Ibudilast in healthy volunteers: safety, tolerability and pharmacokinetics with single and multiple doses

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Ibudilast is an oral drug approved in Asia for asthma.• Tolerability of 10-mg regimens has been described previously.• Published pharmacokinetics (PK) are limited: single or 7-day repeat oral administration of 10 mg in healthy male Asian volunteers. WHAT THIS STUDY ADDS• Safety/tolerability and PK of a single 30-mg dose and a 30-mg twice daily (b.i.d.) 2-week regimen in male and female healthy volunteers. • Higher-dose regimens are relevant for testing in new neurological indications.• LC-MS/MS analytics for quantification of plasma and urine levels of ibudilast parent and its primary metabolite (6,7-dihydrodiol-ibudilast). AIMSTo investigate the safety, tolerability and pharmacokinetics (PK) of ibudilast after a single-dose and a multiple-dose regimen. METHODSHealthy adult male (n = 9) and female (n = 9) volunteers were evaluated over a 17-day stay in a Phase 1 unit. Subjects were randomized 1 : 3 to either oral placebo or ibudilast at 30-mg single administration followed by 14 days of 30 mg b.i.d. Complete safety analyses were performed and, for PK, plasma and urine samples were analysed for ibudilast and its major metabolite. RESULTSIbudilast was generally well tolerated. No serious adverse events occurred. Treatment-related adverse events included hyperhidrosis, headache and nausea. Two subjects discontinued after a few days at 30 mg b.i.d. because of vomiting. Although samples sizes were too small to rule out a sex difference, PK were similar in men and women. The mean half-life for ibudilast was 19 h and median Tmax was 4-6 h. Mean (SD) steady-state plasma Cmax and AUC0-24 were 60 (25) ng ml -1 and 1004 (303) ng h ml -1 , respectively. Plasma levels of 6,7-dihydrodiol-ibudilast were approximately 30% of the parent. CONCLUSIONSIbudilast is generally well tolerated in healthy adults when given as a single oral dose of 30 mg followed by 30 mg b.i.d. (60 mg day -1 ) for 14 days. Plasma PK reached steady state within 2 days of starting the b.i.d. regimen. Exposure to ibudilast was achieved of a magnitude comparable to that associated with efficacy in rat chronic pain models.

Allosteric inhibition of macrophage migration inhibitory factor revealed by ibudilast

“…This allosteric site provides a foundation for the discovery and development of MIF inhibitors as therapeutics for disorders including inflammatory, autoimmune, oncogenic, and neurological diseases. Our studies also provide a possible pharmacological mechanism by which clinically relevant AV411 concentrations may contribute therapeutically to MIF-associated bronchial asthma (42,43), glial attenuation, and related chronic pain (4,6,9,26).…”

“…S1 B and C). AV411 inhibits MIF-mediated chemotaxis in clinically relevant concentrations (6,26) (Fig. 2A).…”

“…MIF chemotactic inhibition occurs at concentrations of AV411 demonstrated to be clinically relevant in its therapeutic use in humans (26). NMR spectroscopic data mapped the AV411 and AV1013 binding sites on the MIF trimer, and crystal structures of the binary rhMIF/AV1013 and ternary rhMIF/ (R)-AV1013/p-hydroxyphenylpyruvate (HPP) complexes have been determined.…”

Cellular crosstalk mechanism of Toll-like receptors in gingival overgrowth (Review)

“…This antibody remains in the preclinical developmental stage and has some potential indications including rheumatoid arthritis, asthma, acute lung injury and acute respiratory distress syndrome (95). AV411 is another TLR-4-targeted antagonist that has potential utility for the treatment of neurological indications (96). In addition to antibodies, a synthetic analog of lipid A eritoran is targeted TLR-4, which inhibited the production of LPS-induced TNF-α and IL-6 (97,98).…”

Medication-overuse headache and opioid-induced hyperalgesia: A review of mechanisms, a neuroimmune hypothesis and a novel approach to treatment

“…Ibudilast, a relatively non-selective phosphodiesterase inhibitor that has been licensed for more than 20 years in Japan for the treatment of asthma, 140 may be a more promising treatment option for opioid overuse headache. In recent times it has been found to have glial attenuating properties, in particular the ability to inhibit TLR-4 signalling 117 and, unlike minocycline, it is effective in reversing allodynia when given after the glial activating stimulus.…”