection episodes in organ transplantation. The minimally effective serum concentration necessary to saturate receptor epitopes in kidney transplant patients is 0.2 microgram/ml. To guide dose selection for Phase 3 efficacy trials, a population pharmacostatistical model was fitted to intensively sampled Phase 2 pharmacokinetic data. This served as a basis from which to examine candidate dose regimens with respect to the duration over which receptor-saturating concentrations would be achieved posttransplant. Three prediction methods were assessed: one based on simulations, and two others based on first-order approximation using either inverse regression or inversion of confidence intervals. An 80% prediction interval was generated by each method to evaluate its predictive performance against prospectively collected Phase 3 data in 39 renal transplant patients who received two injections of 20 mg basiliximab, one prior to surgery and one on Day 4 posttransplant. All methods provided correct prediction of the duration of receptor-saturating concentration. As anticipated, the best performance was obtained from the simulation method which predicted 30 values in the 80% prediction interval, 19.7-52.7 days. The actually observed 80% interval from the Phase 3 data was 23.7-58.3 days.

Algorithms↗
PubMed1999

Screening for basiliximab exposure-response relationships in renal allotransplantation.

The immunosuppressant basiliximab--a chimeric monoclonal antibody specific to the interleukin-2 receptor on activated T-lymphocytes--significantly reduces the incidence of acute cellular rejection following renal transplantation. Screening for exposure-response relationships was performed within a randomized, blinded, placebo-controlled efficacy trial in which patients received 40 mg basiliximab (20 mg on days 0 and 4) by intravenous infusion in addition to cyclosporine and corticosteroids. In a subset of patients, serum samples were collected pre-transplant and once in weeks 2, 3 and 4 for determination of basiliximab concentrations. A population pharmacostatistical model was used to derive individual empirical Bayes estimates of each patient's pharmacokinetic parameters. Biopsy-confirmed acute rejection episodes were recorded to month 6 post-transplant. Forty basiliximab-treated patients were evaluated, 30 men and 10 women, aged 48 +/- 12 yr (range, 24-73) and weighing 72.4 +/- 12.9 kg (range, 52.5-107.5). The basiliximab distribution volume was 7.5 +/- 1.7 L, the half-life 7.5 +/- 2.5 d and the clearance 33 +/- 12 mL/h. There was no clinically relevant influence of weight, age, or gender on basiliximab disposition. Receptor-saturating serum basiliximab concentrations (> 0.2 microgram/mL) were maintained for 41 +/- 23 d. Twenty-five patients remained rejection-free over the 6-month observation period, while a total of 26 biopsy-confirmed acute rejection episodes occurred in the remaining 14 patients. Of these episodes, 12 occurred during receptor blockade. No apparent relationship to basiliximab concentration on the day of onset was observed range, 0.1-9.0 microgram/mL) nor did the time of suppression offset represent a period of increased risk for rejection episodes. Fourteen rejection episodes occurred after basiliximab had cleared from the serum. The durations of receptor suppression preceding these events did not differ compared with those in patients who remained rejection-free: 32 +/- 11 versus 45 +/- 26 d, respectively (p = 0.1269). Given the durations of receptor saturation achieved with the chosen basiliximab regimen, this screen for exposure-response relationships did not identify the duration of receptor saturation in peripheral blood as a predictive factor for acute rejection episodes. Further exploration for exposure-effect relationships in a larger population is warranted.

Adult↗
PubMed1999

Longitudinal assessment of a P-glycoprotein-mediated drug interaction of valspodar on digoxin.

OBJECTIVES: Valspodar is a P-glycoprotein modulator currently under development as a multidrug resistance reversal agent in clinical oncology. A multiple-dose drug interaction study was performed to assess the influence of valspodar on digoxin, a substrate for P-glycoprotein. METHODS: Twelve healthy volunteers received an oral digoxin loading dose of 1 mg on day 1, followed by 0.125 mg once daily to day 11. On day 7, a single oral 400-mg dose of valspodar was given, followed by a regimen of 200 mg twice daily from days 8 to 11. Serial blood samples and urine collections were obtained on days 6, 7, and 11 for digoxin pharmacokinetics and on days 7 and 11 for valspodar pharmacokinetics. On these days, blood pressure, pulse rate, and electrocardiograms were recorded at multiple time points. RESULTS: Coadministration of single-dose valspodar with steady-state digoxin on day 7 yielded an average 76% increase in digoxin AUC and a 62% decrease in digoxin renal clearance (both P = .0001). After a 5-day coadministration period, digoxin AUC increased by an average 211% and apparent total body clearance was decreased by 67% (day 11) compared with steady-state administration of digoxin alone (day 6). Contributing to the change in total body clearance were decreases in both renal clearance (73%) and apparent nonrenal clearance (58%). Both drugs were well tolerated throughout the study. There was no clinically relevant change in the effect of digoxin on vital signs or electrocardiographic parameters when administered with single- or multiple-dose valspodar compared with administration alone in volunteers with healthy cardiovascular systems. CONCLUSIONS: Coadministration of oral valspodar and oral digoxin resulted in a twofold to threefold increase in digoxin systemic exposure. On the basis of these data in healthy volunteers, an initial digoxin dose reduction of 50% would appear to be appropriate when beginning oral valspodar treatment. Throughout the period of coadministration, patients should be carefully monitored for clinical signs of digoxin toxicity in conjunction with digoxin therapeutic drug monitoring. Together, these should serve as the basis for individualized digoxin dose titration.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Disposition and immunodynamics of basiliximab in liver allograft recipients.

A randomized, open-label prospective study was conducted with recipients of primary cadaveric liver allografts to characterize the disposition and immunodynamics of basiliximab, an interleukin-2 receptor, alpha-chain chimeric monoclonal antibody for immunoprophylaxis of acute rejection. Patients received a total intravenous dose of 40 mg basiliximab in addition to baseline dual immunosuppression consisting of cyclosporine (INN, ciclosporin) and steroids. The central distribution volume was 5.6 +/- 1.7 L with a steady-state volume of 7.5 +/- 2.5 L. It was cleared slowly with a total body clearance of 75 +/- 24 ml/hr and an elimination half-life of 4.1 +/- 2.1 days. Basiliximab was measurable in drained ascites fluid, and clearance by this route was an average of 20% of total clearance. Total body clearance correlated positively with volume of postoperative blood loss (r = 0.5253, p = 0.0101), suggesting that bleeding may represent an additional route of drug removal. A threshold relation was observed between serum concentration of basiliximab and CD25 expression on T lymphocytes whereby complete saturation of interleukin-2 receptor alpha-chain was maintained as long as serum concentrations exceeded 0.1 microgram/ml. The duration of receptor saturation was 23 +/- 7 days after transplantation (range, 13 to 41 days).

Adolescent↗
PubMed1997

Disposition of basiliximab, an interleukin-2 receptor monoclonal antibody, in recipients of mismatched cadaver renal allografts.

BACKGROUND: Basiliximab is an interleukin-2 receptor (IL-2R; CD25) chimeric monoclonal antibody for immunoprophylaxis against acute rejection in renal transplantation. Its pharmacokinetics were characterized in a multicenter open-label, prospective dose-escalation study to identify a single-dose regimen providing IL-2R-saturating serum concentrations in the critical first posttransplant month. METHODS: Thirty-two recipients of primary, mismatched cadaver kidneys were enrolled: 20 men and 12 women, who were 47+/-11 years old and weighed 65+/-12 kg. The immunosuppression regimen consisted of steroids and azathioprine from day 0 and cyclosporine from day 10. Basiliximab was infused over 30 min as a single dose preoperatively. RESULTS: Thirty patients were evaluable for basiliximab pharmacokinetics: 24 received 40 mg and 6 received 60 mg. Basiliximab was well tolerated without evidence of cytokine-release syndrome, hypersensitivity reactions, or anti-idiotype antibody response. Peak concentration and area under the concentration curve increased proportionally with dose. Postinfusion concentrations declined in a biphasic manner with a terminal half-life of 6.5+/-2.1 days. Weak, widely dispersed correlations were noted between body weight versus distribution volume (r=0.29) and versus clearance (r=0.45), suggesting no clinical relevance for weight-adjusted dosing. There were no apparent gender-related differences in basiliximab disposition. Previous phase II data indicated that serum concentrations in excess of 0.2 microg/ml are sufficient to saturate IL-2R epitopes on circulating T lymphocytes. Concentrations were above this threshold for 26+/-8 days (range 16 to 46) at the 40-mg dose level and for 32+/-11 days (range 22 to 51) at the 60-mg dose level. CONCLUSIONS: Total basiliximab doses of 40-60 mg were well tolerated, nonimmunogenic, and estimated to provide immunoprophylaxis to cover the first posttransplant month.

Adult↗
PubMed1997

Cyclosporine and nonsteroidal antiinflammatory drugs: exploring potential drug interactions and their implications for the treatment of rheumatoid arthritis.

A series of clinical pharmacology studies was performed to screen for possible pharmacokinetic/dynamic contributions to drug interactions reported in rheumatoid arthritis patients receiving cyclosporine and nonsteroidal antiinflammatory drugs (NSAIDs). No clinically relevant pharmacokinetic changes in any of the drugs were noted when single-dose cyclosporine was coadministered during a steady-state regimen of aspirin, indomethacin, or piroxicam in healthy volunteers. Only with diclofenac was an interaction observed whereby the diclofenac area under the concentration-time curve was doubled in the presence of cyclosporine. Based on the outcomes of the screening studies, steady-state coadministration of both diclofenac and cyclosporine was assessed in rheumatoid arthritis patients, confirming the drug interaction of diclofenac with cyclosporine. Although the drug interaction was accompanied by a significant rise in serum creatinine, there was no apparent concentration-effect relationship, inasmuch as the increase in diclofenac exposure was not related to the magnitude of increase in serum creatinine. Based on the results of these five drug-drug interaction studies and the known biotransformation pathways of nonsteroidal antiinflammatory drugs, it is speculated that the pharmacokinetic interaction, which is unique to diclofenac, is caused by inhibition by cyclosporine of diclofenac's first-pass metabolism. Caution and appropriate clinical monitoring are recommended whenever cyclosporine and NSAIDs are coadministered; however, diclofenac in particular should be administered near the lower end of its therapeutic range when it is initially combined with cyclosporine in the treatment of rheumatoid arthritis.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1997

Pharmacokinetic-pharmacodynamic model relating spiraprilat plasma concentrations to systemic and regional hemodynamic effects in congestive heart failure.

The aim of this study was to investigate the relations between the plasma concentrations of spiraprilat (the active metabolite of the angiotensin-converting enzyme inhibitor spirapril) and its effects on plasma converting enzyme activity (PCEA), pulmonary capillary wedge pressure (PCWP), and brachial blood flow (BBF), after a single oral administration of 6 mg of spirapril in eight patients with severe congestive heart failure (CHF). Concentrations and effects were determined before and repeatedly during 48 h after drug intake. A sigmoid model was fitted to individual observations. Maximal effects, concentrations inducing half-maximal effects, and Hill coefficients were -99 +/- 2%, 3.9 +/- 1.9 ng/ml, and 2.4 +/- 0.7 for PCEA inhibition, -15 +/- 8 mm Hg, 11.8 +/- 9.2 ng/ml, and 2.6 +/- 1.3 for PCWP decrease, and 36 +/- 19 ml/min, 13.8 +/- 7.6 ng/ml, and 3.3 +/- 1.0 for BBF increase. In severe CHF, although a 14 ng/ml plasma concentration of spiraprilat may induce a 95% inhibition of PCEA, a 30 ng/ml plasma concentration is mandatory to normalize PCWP and BBF. This concentration corresponds to the peak achieved after a 6-mg oral dose of spirapril.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

Evaluation of pharmacokinetic studies: is it useful to take into account concentrations below the limit of quantification?

PURPOSE: Based on real data, to evaluate the usefulness of taking into account samples with values below the limit of quantification (LOQ) for the evaluation of pharmacokinetic studies. METHODS: To compare for two drugs, after single dose administration the pharmacokinetic parameters obtained by using a poorly sensitive assay (PSA) and a highly sensitive assay (HSA), acting as reference; To evaluate the results of pharmacokinetic studies in the light of different values for the LOQ. RESULTS: Under certain conditions, such as homogeneous population, sufficient subject number, sufficient sampling times and acceptable accuracy (CV < 20%) for the concentrations, it is possible to get valuable and more reliable kinetic information by using concentrations obtained with a poor precision (CV > 20%). This is especially true for the parameters associated with the terminal phase, such as t1/2 beta and AUC, but also for parameters depending to a lesser extent on the terminal phase, such as t1/2 alpha and AUCm. Moreover, the mean concentration time curve is by far best defined by using all the concentrations. CONCLUSIONS: In some situations, it is preferable to use concentrations with values below the LOQ to evaluate the results of pharmacokinetic studies. However, this should not be the rule, especially when this does not bring any additional information, or when it is possible to increase the sensitivity of the bioanalytical assay.

Area Under Curve↗
PubMed1996

Successful pregnancy in an infertile woman with a thyrotropin-secreting macroadenoma treated with somatostatin analog (octreotide).

Somatostatin analogs are an alternative medical treatment in patients with TSH-secreting pituitary adenoma. A 31-yr-old infertile woman with a TSH-secreting macroadenoma was treated with continuous sc infusion of 300 micrograms octreotide/day. After 3 months, euthyroid status was restored, and pituitary magnetic resonance imaging showed a reduction of the macroadenoma. Subsequently, the patient was found to be pregnant, and octreotide was stopped after 1 month of gestation. Serum TSH and free thyroid hormone concentrations returned to pretreatment values. At 6 months of pregnancy, a visual field examination was abnormal, and a magnetic resonance imaging scan showed an enlargement of the pituitary adenoma. Reinstitution of octreotide treatment was associated with normalization of TSH and free thyroid hormone concentrations, a rapid improvement of visual fields, and a new reduction in the size of pituitary macroadenoma. Octreotide treatment was continued until an elective cesarean section was performed at 8 months gestation. Despite the presence of immunoreactive octreotide in the umbilical cord, neonatal thyroid parameters were normal, and a physiological rise in TSH with the increase in thyroid hormone concentrations occurred in the neonate. In conclusion, 1) octreotide treatment is effective in controlling TSH-secreting macroadenoma during pregnancy; 2) despite the transplacental passage of immunoreactive octreotide, physiological changes in thyroid parameters occur in the neonate, and 3) exposure of the fetus to octreotide during the first month as well as the last trimester of gestation did not induce any malformation or affect fetal development.

Adenoma↗
PubMed1994

Spirapril: pharmacokinetic properties and drug interactions.

Spirapril is a prodrug that is converted by esterolysis to the active (but poorly absorbed) diacid spiraprilat. After intravenous infusion, the disposition of spirapril is monophasic with a terminal half-life of 20-50 minutes. Plasma clearance was 56 l/h and renal clearance was 11 l/h; the volume of distribution was 28 litres. After intravenous infusion of spiraprilat, the disposition was biphasic with half-lives of 2 hours and 35 hours, respectively. Plasma clearance of spiraprilat was 10 l/h, of which 7.6 l/h was cleared by the kidneys. The volume of distribution was 43 litres. The bioavailability of orally administered spirapril was 50% whereas the bioavailability of orally administered spiraprilat was virtually zero. There was a significant first-pass metabolism of spirapril after oral administration. The pharmacokinetics of spirapril were linear within the dose range of 6-50 mg whereas the disposition of spiraprilat was non-linear with respect to the terminal phase. Variability of the pharmacokinetic parameters of spiraprilat were significantly less than that of spirapril. Plasma concentrations of both spirapril and spiraprilat were increased by 30% in the elderly. Similarly, in patients with impaired liver function, plasma concentrations of spiraprilat were reduced by 30%. In patients with severe renal impairment, spiraprilat concentrations were significantly increased by a factor of 3-4. Spirapril showed no clinically relevant drug interactions with either glibenclamide, diclophenac, cimetidine, rifampicin, hydrochlorothiazide or nicardipine.

Adult↗
PubMed1992

Radioimmunoassays for spirapril and its active metabolite spiraprilate: performance and application.

Radioimmunoassays for a nonsulfhydryl angiotensin converting enzyme inhibitor prodrug--spirapril--and its active metabolite--spiraprilate--are described. Nonextraction equilibrium assays using antibodies with a high specificity for spirapril or spiraprilate were used, with charcoal separation of bound and free tracer. Within-assay reproducibility (CV%) was less than 20% in the concentration range 0.5-40 micrograms/L for both analytes and the comparable value for between-assay reproducibility was less than 25%. Results for external quality control samples were in good agreement with the expected values of 0-250 micrograms/L (spirapril, r = 0.997) and 0-300 micrograms/L (spiraprilate, r = 0.999). Overall, samples circulated to four laboratories gave good agreement for measured values, including one center using gas chromatography-mass spectrometry analysis for the two compounds. Data are presented to show the suitability of these two assays to the measurement of spirapril and spiraprilate in clinical samples from assays to the measurement of spirapril and spiraprilate in clinical samples from dose-ranging and bioequivalence studies. Results are also shown relating drug plasma concentration data to a measurement of the pharmacodynamic effects of spiraprilate, namely inhibition of angiotensin converting enzyme activity. It is concluded that these assays have the sensitivity for use in studies to model the relationship between the pharmacokinetics and pharmacodynamics of the two compounds.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1990

A radioreceptor assay for determination of nicardipine in human serum using 3H(+)PN 200-110 as radioligand.

A radioreceptor assay for the determination of nicardipine in human serum using the active enantiomer 3H(+)PN 200-110 as radioligand is described. The assay is simple to perform, of low cost and requires only a small volume of serum. The standard curve permits measurements in the range 2.5 to 320 nM nicardipine (i.e. 1.2 to 153 ng/ml). The precision and the reproducibility of the method, evaluated from two different concentrations: 120 and 12 nM, show coefficients of variation for within and between assays, of 6% and 15% and 6% and 9%, respectively. Concentrations of nicardipine from 3 ng/ml could be measured with a satisfactory precision. The performances of the method permit the determination of nicardipine concentrations reached after therapeutic administration. Other dihydropyridine calcium channel antagonists may be measured using this assay if these compounds are used to generate the standard curves.

Animals↗