Results of single and repeat dose studies of the oral matrix metalloproteinase inhibitor marimastat in healthy male volunteers

Abstract

Aims To assess the tolerability and pharmacokinetic profile of single and repeat doses of the oral matrix metalloproteinase inhibitor marimastat in healthy male volunteers. Methods A total of 31 subjects participated in two placebo-controlled, rising-dose studies. The first study assessed the pharmacokinetics and tolerability of single doses of marimastat of 25, 50, 100, 200, 400 and 800 mg. In the second study, continuous dosing over 6.5 days with three incremental dose levels of 50, 100 and 200 mg twice daily was assessed. Full pharmacokinetic profiles were obtained on days 0 and 6, and trough concentrations were measured on all days. For each pharmacokinetic profile in the studies, summary measures including C max , t max , elimination half-life and AUC were calculated. Urinary drug weights were also measured. All adverse events were documented, and haematological and biochemical variables, vital signs and ECGs were monitored throughout the study. Results Peak plasma concentrations were observed at 1.5-3 h for all subjects at all doses. Peak levels were approximately proportional to dose, as was drug exposure as calculated by AUC. Data from both studies indicate that the terminal elimination half-life is of the order of 8-10 h, and that there is no unexpected drug accumulation. Marimastat was well-tolerated, with adverse effects being mild and occurring with similar frequency to placebo. Small but reversible elevations in liver transaminases were noted with repeat dosing of marimastat, the most significant of these occurring at a dose of 200 mg twice daily. Conclusion Single and repeat oral doses of marimastat in healthy male subjects appear to be well-tolerated. The drug is rapidly absorbed with high peak levels achieved. It has a terminal elimination half-life of 8-10 h which would support twice daily dosing in further clinical trials.

Inhibition of metalloproteinases enhances the internalization of anti‐CD30 antibody Ki‐3 and the cytotoxic activity of Ki‐3 immunotoxin

“…In this respect, it is also encouraging that clinical trials in man have shown that effective concentrations of hydroxamate inhibitors are either well tolerated or caused a few mild but reversible side effects. 23,24 Therefore, hydroxamate inhibitors such as BB-3644 might provide a promising tool to improve the treatment of human CD30 ϩ lymphomas with immunotoxins.…”

The role of proteases in pathologies of the synovial joint

“…A number of degenerative changes have been reported including, hypoxia, loss Drake et al (1996), Everts et al (1992), Garnero et al (1998), Hou et al (1999), Kamiya et al (1998) MMP-13 Metallo Cleavage of matrix from demineralised zones Delaissé et al (2003), Everts et al (2002), Fuller and Chambers (1995) Osteoclast activation and migration MMP-13 Metallo Cleavage of type I collagen generating an activation factor for osteoclasts Millar et al (1998), Riley et al (2002) of fibrillar collagen structure, glycosaminoglycan accumulation between the collagen fibres and cell rounding together with an absence of inflammatory cells (Kannus & Józsa, 1991). Similar changes have been reported in chronic tendinopathy, including an abnormal fibre structure and arrangement, focal changes in cellularity, rounded cells and an increase in proteoglycan content (Movin, Gad, Reinholt, & Rolf, 1997).…”

“…MMP proteases have been implicated in this collagen turnover and comparisons of normal and ruptured tendon have demonstrated an increase in the amount of active MMP-1, and a decrease in the amounts of MMP-2 and -3 together with increased collagen denaturation and turnover (Riley, 2005;Riley et al, 2002). A key role for the inhibition of metalloprotease activity in the development of tendinopathy is inferred from the effects of the broad-spectrum metalloprotease inhibitor Marimastat, which induces tendinopathy by an unknown mechanism (Millar et al, 1998). Other pharmacologicals, the fluoroquinolones, have been associated with tendinopathy in some patients and have also been shown to modulate MMP activity in vitro (Corps et al, 2002;Williams, Attia, Wickiewicz, & Hannafin, 2000).…”

Drug delivery to equine digital lamellar tissue

“…Unfortunately, marimastat is impractical for systemic administration in horses due to expense, systemic side effects, lack of oral bioavailability and rapid clearance after intravenous administration (Barlaam et al 1999;Levin et al 2006, Pollitt and Pass, unpublished data). Musculoskeletal side effects include tendonitis like fibromyalgia and arthritis and affect >90% of patients in some studies; additional side effects such as headache, nausea, diarrhoea, coughing, pharyngitis and fatigue have also been reported (Millar et al 1998, Miller et al 2002, Peterson 2006. However, marimastat has great potential for laminitis prophylaxis if a suitable method of local delivery that yields sustained lamellar drug levels can be established.…”

“…In the human field, protease inhibitors have been developed as chemotherapeutic agents for the treatment of cancer and arthritis (Li and Wu 2010). Marimastat is a synthetic, low molecular weight peptidomimetic inhibitor that binds to the zinc ion in the active site of MMPs (Millar et al 1998;Barlaam et al 1999). It has been used in multiple oncologic clinical trials (Rosenbaum et al 2005;Levin et al 2006), has anti-inflammatory properties (Bruce and Thomas 2005;Nenan et al 2007) and protects against ischaemia reperfusion injury (Novak et al 2010) in preclinical trials.…”