PMID- 24486335 OWN - NLM STAT- MEDLINE DCOM- 20141028 LR - 20220331 IS - 1879-114X (Electronic) IS - 0149-2918 (Linking) VI - 36 IP - 2 DP - 2014 Feb 1 TI - Tolerability and pharmacokinetic properties of ondansetron administered subcutaneously with recombinant human hyaluronidase in minipigs and healthy volunteers. PG - 211-24 LID - S0149-2918(13)01157-0 [pii] LID - 10.1016/j.clinthera.2013.12.013 [doi] AB - 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, t(1/2)) 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. CI - Copyright (c) 2014 Elsevier HS Journals, Inc. All rights reserved. FAU - Dychter, Samuel S AU - Dychter SS AD - Halozyme Therapeutics, Inc, San Diego, California. Electronic address: sdychter@halozyme.com. FAU - Harrigan, Rena AU - Harrigan R AD - Halozyme Therapeutics, Inc, San Diego, California. FAU - Bahn, Jesse D AU - Bahn JD AD - Halozyme Therapeutics, Inc, San Diego, California. FAU - Printz, Marie A AU - Printz MA AD - Halozyme Therapeutics, Inc, San Diego, California. FAU - Sugarman, Barry J AU - Sugarman BJ AD - Halozyme Therapeutics, Inc, San Diego, California. FAU - DeNoia, Emanuel AU - DeNoia E AD - ICON Development Solutions, San Antonio, Texas. FAU - Haughey, David B AU - Haughey DB AD - ICON Development Solutions, Whitesboro, New York. FAU - Fellows, Daniel AU - Fellows D AD - ICON Development Solutions, Whitesboro, New York. FAU - Maneval, Daniel C AU - Maneval DC AD - Halozyme Therapeutics, Inc, San Diego, California. LA - eng SI - ClinicalTrials.gov/NCT01572012 PT - Clinical Trial, Phase I PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20140131 PL - United States TA - Clin Ther JT - Clinical therapeutics JID - 7706726 RN - 0 (Recombinant Proteins) RN - 4AF302ESOS (Ondansetron) RN - EC 3.2.1.35 (Hyaluronoglucosaminidase) SB - IM MH - Administration, Oral MH - Adult MH - Aged MH - Animals MH - Cross-Over Studies MH - Drug Therapy, Combination MH - Female MH - Humans MH - Hyaluronoglucosaminidase/administration & dosage/*adverse effects/*pharmacokinetics MH - Injections, Intramuscular MH - Injections, Intravenous MH - Injections, Subcutaneous MH - Male MH - Middle Aged MH - Ondansetron/administration & dosage/*adverse effects/*pharmacokinetics MH - Recombinant Proteins/administration & dosage/*adverse effects/*pharmacokinetics MH - Swine MH - Swine, Miniature MH - Therapeutic Equivalency OTO - NOTNLM OT - ondansetron OT - pharmacokinetic OT - recombinant human hyaluronidase OT - safety OT - subcutaneous EDAT- 2014/02/04 06:00 MHDA- 2014/10/29 06:00 CRDT- 2014/02/04 06:00 PHST- 2013/10/30 00:00 [received] PHST- 2013/12/02 00:00 [revised] PHST- 2013/12/20 00:00 [accepted] PHST- 2014/02/04 06:00 [entrez] PHST- 2014/02/04 06:00 [pubmed] PHST- 2014/10/29 06:00 [medline] AID - S0149-2918(13)01157-0 [pii] AID - 10.1016/j.clinthera.2013.12.013 [doi] PST - ppublish SO - Clin Ther. 2014 Feb 1;36(2):211-24. doi: 10.1016/j.clinthera.2013.12.013. Epub 2014 Jan 31.