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The Pharmacokinetics and Pharmacodynamics of a Human Relaxin in the Mouse Pubic Symphysis Bioassay

Department of Pharmacological Sciences, Genentech, Inc South San Francisco, California 94080

Address requests for reprints to: Bobbe L. Ferraiolo, Ph.D., Genentech, Inc., 460 Point San Bruno Boulevard, South San Francisco, California 94080.

Abstract

The effects of dose, route, regimen, and the presence or absence of a repository vehicle [benzopurpurine (BPP)] were determined for a human relaxin (hRlx) in the mouse pubic symphysis bioassay. Administration of 88 µg/kg hRlx sc in 1% BPP resulted in delayed, prolonged absorption. Although peak hRlx concentrations were lower, serum concentrations remained elevated longer in the presence of BPP compared to a single sc administration of hRlx in saline at the same dose. The bioavailabilities with and without BPP were similar (109 and 96%, respectively). While the pharmacodynamic effect (i.e. lengthening of the pubic ligament in estrogen-primed mice) was approximately maximum at 88 µg/kg hRlx sc with BPP, single sc administration of hRlx without BPP up to 264 had no effect on pubic ligament length. In the absence of the BPP vehicle, manipulation of the regimen (e.g. multiple sc doses) showed that emulation of the serum concentration-time profile observed for hRlx in the presence of BPP resulted in similar pharmacodynamic effects.

It appears that BPP delays the absorption of hRlx after sc administration, resulting in prolonged, elevated hRlx serum concentrations. hRlx has been shown to be effective in this model without BPP if it is administered by a multidose sc schedule. As has been observed with other protein therapeutics, the dosage regimen employed for hRlx delivery appears to be an important determinant of the expression of its pharmacodynamic effects.

Received June 16, 1989.

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