Abstract
Background
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.
Objective
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.
Methods
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.
Results
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.
Conclusions
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. ClinicalTrials.gov identifier: NCT01572012.
Key words
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Clinical TherapeuticsAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Subcutaneous drug delivery: a route to increased safety, patient satisfaction, and reduced costs.J Infus Nurs. 2012; 35: 154-160
- Intramuscular injection: an integrative research review and guideline for evidence-based practice.Appl Nurs Res. 2002; 15: 149-162
- Drawing up and administering intramuscular injections: a review of the literature.J Adv Nurs. 2000; 31: 574-582
- Intravenous therapy: a review of complications and economic considerations of peripheral access.J Infus Nurs. 2012; 35: 84-91
- Subcutaneous fluid administration: better than the intravenous approach?.J Hosp Infect. 1999; 41: 269-272
- A recombinant human enzyme for enhanced interstitial transport of therapeutics.J Control Release. 2006; 114: 230-241
Hylenex Recombinant (hyaluronidase human injection) [prescribing information]. San Diego, Calif: Halozyme Therapeutics, Inc; 2012.
- Recombinant human hyaluronidase-facilitated subcutaneous infusion of human immunoglobulins for primary immunodeficiency.J Allergy Clin Immunol. 2012; 130: 951-957
- Treatment of severe nausea and vomiting of pregnancy with subcutaneous medications.Am J Perinatol. 2011; 28: 715-722
- Measuring outpatient outcomes of emesis and nausea management in pregnant women.Manag Care. 2004; 3: 48-52
- Improved outcome with chronic subcutaneous infusion of ondansetron for intractable nausea and vomiting.Anesth Analg. 1996; 83 (Letter): 194-195
- Subcutaneous ondansetron.Lancet. 1992; 339: 1059
- Porcine model to evaluate local tissue tolerability associated with subcutaneous delivery of protein.J Pharmacol Toxicol Methods. 2013; 67: 140-147
- Minipig as a potential translatable model for monoclonal antibody pharmacokinetics after intravenous and subcutaneous administration.MAbs. 2012 Mar 1; ([Epub ahead of print])
- . Guidance for Industry. Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers.CDER, Rockville, Md2005
- Drug interactions due to cytochrome P450.Proc (Bayl Univ Med Cent). 2000; 13: 421-423
- Ondansetron absorption in adults: effect of dosage form, food, and antacids.J Pharm Sci. 1994; 83: 1011-1013
- 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
- Ondansetron clinical pharmacokinetics.Clin Pharmacokinet. 1995; 29: 95-109
- Age and gender effects on ondansetron pharmacokinetics: evaluation of healthy aged volunteers.Clin Pharmacol Ther. 1992; 51: 51-55
- Subcutaneous fluids in elderly hospital patients with cognitive impairment.Gerontology. 1996; 42: 36-39
- 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
Article info
Publication history
Published online: February 03, 2014
Accepted:
December 20,
2013
Identification
Copyright
© 2014 Elsevier HS Journals, Inc. Published by Elsevier Inc. All rights reserved.
