Author’s Reply to Srinivas: “A Single Dose-Escalation Study to Evaluate the Safety and Pharmacokinetics of Orally Administered Des-Aspartate Angiotensin I in Healthy Subjects”

Section 2.6 of the article by Lee et al. [2] describes the rationale for the sampling time points, viz: ‘‘Serial venous blood samplings (10 ml) for pharmacokinetic analyses were carried out on all subjects at 0, 0.25, 0.5, 1, 2, 3, 4, 5, 6 and 12 h post study drug administration. We anticipated that the range of sampling time points would cover the duration of early blood pressure response to intravenous administration of DAA-I observed in human subjects [19], and the detection of chromatographic []C-DAA-I-like peak at 4 h after []CDAA-I was orally administered to rats during the preclinical toxicology studies.’’ In the human study reported by Kono et al. [3], the increase in blood pressure to an intravenous infusion of des-aspartate-angiotensin I (DAA-I) was caused by angiotensin III, the immediate metabolite of DAA-I. The increase occurred within 2 min of the intravenous administration, indicating that DAA-I was rapidly degraded in the systemic circulation. When [C-Val]-DAA-I was incubated in a plasma sample, the degradation to angiotensin III, angiotensin IV and smaller fragments was a seamless process that lasted less than 3 min (unpublished data from a preclinical toxicology study). The oral bioavailability of DAA-I has been estimated to be 0.06 [4]. This low bioavailability together with its rapid degradation in the blood would indicate that orally administered DAA-I, like many endogenously produced compounds, does not have a canonical blood profile. Blood samplings at intervals of 2–3 min in the first 30 min post-DAA-I oral administration, as suggested by Dr. Srinivas, would approximate a continuous sampling, which is logistically difficult to execute and psychologically unfavourable to the volunteers. It also assumes that the peak plasma would be within the first 30 min post-DAA-I administration, which is not supported by preclinical data.