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Rheumatology 2001; 40: 537-543
© 2001 British Society for Rheumatology
Original Papers |
Tolerability and pharmacokinetics of the collagenase-selective inhibitor TrocadeTM in patients with rheumatoid arthritis
Roche Products Ltd, Welwyn Garden City, UK,
1 F. Hoffmann-La Roche, Basel, Switzerland and
2 North Shore University Hospital, New York, USA
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Abstract |
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Objectives. The purpose of this study was to assess the tolerability and multiple-dose pharmacokinetics of TrocadeTM in rheumatoid arthritis patients.
Methods. Forty-eight patients entered this double-blind, placebo-controlled, multiple ascending dose study. Patients received Trocade (25, 50, 100 or 150 mg) or placebo once daily for 28 days. Tolerability was assessed daily. Plasma pharmacokinetics was assessed on days 1 and 28. Trough blood samples were collected weekly.
Results. Trocade was well tolerated, with no differences in the adverse event profile compared with placebo. There were no relevant changes in laboratory parameters, vital signs or 12-lead ECG recordings. Plasma concentration profiles showed that Trocade was rapidly absorbed and most was eliminated within 24 h. The area under the plasma concentration–time curve and the maximum plasma concentration reached increased with dose, but this increase was not proportional to dose. No relevant accumulation was seen.
Conclusions. Trocade was well tolerated for the 28-day study period. From exposure data, doses of 100 and 150 mg were expected to yield plasma levels associated with efficacy, and from trough concentrations the doses of 25 and 50 mg were also expected to be efficacious.
KEY WORDS: Trocade, Rheumatoid arthritis, Safety, Pharmacokinetics, Collagenase-selective inhibitor.
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Introduction |
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Structural joint damage, typically assessed by radiographic findings, is a characteristic feature of rheumatoid arthritis (RA) and is accepted by many as a strong predictor of the long-term outcome. Given sufficient time, this damage contributes to functional decline, disability and major surgical procedures [1–3]. Indeed, it has been reported that patients with extensive radiographic damage (stages III and IV) have significantly more work disability than those at stages I and II [K. M. Pugner, J. W. Holmes, K. Hieke, D. L. Scott, manuscript in preparation]. Similarly, this joint destruction is also associated with a significant economic impact, the predicted annual cost of RA-related knee replacements alone in the USA reaching over one billion dollars [4].
Consequently, the prevention of structural joint damage in RA is viewed as a major therapeutic goal in the treatment of this disease. Unfortunately, whilst current therapies slow down the progression of erosive disease, it is not totally abolished [5]. Therefore, although recent advances show some promise, further progress is still needed [6].
The process of joint destruction, including the loss of both articular cartilage and bone, is driven by a family of enzymes known as matrix metalloproteinases (MMPs). Members of this family include collagenases, stromelysins and gelatinases. However, the involvement of the collagenases is considered crucial in the destructive process. The network of collagen fibres within articular cartilage provides the framework in which other macromolecules, such as the proteoglycans, are embedded. Together, these fibres and molecules give cartilage its tensile strength, permitting it to resist loading compression and thereby allowing smooth articulation of the joint. The proteoglycan content is constantly turned over, chondrocytes replacing lost proteoglycan. However, damage to the collagen network is irreversible and leads to permanent joint damage [7].
Under physiological conditions, the collagenases are the only enzymes that are known to cleave collagen and as result of this property they cause a key irreversible step in the destruction of cartilage [8]. Consequently, inhibition of these enzymes has been considered a therapeutic target for many years [9].
TrocadeTM {Ro 32-3555; 3(R)-(cyclopentylmethyl)-2 (R)-[3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl-methyl]-4-oxo-4-piperidino-butyrohydroxamic acid} was specifically designed to inhibit, selectively and potently, collagenases 1, 2 and 3 (MMPs 1, 8 and 13 respectively) and thereby block the final common event in the destructive cascade resulting in the breakdown of cartilage and bone. Trocade has also been shown to inhibit cartilage destruction in vivo and to prevent structural joint damage in animal models of rheumatoid and osteoarthritis [10, 11]. These data, together with the ability of Trocade to selectively inhibit human collagenases, make it a promising therapeutic agent for the prevention of joint damage in patients with RA.
In a study of healthy volunteers, single doses of Trocade up to 150 mg were shown to be well tolerated [12]. The area under the plasma concentration–time curve (AUC) and the maximum plasma concentration (Cmax) increased in a dose-related fashion and the consumption of food reduced Cmax and increased the time to reach maximum concentration (tmax) but had no effect on the AUC [13]. In another study, the absolute bioavailability of Trocade was shown to be 43%, and this was unaffected by the consumption of food [13]. Trocade is cleared mainly (50–55%) by glucuronidation, about 9% unchanged drug being excreted into the urine by glomerular filtration and the balance being excreted in the faeces as an amide and 25 other minor metabolites. Only about 10% of orally administered drug is metabolized by cytochrome P450 (mainly by dimethylation), and drug–drug interactions based on competition for this pathway are therefore unlikely [14].
This paper reports the results of the first study of Trocade in patients with RA, performed in order to establish its multiple-dose pharmacokinetics and tolerability within the intended patient population.
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Patients and methods |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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Design
This was a single-centre, double-blind, randomized, placebo-controlled study. Eligible patients were randomized to receive single daily doses of either Trocade (25, 50, 100 or 150 mg) or placebo, commencing on day 1 and continuing until day 28. Each patient participated at one dose level only. In each of the four groups there were 12 patients, nine of whom received active drug and three received placebo.
Patients
Forty-eight patients, aged 21 yr and over, were recruited from the rheumatology out-patient clinic at the North Shore University Hospital, NY, USA or via local recruitment methods. All patients had RA according to the 1987 American College of Rheumatology criteria, with a disease duration of at least 6 months. All female patients were post-menopausal, surgically sterilized or using reliable methods of contraception.
Patients with the following criteria were excluded: positive pregnancy test; a significant chronic concomitant disease, such as ischaemic heart disease, severe asthma, cancer, renal impairment, hepatic impairment, gastrointestinal disorder, a history of alcohol or drug abuse, any major infection (within 30 days of the study start), or treatment with any investigational drug (within 30 days before the study started); or a body weight less than 40 kg.
Patients were allowed to remain on stable disease-modifying anti-rheumatic drugs (DMARDs), non-steroidal anti-inflammatory drugs (NSAIDs) and/or corticosteroid (prednisolone at a dose of 
10 mg or equivalent) treatment for RA. All medication (except prednisolone) was kept unchanged during the study. Analgesics, such as acetaminophen, propoxyphene, codeine or combinations thereof, were used as rescue medication for severe pain. All other analgesics were excluded unless their administration was kept constant during the study. All patients gave written informed consent and approval was obtained from the institutional review board.
Methods
On study day 1, patients attended the clinic, having fasted from midnight on the previous day. Before dosing, a negative pregnancy test result was obtained for all female patients of childbearing potential and blood and urine samples were collected for laboratory safety tests. Vital signs and 12-lead ECG recordings were obtained after at least 5 min in the semisupine position predose and at intervals up to 24 h after dosing. Oral dosing with Trocade or placebo occurred within 10 min of each subject consuming a standard continental breakfast, and continued once daily for a further 27 days.
Patients returned on the mornings of days 7, 14 and 21, when a single blood sample was collected before dosing to measure trough plasma concentrations of drug.
On study day 28, patients attended the unit after having fasted from midnight on the previous day. The same procedures as for day 1 were then performed, including blood sampling and administration of the final dose of Trocade.
On days 1 and 28, blood samples were taken before the dose was given and 0.5, 1, 1.5, 2, 4, 5, 6, 8, 10, 12, 18, 24, 30, 48, 72 and 96 h after dosing.
Throughout the study, venous blood samples were collected into vacutainers containing EDTA as an anticoagulant. Immediately after collection, blood samples were immediately placed on ice, and they were centrifuged at 3000 r.p.m. and 4°C for 10 min within 30 min of collection. The plasma supernatant was removed into plain plastic tubes and stored at -20°C until assays were performed. Plasma samples were analysed for Trocade by a high-performance liquid chromatography coupled with tandem mass spectrometry method. Analysis was carried out over two calibration ranges: 0.5–22 and 5–5000 ng/ml. During the analysis the overall mean precision and accuracy were ±4.57 and ±2.23% respectively.
Statistical methods
The plasma pharmacokinetic parameters AUC0–
, Cmax, tmax and elimination half-time (t½) were derived by non-compartmental methods using WinNonlin Professional, version 1.5 (Pharsight Corp; Mountain View, CA, USA). Trough levels were the measured concentrations of Trocade immediately before the next dose.
Accumulation was assessed by examining ratios of AUC0-24 and Cmax on day 28 to AUC0- and Cmax respectively on day 1. To check for dose-dependence, an analysis of variance (ANOVA) with the factor dose was applied to the log-transformed ratios. The result was interpreted in an exploratory manner only.
Outcome measures
Tolerability
This was assessed from reported adverse events together with haematology and blood biochemistry. Samples for haematology and biochemistry were collected at screening, before dosing and 24 h after dosing on days 1 and 28, before dosing on day 14 and at follow-up (4–10 days after the last dose of the study medication).
The haematological variables assessed were haemoglobin concentration, haematocrit, red blood cell count, total and differential white blood cell counts and platelet count; the serum biochemical variables assessed were aspartate aminotransferase, alanine aminotransferase, total bilirubin, albumin, creatinine, urea, total protein, sodium, chloride, potassium and glucose; and urinalysis comprised dipsticks for pH, glucose, blood and protein.
Adverse events were recorded in response to the question ‘Have you felt in any way unwell since you were last asked?’ This question was asked at regular intervals throughout the study and spontaneous reports were recorded at any time. Adverse events were graded on a three-point scale: mild, moderate and severe. The relationship between each event and the trial medication was determined by the investigator and categorized on a four-point scale: unrelated, remotely related, possibly related or probably related.
Pharmacokinetics
The primary parameters were AUC, Cmax and tmax. The secondary parameters were trough levels and evidence of accumulation. An effective half-life was determined to explain the lack of accumulation on multiple dosing, using the method developed by M. Rowland and D. Weiner (personal communication during the Advanced Workshop in Pharmacokinetics and Pharmacodynamics, 1994). This was calculated by determining the relative contributions of each phase of the concentration–time curve and adjusting the half-life associated with each portion to reflect this.
After correction for protein binding to 
1-acid glycoprotein (90% in man and 70% in the rat), the free AUC and Cmax values were obtained. These were compared with those associated with efficacy in the rat sponge cartilage model and with the concentration associated with 50% inhibition (IC50) of the isolated human collagenase enzymes.
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Results |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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Forty-eight patients with RA, aged 34–82 yr, entered the study and of these 47 completed all assessments. Demographic details and measures of disease activity are presented in Table 1
. One patient in the 150 mg dose group withdrew after 7 days of dosing following withdrawal of consent. This patient was evaluable for safety but not for pharmacokinetics. Thirty-five patients (73%) were female and 13 were male. The majority of patients (88%) had active concomitant diseases in addition to their RA, the most common diseases being cardiopulmonary (hypertension, ECG abnormalities), and a history of drug hypersensitivity. Concomitant medications included NSAIDs, corticosteroids, vitamin and mineral supplements and hormonal therapies.
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Thirty-two patients were receiving DMARDs. Of these, 60% were taking methotrexate and 10% were taking multiple DMARDs.
Tolerability
Twenty-three patients reported a total of 38 adverse events. The adverse events reported by more than one patient are presented in Table 2. The most commonly reported adverse events were headache, upper respiratory tract infection and dyspepsia. However, each accounted for fewer than 11% of the total adverse events reported. Thirty-six (95%) of the events were considered to be of mild intensity and two (5%) events were considered moderate. The investigator considered 27 (71%) adverse events to be unrelated to the trial treatment, eight remotely related and three possibly related.
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There were no serious adverse events or deaths reported in this study. No patient withdrew from the study because of adverse events. Furthermore, all adverse events had resolved by the end of the study.
Adverse events occurred with similar frequency in the placebo and active treatment groups. There did not appear to be any increase in frequency or intensity of adverse events with increasing dose of Trocade.
There were no clinically relevant changes in laboratory parameters, vital signs or 12-lead ECG recordings after 28 days of dosing with Trocade or placebo. The absence of any relevant changes in vital signs indicated that collagenase inhibition by Trocade did not affect haemodynamics.
Pharmacokinetics
After the first dose, Trocade was rapidly absorbed and a maximum plasma concentration was achieved within approximately 1–3 h of dosing. After absorption, a biphasic decline was seen, comprising an initial rapid phase lasting 6–8 h followed by a slow terminal phase (Fig. 1). Plasma concentration–time profiles after 28 days’ dosing were similar to those obtained on day 1 (Fig. 2).
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After both single and multiple Trocade dosing, both AUC and Cmax increased with dose (Table 3
). However, dose-adjusted AUC and Cmax decreased with increasing dose. For dose-adjusted AUC and Cmax on day 28, the one-way ANOVA with the factor dose indicated that there were differences between the dose groups (P values: 0.020 for AUC and 0.0025 for Cmax). A less than dose-proportional increase in AUC and Cmax was seen at the highest dose.
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Little accumulation of Trocade was seen upon multiple dosing for 28 days. Because only 10% of the AUC0–
remains after 24 h, the contribution of the doses administered on days 2, 3 and 4 was considered negligible. In the ANOVA for accumulation from day 1 to day 28, differences in accumulation between dose groups were found (P values: 0.0053 for AUC and 0.027 for Cmax). In the 25-mg dose group only, 38% accumulation was estimated for the dose-adjusted AUC and 52% accumulation for the dose-adjusted Cmax. For other dose groups no relevant accumulation was found. Trough values obtained before dosing on days 7, 14, 21 and 28 confirmed the lack of accumulation on multiple dosing (Table 4).
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The terminal phase of the concentration–time profile represents so little of the AUC of Trocade that the half-life of 24–28 h calculated from this terminal phase does not predict the lack of accumulation of Trocade seen upon multiple dosing. Therefore, the ‘effective’ half-life was calculated. This was done with a multi-exponential curve-stripping technique whereby, using derived parameters describing the curve, we determined the relative contributions of each portion of the plasma concentration–time profile. These values were then used to correct the half-life values obtained for each portion of the curve and hence calculate the effective half-life. The effective half-life was 8–10 h (Table 3
), which is consistent with the lack of accumulation.
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Discussion |
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TopAbstractIntroductionPatients and methodsResultsDiscussionReferences |
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This study demonstrated that Trocade was well tolerated in RA patients who were receiving DMARDs along with other therapies. There were no serious adverse events and most of the adverse events reported were of mild intensity and were considered to be unrelated to the trial medication. There were no differences in the frequency, nature or intensity of adverse events in patients administered Trocade when compared with placebo. There were no clinically relevant changes in laboratory parameters, vital signs or 12-lead ECG recordings after 28 days of treatment with either Trocade or placebo. Previous clinical experience has shown musculoskeletal adverse events to be the principal treatment-related side-effects of MMP inhibitors. In a previous study with marimastat in patients with gastric cancer, the occurrence of these events was seen to be related to both dose and duration of therapy, arthralgia and myalgia being those most commonly reported [15]. However, as can be seen in Table 2
, no musculoskeletal events of concern were reported in this study. After single-dose administration of Trocade, there was initial rapid absorption followed by a biphasic decline in concentration with time. Both AUC and Cmax increased with dose, although the increases were less than proportional. There was no accumulation upon multiple dosing at doses greater than 25 mg.
From the data obtained in this study, the free AUC and Cmax of Trocade were predicted assuming a fixed fraction of protein-binding of Trocade of 90%. In Table 5 and Fig. 3 a comparison is made of the free exposure associated with the concentration associated with the half-maximal effect (EC50) in the rat sponge cartilage model [11] and those estimated in this study. The target free AUC of 1.05 mg/h/l was exceeded after 28 days dosing at 100 and 150 mg, indicating the potential for efficacy with these doses.
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Despite the terminal half-life of Trocade of 24–28 h, obtained on day 28, the expected accumulation of Trocade on once-daily dosing was not seen. It is possible, therefore, that the effective half-life of Trocade cannot be represented by this terminal phase half-life as the majority of the drug was eliminated within 24 h of dosing. Indeed, the AUC achieved after 24 h of dosing represented approximately 90% of the AUC0–
. Consequently, the effective half-life was determined to be approximately 8–10 h. A comparison of the free trough levels of Trocade after once-daily dosing and the IC50 for human collagenase of 3 ng/ml illustrated in Table 5 and Fig. 4 indicates that, at all doses investigated, a large degree of inhibition was maintained throughout the 24-h dosing period, which increases the likelihood of showing efficacy over the entire dose range investigated.
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The efficacy of Trocade can only be determined by the assessment of structural damage, and no such measurements were taken in this study because of its short duration. However, the pharmacokinetics determined in this trial suggest that good inhibition of collagenase enzymes can be achieved over the 24-h dosing period and that the dose range used in this trial has potential for efficacy in future studies.
In summary, the results of this study show that Trocade was well tolerated after 28 days of treatment at doses of up to and including 150 mg once daily in patients with RA. There were no differences in the frequency, nature or intensity of adverse events in patients receiving Trocade compared with placebo. Once-daily dosing provided plasma levels of Trocade that could be expected to give therapeutic benefit. The potential for Trocade to provide new therapeutic intervention, primarily aimed at preventing joint damage and maintaining patients’ functionality, coupled with the results of this study, has resulted in the entry of Trocade into phase III trials.
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Acknowledgments |
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The authors would like to thank Dr R. Furie, Dr E. K. Chartash and Dr N. Chiorazzi for their contribution and dedication, as the coinvestigators for this study.
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Notes |
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Correspondence to: F. Hemmings, Roche Products Ltd, Albany Place, Broadwater Road, Welwyn Garden City, Hertfordshire AL7 2JL, UK.
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