# AOD-9604 Dosage Research — Doses, routes, and PK from the published record > A research-context review of every dose and route that has appeared in AOD-9604 studies: preclinical rodent (500 μg/kg oral, IV, IP), Phase I IV escalation, Phase II oral, intra-articular rabbit OA, and the GRAS nutraceutical level. Not a dosing recommendation. An index of the doses and routes that have appeared in published AOD-9604 work — preclinical to Phase IIb to the GRAS nutraceutical level. No human regimen is recommended. ## How to read this exhibit AOD-9604 has no approved human label and no validated clinical dosing protocol. The obesity development programme closed in 2007 after the Phase IIb pivotal failed; the December 2024 FDA PCAC vote closed the 503A pharmacy-compounding route; and the cartilage-repair work never reached a registered human trial. What follows is therefore a strict research-context index — every numeric value is a description of what an investigator administered in a published study, with the citation attached. The record covers preclinical rodent doses (oral, intraperitoneal, continuous infusion), Phase I intravenous escalation in healthy volunteers, oral Phase II doses across the six-trial METAOD programme, the intra-articular rabbit osteoarthritis dose, and the GRAS nutraceutical level. No human protocol is suggested, and the doses are not comparable across species without allometric context. ## How this page is framed AOD-9604 is not an approved drug in any major jurisdiction. The obesity programme was discontinued in 2007 after the Phase IIb pivotal failed, the December 2024 FDA PCAC vote effectively closed the 503A pharmacy-compounding route in the U.S., and the WADA Prohibited List places the peptide in Section S2 (Peptide Hormones, Growth Factors, Related Substances and Mimetics) for athletes subject to the Code [5][14][16]. There is no approved human label to cite, no titration schedule that has been validated to a primary endpoint, and no compounding-pharmacy SOP that can be quoted as professional practice. What follows is therefore strictly a research-context index of the doses and routes that have actually been published — not a dosing recommendation, not a protocol, and not a guide. Every numeric value below is a description of what an investigator administered in a peer-reviewed study, with the citation attached. ## Preclinical: rodent doses across three principal study designs The foundational anti-obesity preclinical dose was 500 μg/kg/day oral AOD-9604 in genetically obese Zucker rats for 19 days, which produced a >50% reduction in body-weight gain (15.8 ± 0.6 g vs 35.6 ± 0.8 g) compared with vehicle controls [1]. This is the dose that anchors the preclinical-to-clinical translation argument and is the most-cited value in the popular literature about AOD-9604, although it is a rodent dose by weight and should not be casually allometrically scaled to humans. The ob/ob mouse studies (Heffernan 2001, Int J Obesity) used 14-day continuous subcutaneous infusion delivered through implanted mini-osmotic pumps rather than discrete daily doses — a methodological choice that maximises exposure homogeneity in mechanistic studies but bears no resemblance to any plausible human protocol [2]. The β3-AR knockout work (Heffernan 2001, Endocrinology) used variable intraperitoneal dosing across both acute and 14-day chronic paradigms in obese C57BL/6J mice and lean controls [3]. The chronic-toxicology studies that anchored the safety case used much higher repeat doses than the efficacy studies. The 6-month rat study established a no-observed-adverse-effect level (NOAEL) of 100 mg/kg/day oral, and a parallel 9-month cynomolgus monkey study established a NOAEL of 50 mg/kg/day [7]. Genotoxicity panels — Ames bacterial reverse-mutation, CHO chromosomal aberration, and mouse bone-marrow micronucleus — were all negative [7]. ## The cartilage-repair preclinical dose The Kwon & Park (2015) rabbit knee-osteoarthritis study used 0.25 mg AOD-9604 in a 0.6 mL volume per injection, delivered intra-articularly under ultrasound guidance, weekly for four to seven weeks [9]. The combination arm added 6 mg hyaluronic acid to the same intra-articular volume. This is the only published in-vivo dose for an intra-articular indication, and it is the dose that the 2024 Cartilage review cites when AOD-9604 appears in chondrogenic-peptide summary tables [9][10]. No equivalent human intra-articular dose has been studied in a registered trial. ## The human Phase I/II programme: IV escalation through to the oral pivotal The Metabolic Pharmaceuticals programme covered both IV and oral administration. Phase I IV dose-escalation in the early METAOD studies tested single intravenous doses of 25, 50, 100, 200, and 400 μg/kg in healthy volunteers, with pharmacokinetic and tolerability endpoints [6]. The Phase I to Phase IIa oral progression climbed from 0.25 mg through 54 mg daily across studies METAOD003 (single oral dose), METAOD004 (7-day oral repeat), and METAOD005 (12-week dose-finding at 1, 5, 10, 20, and 30 mg daily, n=300) [4][6]. Mild gastrointestinal complaints were associated with the higher oral arms (≥54 mg); the lower oral arms were not distinguishable from placebo on tolerability [6]. The Phase IIb pivotal trial METAOD006 narrowed to three oral doses — 0.25, 0.5, and 1 mg daily — for 24 weeks across 502 obese adults at 16 Australian sites [5]. The dose-narrowing strategy reflected the 12-week Phase IIb dose-finding result, in which the 1 mg arm had outperformed the higher doses on the 12-week weight-loss endpoint [4]. The 24-week pivotal did not separate from placebo by a statistically significant margin at any of those three doses on its primary endpoint, and Metabolic Pharmaceuticals halted the obesity programme in February 2007 [5]. ## The GRAS nutraceutical use level Outside the failed obesity programme and the closed compounding pathway, AOD-9604 has a U.S. self-affirmed GRAS designation for use as an ingredient in food, beverages, and dietary supplements at approximately 1 mg per serving [15]. This is two orders of magnitude below the highest oral doses tested in the Phase II clinical programme, and it is a food-ingredient regulatory status rather than a drug approval. The GRAS dose level is supported by the chronic-toxicology NOAELs and by the human safety pool from the Phase I/II programme, but it does not transfer upward — the GRAS conclusion at ~1 mg/serving oral is not a safety endorsement for injectable use, compounded preparations, or multi-milligram daily clinical doses [15]. ## Pharmacokinetics that constrain any dosing discussion The pharmacokinetic profile is one of the more constraining elements of the AOD-9604 story. Plasma half-life is approximately 3-4 minutes after IV administration in pigs, with the intact molecule effectively gone from circulation roughly 56 minutes after an IV bolus [8]. Rapid sequential N-terminal proteolysis is the principal metabolic pathway, producing -1aa, -2aa, and -3aa degradation fragments [8]. Oral bioavailability in rats was reported at approximately 40%, which supported the choice of oral capsule format for the human METAOD003-006 programme but did not, in the event, translate into clinical efficacy at the 24-week endpoint [5][8]. The disulfide bridge between the two cysteines lends the lyophilised peptide reasonable stability in dry form. Plasma stability, by contrast, is short — hence the short half-life and the requirement for chronic dosing in the rodent efficacy studies that established the original phenotype [8]. None of these PK observations alter the regulatory picture; they are presented here as descriptive context for the dosing record above. ## Routes that have appeared in the literature For completeness, the routes of administration that have appeared in published AOD-9604 work are: oral (the primary route in the Metabolic Pharmaceuticals human programme and the GRAS nutraceutical use case), intravenous (Phase I dose-escalation and PK studies in pigs and humans), intraperitoneal (rodent mechanistic studies, especially the β3-AR knockout work), subcutaneous infusion (the ob/ob mouse mini-osmotic-pump studies), intra-articular (the rabbit knee-OA model), and topical / nutraceutical matrices (downstream GRAS use cases) [1][2][3][6][8][9][15]. Subcutaneous bolus injection is the route most associated with online research-peptide marketing; it does not appear as a primary route in the foundational published programme, and there is no validated human subcutaneous bolus PK or efficacy dataset for AOD-9604. --- An indexed review of the published record — not a clinic, not a vendor, not a recommendation.