Ibudilast in healthy volunteers: safety, tolerability and pharmacokinetics with single and multiple doses
P Rolan, JA Gibbons, L He, E Chang… - British journal of …, 2008 - Wiley Online Library
P Rolan, JA Gibbons, L He, E Chang, D Jones, MI Gross, JB Davidson, LM Sanftner…
British journal of clinical pharmacology, 2008•Wiley Online LibraryWHAT 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 (bid) 2‐week regimen in male and female
healthy volunteers.• Higher‐dose regimens are relevant for testing in new neurological …
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 (bid) 2‐week regimen in male and female
healthy volunteers.• Higher‐dose regimens are relevant for testing in new neurological …
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).
AIMS
To investigate the safety, tolerability and pharmacokinetics (PK) of ibudilast after a single‐dose and a multiple‐dose regimen.
METHODS
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.
RESULTS
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 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.
CONCLUSIONS
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.
Wiley Online Library