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

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT center dot Ibudilast is an oral drug approved in Asia for asthma. center dot Tolerability of 10-mg regimens has been described previously. center dot Published pharmacokinetics (PK) are limited: single or 7-day repeat oral administration of 10 mg in healthy male Asian volunteers. WHAT THIS STUDY ADDS center dot 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. center dot Higher-dose regimens are relevant for testing in new neurological indications. center dot LC-MS/MS analytics for quantification of plasma and urine levels of ibudilast parent and its primary metabolite (6,7-dihydrodiol-ibudilast). To investigate the safety, tolerability and pharmacokinetics (PK) of ibudilast after a single-dose and a multiple-dose regimen. Healthy 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. Ibudilast 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 T-max was 4-6 h. Mean (SD) steady-state plasma C-max and AUC(0-24) 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. Ibudilast 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.