PII-122 - INCREASED DOSE CORRECTED AUC FOLLOWING SLOW SUBCUTANEOUS, INTRAMUSCULAR AND ORAL VERSUS INTRAVENOUS BOLUS HUMAN DRUG DOSING AND ITS POTENTIAL FOR INCREASED DOSE CORRECTED PHARMACODYNAMIC EFFECTS.

L. Benet¹, J. Sodhi^1,2, Y. Xiang³, V. Tiitto¹; ¹University of California, San Francisco, San Francisco, CA, USA, ²Department of Drug Metabolism and Pharmacokinetics. Septerna., South San Francisco, CA, USA, ³University of California, San Francisco, San Francisco, CA, USA.

Background: Benet and Sodhi (2023) recently demonstrated that slow absorption following subcutaneous (SubQ), intramuscular (IM) and oral (PO) dosing, as compared to an iv bolus dose, can result in increased dose corrected area under the systemic concentration-time curve (AUC). This is the explantion for systemic concentration measures leading to a calculated bioavailability (Fsys) that exceeds 100%, which is greater than Furine for the same study. We documented multiple occasions where published literature is consistent with this analysis.

Methods: We conducted a literature search, using PubMed, for drugs where measures of F in humans were available for SubQ, IM or PO dosing together with iv bolus dosing or where F was measured using both AUC and urinary excretion data.

Results: Published data for 22 drug studies in humans (3 IM dosing, 5 SubQ dosing and 15 PO dosing) exhibit increased dose corrected systemic AUC that exceeds either 1.0 or an Furine measure. In 8 of these 22 studies, statistically significant differences were found in Fsys being greater than 1.0 and/or renal clearance (CLR) being significantly lower for non-parenteral compared to iv bolus dosing. An example of each dosing route is detailed here. Teicoplanin, 100 mg IM and iv doses in 10 healthy subjects, the 90% confidence interval for the mean 1.12 Fsys ratio is 1.08-1.16; 1-Deamino-8-arginine vasopressin 2 mg SubQ and iv doses in 8 healthy subjects where CLR following SubQ is 76% of CLR following iv, p < 0.05; Cilazapril 2.5 mg PO and iv doses in 12 healthy subjects, where measures of active cilazaprilat yielded Fsys = 0.775 ± 0.101 and Furine = 0.571 ± 0.103, p < 0.0001. However, in none of the remaining 14 studies, due to small subject numbers, were authors able to show that differences were or were not significantly different. Since pharmacodynamic (PD) outcomes and clinical response are a result of AUC measures, increased PD vs iv bolus doses was explored initially for cilazapril and semaglutide.

Conclusion: F cannot be determined using systemic concentration measurements for many drugs since AUC reflects not only systemic elimination but also absorption characteristics, potentially giving increased pharmacodynamic effects. Clearance of drug from the absorption site must be significantly greater than clearance following an iv bolus dose for Fsys to be correct.