Research Article| Volume 36, ISSUE 2, P211-224, February 01, 2014

Tolerability and Pharmacokinetic Properties of Ondansetron Administered Subcutaneously With Recombinant Human Hyaluronidase in Minipigs and Healthy Volunteers



      Subcutaneous ondansetron facilitated by recombinant human hyaluronidase PH20 (rHuPH20) is an alternative for treating nausea/vomiting in patients who cannot receive ondansetron by other routes of administration.


      Based on preclinical results in minipigs, a Phase I study was designed to assess the tolerability and pharmacokinetic properties of subcutaneous ondansetron + rHuPH20 compared with intramuscular, intravenous, or oral ondansetron monotherapy in healthy volunteers.


      In a crossover design, 3 minipigs were dosed with subcutaneous ondansetron 0.08 mg/kg + rHuPH20, or as intramuscular or intravenous monotherapy, for the evaluation of plasma ondansetron concentrations and local tolerability. In a randomized, open-label, 4-way crossover study, subjects received a randomized sequence of SC ondansetron 4 mg + rHuPH20, or ondansetron monotherapy IM (4 mg), IV (4 mg), or PO (8 mg), over 4 daily visits. Study participants included healthy volunteers aged 19 to 65 years with adequate venous access in both upper extremities and no history of QT-interval prolongation. Primary tolerability end points (administration-site observations, systemic adverse events [AEs], and subject-assessed pain) were assessed, and pharmacokinetic parameters (AUC, Cmax, Tmax, t½) were computed to compare relative rate and extent of systemic exposure. Results were described using summary statistics, and bioequivalence was determined with a linear mixed-effects model.


      In the preclinical study, no adverse events or significant local reactions were observed. The Cmax (45.8 ng/mL at 0.08 hour) with subcutaneous administration + rHuPH20 was 83% greater and was achieved 68% faster than with intramuscular administration (Cmax = 25 ng/mL at 0.25 hour). In the clinical study, a total of 12 subjects (7 women, 5 men; white majority; mean age, 44.8) were randomized. The majority of AEs were at the injection site, mild in severity, and transient. After subcutaneous administration of ondansetron + rHuPH20, geometric mean Cmax was 35% higher than with intramuscular ondansetron, 43% lower than with intravenous ondansetron, and 126% higher than with oral ondansetron (corrected for dose). Bioequivalence tests demonstrated that systemic exposure after subcutaneous administration was similar to that after intramuscular or intravenous administration and significantly greater than that after oral administration.


      Subcutaneous ondansetron + rHuPH20 was generally well-tolerated. Subcutaneous dosing resulted in an extent of systemic exposure similar to that with intramuscular or intravenous dosing and greater than that with oral administration, and may be an option for clinical administration of ondansetron. identifier: NCT01572012.

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        • Dychter S.S.
        • Gold D.A.
        • Haller M.F.
        Subcutaneous drug delivery: a route to increased safety, patient satisfaction, and reduced costs.
        J Infus Nurs. 2012; 35: 154-160
        • Nicoll L.H.
        • Hesby A.
        Intramuscular injection: an integrative research review and guideline for evidence-based practice.
        Appl Nurs Res. 2002; 15: 149-162
        • Rodger M.A.
        • King L.
        Drawing up and administering intramuscular injections: a review of the literature.
        J Adv Nurs. 2000; 31: 574-582
        • Dychter S.S.
        • Gold D.A.
        • Carson D.
        • Haller M.
        Intravenous therapy: a review of complications and economic considerations of peripheral access.
        J Infus Nurs. 2012; 35: 84-91
        • Jain S.
        • Mansfield B.
        • Wilcox M.H.
        Subcutaneous fluid administration: better than the intravenous approach?.
        J Hosp Infect. 1999; 41: 269-272
        • Bookbinder L.H.
        • Hofer A.
        • Haller M.F.
        • et al.
        A recombinant human enzyme for enhanced interstitial transport of therapeutics.
        J Control Release. 2006; 114: 230-241
      1. Hylenex Recombinant (hyaluronidase human injection) [prescribing information]. San Diego, Calif: Halozyme Therapeutics, Inc; 2012.

        • Wasserman R.L.
        • Melamed I.
        • Stein M.R.
        • et al.
        • for the IGSC, 10% With rHuPH20 Study Group
        Recombinant human hyaluronidase-facilitated subcutaneous infusion of human immunoglobulins for primary immunodeficiency.
        J Allergy Clin Immunol. 2012; 130: 951-957
        • Klauser C.K.
        • Fox N.S.
        • Istwan N.
        • et al.
        Treatment of severe nausea and vomiting of pregnancy with subcutaneous medications.
        Am J Perinatol. 2011; 28: 715-722
        • Lombardi D.G.
        • Istwan N.B.
        • Rhea D.J.
        • et al.
        Measuring outpatient outcomes of emesis and nausea management in pregnant women.
        Manag Care. 2004; 3: 48-52
        • Macario A.
        • Ronquillo R.B.
        • Brose W.G.
        • Gaeta R.R.
        Improved outcome with chronic subcutaneous infusion of ondansetron for intractable nausea and vomiting.
        Anesth Analg. 1996; 83 (Letter): 194-195
        • Mulvenna P.M.
        • Regnard C.F.
        Subcutaneous ondansetron.
        Lancet. 1992; 339: 1059
        • Kang D.W.
        • Oh D.A.
        • Fu G.Y.
        • et al.
        Porcine model to evaluate local tissue tolerability associated with subcutaneous delivery of protein.
        J Pharmacol Toxicol Methods. 2013; 67: 140-147
        • Zheng Y.
        • Tesar D.B.
        • Benincosa L.
        • et al.
        Minipig as a potential translatable model for monoclonal antibody pharmacokinetics after intravenous and subcutaneous administration.
        MAbs. 2012 Mar 1; ([Epub ahead of print])
        • US Dept of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER)
        . Guidance for Industry. Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers.
        CDER, Rockville, Md2005
        • Ogu C.C.
        • Maxa J.L.
        Drug interactions due to cytochrome P450.
        Proc (Bayl Univ Med Cent). 2000; 13: 421-423
        • Bozigian H.P.
        • Pritchard J.F.
        • Gooding A.E.
        • Pakes G.E.
        Ondansetron absorption in adults: effect of dosage form, food, and antacids.
        J Pharm Sci. 1994; 83: 1011-1013
        • Hsyu P.-H.
        • Pritchard J.F.
        • Bozigian H.P.
        • et al.
        Comparison of the pharmacokinetics of an ondansetron solution (8 mg) when administered intravenously, orally, to the colon, and to the rectum.
        Pharm Res. 1994; 11: 156-159
        • Roila F.
        • Del Favero A.
        Ondansetron clinical pharmacokinetics.
        Clin Pharmacokinet. 1995; 29: 95-109
        • Pritchard J.F.
        • Bryson J.C.
        • Kernodle A.E.
        • et al.
        Age and gender effects on ondansetron pharmacokinetics: evaluation of healthy aged volunteers.
        Clin Pharmacol Ther. 1992; 51: 51-55
        • O’Keeffe S.T.
        • Lavan J.N.
        Subcutaneous fluids in elderly hospital patients with cognitive impairment.
        Gerontology. 1996; 42: 36-39
        • Yang S.H.
        • Lee M.G.
        Dose-independent pharmacokinetics of ondansetron in rats: contribution of hepatic and intestinal first-pass effects to low bioavailability.
        Biopharm Drug Dispos. 2008; 29: 414-426