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PHARMACOKINETICS

Pharmacokinetics of PC-SOD, a Lecithinized Recombinant Superoxide Dismutase, After Single- and Multiple-Dose Administration to Healthy Japanese and Caucasian Volunteers

Jun Suzuki, PhD, Freerk Broeyer, MD, Adam Cohen, MD, PhD, Masato Takebe, BSc, Jacobus Burggraaf, MD, PhD and Yutaka Mizushima, MD, PhD

From LTT Bio-Pharma Co, Ltd, Atago, Minato-ku, Tokyo 105-6201, Japan (Dr Suzuki and Dr Mizushima); Centre for Human Drug Research, Leiden, The Netherlands (Dr Broeyer, Dr Cohen, Dr Burggraaf); Institute for Drug Development, Inc, Minami-azabu, Minato-ku, Tokyo, Japan (Mr Takebe); and DDS Institute, Jikei University, Nishi-shinbashi, Minato-ku, Tokyo, Japan (Dr Suzuki and Dr Mizushima).

To study the pharmacokinetics of single increasing intravenous doses (40-160 mg) and repeated doses (80 mg for 7 days) of lecithinized superoxide dismutase (PC-SOD) in Japanese volunteers and to compare the pharmacokinetics of PC-SOD between Caucasians and Japanese. The Japanese study consisted of 2 parts: a single-dose, open-label, dose-escalation part and a multiple-dose, single-blind, placebo-controlled part. The pharmacokinetics of PC-SOD were determined using noncompartmental and compartmental methods. Pharmacokinetic data from a study with PC-SOD in Caucasians were reanalyzed using the same methodology. The mean (SD) terminal half-life of PC-SOD in Japanese subjects was 25 (4) hours for the 40-mg and 80-mg doses and 31 (15) hours for the 160-mg dose. There was nonlinearity between dose-normalized Cmax and clearance (P values .002 and .022). After multiple dosing, steady state was reached after 5 days. The observed accumulation ratio was 2.6 (0.5). The pharmacokinetics of the single 80-mg dose were similar for Japanese and Caucasians. The pharmacokinetics of PC-SOD was shown to be nonlinear with dose, which may be attributable to a saturable clearing mechanism. The relatively long half-life of PC-SOD (>24 hours) suggests that it is worthwhile to study the compound as a protective agent in clinical conditions with free radical overload.

Key Words: Pharmacokinetics • superoxide dismutase • free radicals • oxidative stress • PC-SOD

Address for correspondence: Jun Suzuki, PhD, R&D Division, LTT Bio-Pharma Co, Ltd, Tokyo 105-6201, Japan.






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