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PHARMACOKINETICS AND PHARMACODYNAMICS |
4ß1-4ß7 Integrin Antagonist After Oral Administration at Single and Multiple Once-Daily Ascending Doses in Healthy Volunteers
From Hoffmann-La Roche, Clinical Pharmacology, Basel, Switzerland (Dr Hijazi, Dr Welker); XIQ Coordination, Fort Myers, Florida (Dr Dorr); and the Departments of Non-Clinical Drug Safety (Dr Tang, Dr Blain), Discovery Pharmacology (Dr Renzetti), and Clinical Pharmacology (Dr Abbas), Hoffmann-La Roche, Nutley, New Jersey.
Address for reprints: Dr Youssef Hijazi, Department of Clinical Pharmacology, F. Hoffmann-La Roche Ltd, PDMP-Basel, Bldg. 15/1.036, CH-4070 Basel, Switzerland.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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4ß1-4ß7 integrin antagonist under development for the treatment of chronic asthma. The objective of this study was to investigate the pharmacokinetics and safety of R411 and its active metabolite, RO0270608, in humans. A 3-part phase I trial was conducted in 132 healthy volunteers: (1) 12 subjects received 200 mg R411 as a single oral dose or 100 mg RO0270608 as an intravenous infusion in a 1-sequence crossover design; (2) 7 groups of 10 subjects received 1 of 7 single oral doses of R411 (10-1200 mg) in a parallel, placebo-controlled, ascending adaptive dose design; and (3) 5 groups of 10 subjects each received repeated oral qd doses of R411 (50-900 mg) for up to 3 weeks in a parallel, placebo-controlled, ascending adaptive dose design. The absolute bioavailability of RO0270608 (mean ± standard deviation) after oral administration of R411 was 27% ± 4%, and the terminal half-life was 7.33 ± 2.29 hours. After IV infusion of RO0270608, total clearance (mean ± standard deviation) was 19.4 ± 7.1 L/h, and the volume of distribution was 93.1 ± 36.1 L. After single ascending oral doses of R411, area under the concentration-time curve from 0 to infinity of active metabolite RO0270608 increased proportionally from 150 to 1200 mg (P > .05). Following repeated administration, the oral clearance was independent of time. No drug accumulation was observed, and no safety concerns were revealed up to a dose of 900 mg after up to 3 weeks of treatment.
Key Words: Asthma • integrins • R411 • VCAM-1 • RO0270608
4ß1 and 4ß7 with vascular cell adhesion molecule-1 (VCAM-1), located on endothelial and smooth muscle cells and with fibronectin localized to the tissue interstitium.3-5 Dual inhibition of 4ß1-4ß7 integrins might abrogate the chronic inflammatory sequelae associated with asthma.
R411 is a dual antagonist of 4ß1-4ß7 integrins that potentially and selectively targets the underlying inflammatory cascade in asthma by inhibiting activation and recruitment of cells involved in the disease process without compromising the normal immunity. The pharmacologic activity of R411 is due to its active metabolite, RO0270608. Under the current knowledge, R411 was not detectable in human plasma due to rapid and complete biotransformation into RO0270608. Because of this rapid biotransformation of the parent compound, pharmacokinetic characterization was done only on the active metabolite. RO0270608 binding to the activated 4ß1-4ß7 ligands was characterized by high affinity and slow dissociation. In contrast, the binding affinity was lower and dissociation was rapid when the receptor was not activated. RO0270608 immediately reversed the binding of leukocytes to VCAM-1, inhibited anti-CD3-induced human T cell stimulation/proliferation, and abolished 4-mediated excitation and survival of human eosinophils.6 RO0270608 inhibited the accumulation of eosinophils in the lungs in both murine and nonhuman primate models of allergic airway inflammation/asthma and also inhibited the development of AHR to methacholine in these models.7
R411 has entered into clinical development for the oral prophylaxis and treatment of chronic asthma. The objective of this study was to determine the pharmacokinetics of the active metabolite RO0270608 after oral administration of R411 at single and multiple once-daily ascending doses and to assess its safety in humans.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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Study Design
Absolute Bioavailability
This was an open-label, single-dose, 1-sequence, 3-period crossover study with a washout period of 1 week. On day 1, male subjects received 200 mg of R411 as a single oral dose (period 1); on day 8, they received 100 mg of RO0270608 as a constant-rate intravenous infusion for 1 hour (period 2); and on day 15, subjects again received 200 mg of R411 as a single oral dose (period 3). The drug was administered after an overnight fast in all periods. The study was conducted at the Roche Clinical Pharmacology Unit (Welwyn Garden City, UK).
Single-Dose Pharmacokinetics
This was a randomized, double-blind, parallel, placebo-controlled, single ascending adaptive dose design with 7 doses of R411 given orally under fasting conditions: 10, 50, 150, 300, 600, 900, and 1200 mg. Ten male subjects were randomized to each dose level, of which 8 were on active treatment and 2 on matching placebo. Dose escalation was based on safety, tolerability, and RO0270608 exposure from the previous dose. The study was conducted at the Roche Clinical Pharmacology Unit (Welwyn Garden City, UK).
Multiple-Dose Pharmacokinetics
This was a randomized, double-blind, parallel, placebo-controlled, multiple ascending adaptive dose design with 5 doses of R411 given orally under fasting conditions: 50, 150, 300, 600, and 900 mg. R411 was administered as a single daily dose on day 1 and then as repeated daily doses for 8 consecutive days (days 3-10 of the study). Ten subjects were randomized per dose level, of which 8 were on active treatment and 2 on matching placebo. Male volunteers were enrolled in all groups, except for the 900-mg group in which only females (of nonchildbearing potential) were included due to recruitment and logistic reasons. In this female group, R411 was administered for 21 days. Dose escalation was based on safety, tolerability, and exposure of RO0270608 from the previous dose after multiple administration. The study was conducted at Simbec Research Ltd (South Wales, UK).
Blood and Urine Sampling
Blood samples for the measurement of RO0270608 plasma concentrations were taken at predose and at 0.25, 0.5, 1, 2, 4, 6, 8, 12, 16, 22, 24, 36, and 48 hours after drug administration. In the multiple-dose pharmacokinetic study, complete blood sampling was done on days 1, 10, and 25 (for the 900-mg dose) and predose on days 6, 8, and 9 (and at days 18, 22, and 24 for the 900-mg dose) of the study for the determination of steady-state plasma concentrations at trough levels (Css,min). Urine samples were collected in quantitative fractions at 0 to 4, 4 to 8, 8 to 12, 12 to 24, and 24 to 48 hours postdose.
Analytical Technique
Plasma and urine samples were assayed for the measurement of RO0270608 concentrations using a validated liquid chromatography/tandem mass spectrometry (LC/MS/MS) method, developed at Roche.
Sample Processing
Blood and urine samples were collected in tubes or containers respectively containing either sodium or potassium EDTA. Blood samples were spun down in a cold centrifuge within 1 hour of drawing the samples. All samples were stored at -70°C until analysis. An aqueous solution of stable isotope internal standard was added to thawed samples, and analytical standards and quality control samples were made up in the same matrix. All were treated with a 2-fold excess of acetonitrile (which, in the case of plasma, served to precipitate the bulk of plasma proteins). Samples, standards, and quality controls (QCs) were then vortex mixed and centrifuged, and the upper layer from each sample was transferred to a 96-well injection block.
Sample Analysis
R411 converts almost immediately in vivo or when added to plasma or urine in vitro to the active drug RO0270608. Samples were analyzed for RO0270608 by using online solid-phase extraction LC/MS/MS (Sciex API 3000), using positive ion electrospray ionization, and monitoring a transition of 505 m/z for the precursor ion to a 153-m/z fragment ion for the analyte, as well as a transition of 515 m/z for the precursor ion to a 153-m/z fragment ion for the isotopically labeled internal standard. A 2-cm x 3-mm i.d. C-8 (Betasil C-8, Thermo Electron, Waltham, Mass) guard column cartridge was used as the extraction column, and a 3-cm x 2-mm i.d. 3-µ endcapped C18 cartridge column (WRC18, ES Industries, West Berlin, NJ) was used for the analytical column. The lower limit of quantification (LLOQ) was 1 µg/L for RO0270608 in plasma and either 1 µg/L or 5 µg/L for RO0270608 in urine. The calibration range was 1 to 1000 µg/L for RO0270608 in plasma and either 1 to 1000 µg/L or 5 to 1000 µg/L for RO0270608 in urine.
Analytical Calibration
Calibration standards were run at the beginning of the bioanalytical run in ascending order and at the end of the run in descending order to eliminate any position effect. In addition, at least duplicate QC samples at 3 levels were scattered throughout each run. Analytical runs were acceptable if two thirds of the back-calculated calibration standards and two thirds of the QC samples met acceptance criteria. Standards and QCs met acceptance criteria if they were within 15% of their nominal value, except for the back-calculated LLOQ standards, which only needed to be within 20% of their nominal value. At least 1 LLOQ standard had to meet acceptance criteria, or the lower limit of quantitation for that run was raised to the level of the next standard. At least 1 standard from this next level would then need to meet acceptance criteria. Dilution of samples was done, if necessary, to have concentrations in the linear range.
Pharmacokinetic Analyses
Pharmacokinetic parameters of RO0270608 were estimated using WinNonlin 4.0.1 (Pharsight Corporation, Mountain View, Calif) and standard noncompartmental methods. The apparent elimination rate constant (ke) was estimated by linear regression of the logarithm of the plasma concentration versus time data from the terminal phase using at least 3 concentration-time points. The terminal t1/2 was calculated from ln(2)/ke. The area under the concentration-time curve from 0 to infinity (AUC0-
) was extrapolated by adding the ratio of Clast/ke to AUC0-last, where AUC0-last was the area under the concentration-time curve from 0 to tlast, calculated using the linear trapezoidal rule; Clast was the last observed measurable concentration; and tlast was the time corresponding to this concentration. The total body clearance (CLt) was calculated by dose/AUC0-, and the volume of distribution (Vd) was determined as CLt/ke. The CLt and Vd were reported only after intravenous (IV) administration. The Cmax was determined as the highest observed concentration, and tmax was the time corresponding to this concentration. The absolute bioavailability (F) of the active metabolite RO0270608 was determined as the ratio of the dose-standardized AUC0- after oral administration of R411 (dose expressed in RO0270608 equivalents) to that after IV administration of RO0270608. The renal clearance (CLR) was computed as the ratio of the amount of unchanged drug excreted in urine (Ae) over a time interval to the area under the plasma concentration-time curve over the same interval. The percent Ae was reported in terms of RO0270608 equivalents. In the multiple-dose pharmacokinetic study, the observed accumulation index (Rac) was determined as the ratio of AUC0- on the last day of administration to AUC0- on day 1.8
Safety Assessment
Safety was evaluated by continuous observation of adverse events (AEs), monitoring of vital signs, ECGs, and safety laboratory parameters at screening, during the study at set time points following drug administration, and at follow-up visits after study completion. Most laboratory parameters, measured at predose and 8, 24, and 48 hours postdose, included the following: hematology (hemoglobin, hematocrit, red blood cells [RBCs], white blood cell [WBC] differential count, international normalized ratio [INR], activated partial thromboplastin time [aPTT], reticulocytes, lymphocyte population), biochemistry (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], creatine phosphokinase [CPK], 
-GT, bilirubin, albumin, cholesterol, triglycerides, urea, creatinine), immunoglobulins (IgE, IgM, IgD, measured only at predose and 24 hours postdose), liver and renal function tests, electrolytes, and urine analysis. Adverse events were classified by body system and by intensity into mild, moderate, and severe. The relationship of AEs to the test drug was classified as probable, possible, remote, or unrelated. The severity of AEs, as well as their relationship to test drug, was assessed by the qualified physician in the unit. Clinically relevant changes in vital signs, ECGs, and laboratory parameters were defined as marked abnormalities. Twelve-lead ECGs were recorded in the semisupine position after a rest of at least 5 minutes. The ECGs were recorded at screening, predose, and 2, 12, 24, and 48 hours postdose. A change in QTc interval was considered significant if the value of this interval increased to more than 430 msec.
Statistical Analyses
Statistical analyses were done using WinNonlin 4.0.1. Due to the exploratory nature of the study, no statistical hypotheses were tested, and no power calculation was done. Sample size was chosen based on clinical judgment. Pharmacokinetic data after a single oral dose administration on day 1, obtained from the 3 parts of the trial, were pooled to assess linearity of exposure (AUC0-) with dose. Possible deviations from dose proportionality in the exposure were tested by an analysis of variance (ANOVA), with factor dose applied on dose-normalized and log-transformed AUC0-. In the multiple-dose pharmacokinetic study, time dependency of the oral clearance (CL/F) was assessed by testing the difference between exposure on day 1 (AUC0-) and on day 10 at steady state (AUC0-
) at each dose level using an ANOVA. The factors evaluated included subject and day on medication using log-transformed data. Subjects who had exposure data on only day 1 were excluded. CLR data were tested by a regression analysis on untransformed data to show if there was a dose effect or an age effect on this parameter. No statistical analyses were performed on safety results.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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Absolute Bioavailability
RO0270608, the active metabolite, could be detected for up to 48 hours after oral administration of 200 mg of R411 and up to 24 hours after IV administration of 100 mg of RO0270608 to healthy volunteers. Average pharmacokinetic profiles are shown in Figure 1. The absolute bioavailability (F) of active metabolite RO0270608 after R411 administration was obtained from results of period 1 (PO) and period 2 (IV). The value of F (mean ± SD) was 27% ± 4%. The terminal t1/2 (mean ± SD) was 7.33 ± 2.29 hours after oral administration (period 1) and 3.46 ± 1.16 hours after IV administration (period 2). When calculated from results of period 3, F and t1/2 were slightly higher. The percentage excreted unchanged in urine (% Ae) of RO0270608 (mean ± SD) was 9.17 ± 3.8 after oral (period 1) and 26.32 ± 9.9 after IV administration. Total clearance CLt (mean ± SD) was 19.4 ± 7.1 L/h, and the volume of distribution (mean ± SD) was 93.1 ± 36.1 L. The highest concentration (Cmax) of RO0270608 was reached within 2 to 3 hours after oral administration. Results in period 1 were compared with those in period 3. The within-subject coefficients of variation (CV) were 23.9% for Cmax and 9.3% for AUC0- following oral administration. Meanwhile, the intersubject CV was 37.6% for Cmax and 33.1% for AUC0- in period 1. The intersubject CV after IV administration (period 2) was 48.4% for Cmax and 35.5% for AUC0-. The pharmacokinetic parameters for all 3 study periods are listed in Table I.
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Single-Dose Pharmacokinetics
The pharmacokinetics of RO0270608 were studied after single oral administration of R411 at doses ranging from 10 to 1200 mg. RO0270608 plasma concentrations showed a biphasic decline (Figure 2). Terminal t1/2 was about 7 to 9 hours at doses of 150 mg and higher. However, at doses of 10 mg and 50 mg, this biphasic decline could not be observed because plasma concentrations dropped below the quantification limit after 12 hours of drug administration for most subjects. This has led to inaccurate estimation of the terminal phase, and a shorter t1/2 (about 2 hours) was observed. On average, AUC0- ranged from about 156 h•µg/L at the 10-mg dose to about 13,725 h•µg/L at the 1200-mg dose, and Cmax ranged from about 35 to 2021 µg/L at the 10-mg and 1200-mg oral doses, respectively. Pharmacokinetic parameters after single ascending dose administration are summarized in Table II.
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Multiple-Dose Pharmacokinetics
Oral administration of repeated daily doses of R411 (50-900 mg) led to dose-dependent plasma concentrations of RO0270608. After 8 consecutive days of dosing, pharmacokinetic parameters did not change. The accumulation index (Rac), calculated as the ratio of the observed AUC0- on day 10 to AUC0- on day 1, was about unity. This indicates the absence of accumulation under the used regimen. The steady-state trough plasma levels (Css,min), pooled from days 6, 8, and 9, presented an average of about 1.2 µg/L after 50-mg dosing and about 107 µg/L at 900-mg dosing (Table III). Average pharmacokinetic profiles of RO0270608 after multiple-dose administration are shown in Figure 3.
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Pharmacokinetic Linearity With Time and Dose
After single ascending oral doses of R411, the exposure (AUC0-) of RO0270608 increased proportionally with dose, and no statistically significant evidence was observed against dose proportionality on the 150- to 1200-mg interval (P > .05, ANOVA). The 10-mg and 50-mg doses were excluded from the statistical analysis as most profiles were incomplete and plasma concentrations were not detectable after 12 and 24 hours of administration, respectively. Dose proportionality of exposure is illustrated in Figure 4. Based on pooled data (n = 16) from the single- and multiple-dose studies (day 1), the intersubject variability (CV) of AUC0- was 38.4% at 50-mg dosing, 35.8% at 300-mg dosing, and 34.6% at 900-mg dosing.
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After multiple oral ascending qd doses of R411, the pharmacokinetics of RO0270608 were not changed. There was no statistically significant difference between AUC0- at day 1 and AUC0- at day 10 for all doses tested (P > .1, ANOVA). This indicates that the oral clearance (CL/F) was independent of time following repeated qd dosing.8 However, the terminal t1/2 was slightly higher at day 10 compared with day 1 (Table III). At the 50-mg dose at day 1, a lower t1/2 was estimated because of undetectable plasma concentrations beyond 24 hours (Figure 3).
After single oral doses, the CLR (mean ± SD) ranged from 5.45 ± 2.07 L/h at 10 mg to 5.15 ± 1.56 L/h at 1200 mg (Table II). As can be seen from Figure 5, and as indicated by regression analysis on untransformed data, there was no statistically significant effect of dose (P = .214) or age (P = .346) on renal clearance of RO0270608. After pooling the data (all subjects, all doses), average CLR (mean ± SD) was 5.51 ± 2.02 L/h.
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Safety and Tolerability
No significant safety concerns were revealed in this trial; R411 was well tolerated up to a single dose of 1200 mg and up to 900 mg for up to 3 weeks. The most frequently reported AE after chronic administration was headache that was considered of mild intensity and possibly related to R411. Most of the other AEs reported were of mild intensity and considered by the investigator to be remotely related to the study drug. None of the subjects experienced a serious AE in this trial. There were no apparent differences between placebo and active treatment with regard to the incidence of AEs. The incidence of AEs did not increase with the dose. However, following chronic administration of 900 mg for 3 weeks, the incidence of AEs was higher. A summary of AEs classified by body system at each dose level and placebo is shown in Table IV. Some laboratory abnormalities were reported in this trial; the most frequent were serum triglyceride elevations, which occurred in 8 out of 50 subjects after chronic administration of R411. Most of them were in the nonfasted state and were transient, but a possible relationship to study drug cannot be excluded. Other transient and less frequent abnormalities included increased red blood cell counts; elevated ALT, albumin, and total bilirubin; decreased lymphocyte count; glycosuria; and hematuria. All of these abnormalities did not appear to be related to study drug, and their incidence did not appear to increase with dose level. None of the subjects in this trial had marked changes in lymphocytes, reticulocytes, prothrombin time, or IgE, IgM, and IgD levels. All other laboratory parameters for heart, liver, and renal function, as well as protein and electrolyte concentrations, were normal for all the subjects in this trial. Due to the exploratory nature of the study and the small sample size per dose group, no statistical analysis on AEs or laboratory parameters was performed.
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In the bioavailability study, both oral administration of R411 (periods 1 and 3) and intravenous infusion of its active metabolite RO0270608 (period 2) showed similar incidences of AEs. One subject contracted a severe infection (cellulitis) after receiving a 200-mg single oral dose of R411, leading to his withdrawal. The cellulitis was related to a venous access procedure undertaken and was not related to study drug.
In the single-dose pharmacokinetic study, transient high diastolic blood pressure (100-110 mmHg) was seen in 2 subjects, 1 in the 10-mg dose group and the other in the 150-mg dose group. Transient high systolic blood pressure (
150 mmHg) was also seen in 1 subject in the 150-mg dose group. One subject in the placebo group had a markedly but transient high body temperature (39°C). All ECGs and other vital signs were recorded as normal.
Multiple-dose administration of R411 or placebo was associated with low body temperature (<35.8°C). The effect appeared in all dose groups and was not considered clinically relevant. One patient receiving 50 mg R411 in the single-dose pharmacokinetic phase of the trial also experienced low body temperature. There were transient changes in diastolic blood pressure (low in 4 subjects), systolic blood pressure (high in 1 subject), and respiratory rate (high in 1 subject). There were also transient changes in PQ, QRS, and QT intervals from baseline in some subjects that were not considered clinically relevant. The QT interval corrected for heart rate (QTc) did not change to a significant degree in any of the subjects.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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= 1137 h•µg/L, Cmax = 275 µg/L) was within the range of exposure required to achieve efficacy in animal studies.7 Studies are currently ongoing to establish the efficacy of R411 in asthmatic patients. After IV administration, the total clearance (CLt) of RO0270608 was an average of 19.37 L/h. It represents about 22% of human liver blood flow.9 However, the renal clearance (CLR) presented an average (all subjects, all doses) of 5.51 L/h. CLR was independent of the dose administered over a range of 10 to 1200 mg, and there was no clear relationship between CLR and age over a range of 18 to 65 years. The plasma protein binding of RO0270608 in humans was more than 90% (data not shown). This implies that the glomerular filtration rate of the unbound drug (fu•GFR) is about 0.72 L/h, which is by far smaller than the CLR observed in this study. This indicates that renal tubular secretion of RO0270608 is the principal mechanism of renal clearance.8 The terminal t1/2 was shorter following IV administration as compared to oral administration. This could be due to insufficient plasma concentration-time points in the terminal phase that led to the inaccurate estimation of the t1/2 of the IV profile. However, this could not fully explain this difference in t1/2 because IV and oral profiles did not show a parallel decline in the terminal phase. Absorption from the intestine could be a possible explanation, but this requires further investigation.
Following oral administration, absorption was rapid. The absolute bioavailability (mean ± SD) of the active metabolite RO0270608 after oral administration of R411 at 200 mg was 27% ± 4% under fasting conditions. The intersubject variability (CV) in RO0270608 AUC0- was 33.1% and was similar to that after IV administration (33.5%). However, the estimated intrasubject CV in RO0270608 oral exposure was lower (9.3%). In animals, biliary excretion of RO0270608 had a major contribution to total body clearance. In humans, following administration of 14C-labeled R411, more than 80% of the dose was recovered in feces (data not shown). In addition, it has also been observed that metabolism of RO0270608 in human liver tissue is negligible. The present trial has confirmed the previous findings about the major role of biliary clearance because CLR represents only about 25% of CLt. The intersubject variability in biliary excretion could be the source of the observed intersubject variability in drug exposure following oral or IV doses. The effect of food on bioavailability was not addressed in this trial.
No significant safety concerns were revealed in this trial, and no serious AEs were reported. The drug has shown an acceptable safety profile up to a single dose of 1200 mg and up to 900 mg for up to 3 weeks. However, the incidence of AEs was higher after multiple administrations than after a single administration for both placebo and R411. The most frequent AE was headache, and the most frequent laboratory abnormality was elevated triglycerides. Although both events were of mild intensity and occurred in both R411 and placebo groups, a relationship to test drug cannot be excluded. Other AEs were mild and were unrelated or remotely related to the study drug. Due to the exploratory nature of the study, and due to the small sample size per dose group, no statistical comparison of safety parameters between R411 and placebo was performed. Future multicenter trials will address the safety and tolerability of R411 in the disease population. Among the 132 healthy volunteers who participated in this trial, the safety results observed were promising.
Under repeated single daily dosing, R411 was well tolerated and showed linear pharmacokinetics. The plasma levels of the active metabolite, RO0270608, declined slowly, and the terminal t1/2 was 7 to 9 hours. The exposure parameters of RO0270608 in humans were within the range of those associated with efficacy in preclinical species. In these studies, once-daily treatment with R411 was associated with attenuation of airway inflammation and hyperresponsiveness in murine and primate models of asthma.7 Taken together, these data suggest that an oral once-daily dose regimen of R411 may be appropriate for the treatment and prophylaxis of chronic asthma. Studies are ongoing to assess the safety and efficacy of administration of once-daily R411 in asthmatic patients.
At present, anti-inflammatory drugs for the treatment of chronic asthma include mainly inhaled corticosteroids, leukotriene antagonists, and a combination of inhaled corticosteroids with long-acting ß2-agonists. Corticosteroids are the most potent but are associated with many adverse effects, including adrenal suppression, immunosuppression, and effects on growth and metabolism.10,11 Dual 4ß1-4ß7 integrin antagonists, which selectively control multiple pathways leading to inflammation, may present a novel approach to therapy for inflammatory and autoimmune diseases.12 Monoclonal antibodies against 4 integrins are in development for the treatment of Crohn's disease and multiple sclerosis.13,14 However, no chemical antagonists of 4 integrins are available for oral administration. In this phase I trial, a new chemical compound, R411, has shown promising results concerning safety and pharmacokinetics following oral administration in healthy volunteers.
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CONCLUSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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FOOTNOTES |
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Submitted for publication February 6, 2004; Revised version accepted August 16, 2004.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONACKNOWLEDGEMENTSREFERENCES |
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1. Hemler ME. VLA proteins in the integrin family: structures, functions and role on leukocytes. Annu Rev Immunol. 1990;8: 365-400.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
2. Bochner BS, Luscinskas FW, Gimbrone MA Jr, et al. Adhesion of human basophils, eosinopils, and neutrophils to interleukin-1 activated human vascular endothelial cells: contributions of endothelial cell adhesion molecules. J Exp Med. 1991;173: 1553-1557.
3. Abraham WM, Sielczak MW, Ahmed A, et al. 4 integrins mediate antigen-induced late bronchial responses and prolonged AHR in sheep. J Clin Invest. 1994;93: 776-787.
4. Gonzalo JA, Lloyd CM, Kremer L, et al. Eosinophil recruitment to the lung in a murine model of allergic inflammation: the role of T cells, chemokines, and adhesion receptors. J Clin Invest. 1996;98: 2332-2345.[Web of Science][Medline] [Order article via Infotrieve]
5. Lobb RR, Pepinsky B, Leone DR, Abraham WM. The role of 4 integrins in lung pathophysiology. Eur Respir J. 1996;9: 104S-108S.
6. Renzetti LM, Ramanathan M, Holly M, et al. Inhibition of human T cell and eosinophil activity by RO0270608, a dual a4/b1-a4/b7 integrin antagonist with unique binding properties. Am J Respir Crit Care Med. 2003;167: A215.[CrossRef]
7. Renzetti LM, Tannu S, Connaughton S, et al. Attenuation of airway inflammation and hyperresponsiveness in murine and primate models of asthma by RO0270608, a dual a4/b1-a4/b7 integrin antagonist. Am J Respir Crit Care Med. 2003;167: A640.
8. Rowland M, Tozer TN. Clinical Pharmacokinetics: Concepts and Application. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 1995.
9. Davies B, Morris T. Physiological parameters in laboratory animals and humans. Pharm Res. 1993;10: 1093-1095.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
10. Niitsuma T, Okita M, Sakurai K, et al. Adrenal function as assessed by low-dose adrenocorticitropin hormone test before and after switching from inhaled beclomethasone dipropionate to inhaled fluticasone propionate. J Asthma. 2003;40: 515-522.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
11. Jones G, Ponsonby AL, Smith BJ, Carmichael A. Asthma, inhaled corticosteroid use, and bone mass in prepubertal children. JAsthma. 2000;37: 603-611.
12. Von Andrian UH, Engelhardt B. 4 integrins as therapeutic targets in autoimmune disease. N Engl J Med. 2003;348: 68-72.
13. Miller DH, Khan OA, Sheremata WA, et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2003;348: 15-23.
14. Ghosh S, Goldin E, Gordon FH, et al. Natalizumab for active Crohn's disease. N Engl J Med. 2003;348: 24-32.
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) and the mean (
).
). The small figure shows correlation of renal CLR with age.