This study will evaluate single IV doses of Vestipitant (GW597599) compared to 4 mg IV ondansetron for treating breakthrough postoperative nausea and vomiting (PONV) after failure of PONV prophylaxis with a regimen that includes 4 mg IV ondansetron.

Inclusion Criteria:

• Male or Female post-operative surgical subjects between the ages of 18-75 years.
• Female subject is of non-childbearing potential or of child-bearing potential and agrees to use specified contraception methods.
• Has 3 or more of the following independent risk factors for PONV: female gender; non-smoker; history of PONV or motion sickness; or planned post- operative opioids.
• Has received one dose of ondansetron as part of a PONV prophylaxis regimen for the surgical procedure.
• Has received general anesthesia.
• Meets ASA Physical Status Classification of 1 or 2 without an "E" modifier preoperatively on the day of surgery and has hematology and blood chemistry values within acceptable limits for surgery.
• Is capable of giving written informed consent.
• Experiences breakthrough PONV defined as: post-operative nausea of ≥ 7 on the Nausea Numeric Rating Scale; nausea resulting in a subject request for an anti-emetic; or an episode of emesis or retching.

Exclusion Criteria:

• A history of HIV.
• A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of Screening.
• An ALT or AST >2.5 x ULN at Screening.
• Pregnant or lactating females.
• The subject is scheduled to undergo a laparoscopic biopsy only.
• The subject has a history of or is scheduled to undergo cardiac/cardiothoracic surgery.
• The subject is scheduled to receive neuraxial anesthesia(e.g., epidural, spinal, or caudal anesthesia)or total IV anesthesia.
• The subject is scheduled to receive propofol for maintenance of anesthesia (propofol as an induction agent is allowed).
• The subject is scheduled to receive an NK1 inhibitor (aprepitant/fosaprepitant) as part of a PONV prophylaxis regimen for the surgical procedure.
• The subject is scheduled to have gastric contents suctioned continuously during the surgical procedure via a nasogastric tube, or a nasogastric or oral gastric tube during the post-operative period. A single pass at the beginning or at the end of the procedure, and intraoperative gastric suctioning of air, will be permitted.
• The subject received an investigational drug within 30 days or was scheduled to receive any investigational drug in addition to vestipitant during the study period.
• The subject has persistent or recurrent nausea and/or vomiting due to other etiologies, including, but not limited to, gastric outlet obstruction, hypercalcemia, active peptic ulcer, increased intracranial pressure, chemotherapy, or brain metastases.
• The subject received radiation therapy to the abdomen or the pelvis within 7 days prior to receiving study medications and/or received radiation therapy to the abdomen or the pelvis in the evaluation period.
• The subject has a history of wound dehiscence.
• The subject has a history of any other illness which might pose an unacceptable risk by administering study medication.
• The subject has any current or past medical condition (e.g., vagotomy) and/or required medication to treat a condition that could affect the evaluation of the study.
• The subject has a known contraindication or hypersensitivity to ondansetron or ondansetron injection, any scheduled anaesthetic or analgesic agents, vestipitant or any component of the vestipitant formulation including Captisol.
• The subject received medication with known or potential antiemetic activity after the induction of anaesthesia (during the intraoperative or post- operative period) other than the planned Study Treatment.
• Current or planned use of strong or moderate inhibitors of CYP3A within 7 days or inducers of CYP3A within 14 days prior to study medication administration.
• The subject is unwilling or unable to follow the procedures outlined in the protocol.
• The subject is mentally or legally incapacitated.