Supersaturatable self‐emulsifying drug delivery systems (S‐SEDDS) were explored to improve the oral absorption of AMG 517, a poorly water‐soluble drug candidate. In vitro characterizations indicate the level of Tween 80 in the formulation dictates the initial degree of supersaturation of AMG 517, and, therefore, its precipitation kinetics. The presence of a small amount of cellulosic polymer (e.g., HPMC) effectively sustained a metastable supersaturated state by retarding precipitation kinetics. Precipitates from the S‐SEDDS formulations (with HPMC) from in vitro test media were identified as amorphous AMG 517 while crystalline AMG 517 precipitates were found when either HPMC was absent or PVP was present in the formulation. In vivo pharmacokinetic study in Cynomolgus monkeys reveals that the S‐SEDDS formulation showed ∼30% higher mean Cmax and comparable exposure (AUC) of AMG 517 as compared to an aqueous suspension at a dose of 12.5 mg. The rapid absorption characteristics of AMG 517 from the S‐SEDDS formulation as evidenced by high Cmax and short Tmax are attributed to a high free drug concentration in vivo, implying a supersaturated state. This case demonstrates that S‐SEDDS technology is an effective approach for improving the rate and extent of absorption of poorly soluble drugs. © 2008 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:516–528, 2009