AOD-9604 and Warfarin Interaction: What Patients and Clinicians Need to Know

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Does AOD-9604 interact with warfarin?

AOD-9604 is not an FDA-approved drug, so it has no prescribing information to set beside warfarin's interaction tables: no interactions section and no warnings section [1][2].

Warfarin is the opposite case. Its label carries a full drug interactions section covering pharmacodynamic and pharmacokinetic mechanisms, with named examples [3].

What AOD-9604 is

AOD-9604 is a 16-amino-acid fragment of human growth hormone: hGH amino acids 177 to 191 with an extra tyrosine at the N-terminus [5]. It is not full-length growth hormone, and preclinical work found no binding to the growth hormone receptor [2]. It was developed as an anti-obesity candidate; phase IIa trials were underway by February 2002 and it never reached approval [1][2].

The main human obesity study was a 24-week trial of oral AOD9604 (502 randomized). It failed to show a significant benefit on the primary weight-loss endpoint, and it is described as sponsor-reported phase 2 data rather than a peer-reviewed trial paper [2].

FDA's list of bulk substances that may present significant safety risks in compounding places AOD-9604 in its 'nominated but withdrawn' table. The concerns FDA states there include immunogenicity risk for certain routes of administration, no or only limited safety information, and serious adverse events that may be associated with AOD-9604, though causality is not clear [4]. Removal from category 2 was not a finding that it is safe [4]. Compounded drugs are not FDA-approved, and FDA does not review their safety, effectiveness or quality before marketing [6].

How warfarin is cleared

Warfarin is a racemic mixture. The more potent S-enantiomer, 2 to 5 times the activity of R-warfarin, is cleared mainly by CYP2C9; R-warfarin by CYP1A2 and CYP3A4 [3]. The label states that CYP2C9, 1A2 or 3A4 inhibitors can increase warfarin's effect and raise INR by increasing warfarin exposure, and that inducers can decrease it [3]. FDA's drug-interaction table lists S-warfarin as a moderately sensitive CYP2C9 index substrate [7].

AOD-9604 does not appear among the label's example inhibitors or inducers, nor in its table of drugs that increase bleeding risk. The label says its CYP list should not be considered all-inclusive, so that absence does not show AOD-9604 has no effect [3].

What the warfarin label says to watch for

The boxed warning is bleeding: warfarin can cause major or fatal bleeding, INR must be monitored regularly in all treated patients, and drugs, dietary changes and other factors affect INR levels [3]. Bleeding is more likely in the first month, and risk factors named in the label include INR above 4.0, age 65 or older, highly variable INRs, prior GI bleeding, hypertension, anemia, malignancy, renal impairment and certain concomitant drugs [3]. An INR above 4.0 appears to give no added benefit in most patients and is linked to a higher risk of bleeding [3].

The label also directs more frequent INR monitoring when starting or stopping other drugs, including botanicals, or when their doses change [3].