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Due to dosing frequency, pain, and programmatic challenges, adherence is suboptimal. It has previously been demonstrated that BPG delivered subcutaneously at a standard dose is safe and tolerable and has favorable pharmacokinetics, setting the scene for improved regimens with less frequent administration. The safety, tolerability, and pharmacokinetics of subcutaneous infusions of high-dose BPG were assessed in 24 healthy adult volunteers assigned to receive either 3.6, 7.2, or 10.8 MU (three, six, and nine times the standard dose, respectively) as a single subcutaneous infusion. The delivery of the BPG to the subcutaneous tissue was confirmed with ultrasonography. Safety assessments, pain scores, and penicillin concentrations were measured for 16 weeks post-dose. Subcutaneous infusion of penicillin (SCIP) was generally well tolerated with all participants experiencing transient, mild infusion-site reactions. Prolonged elevated penicillin concentrations were described using a combined zero-order (44 days) and first-order (\n                    <jats:italic>t<\/jats:italic>\n                    <jats:sub>1\/2<\/jats:sub>\n                    = 12 days) absorption pharmacokinetic model. In simulations, time above the conventionally accepted target concentration of 20 ng\/mL (0.02 \u00b5g\/mL) was 57 days for 10.8 MU delivered by subcutaneous infusion every 13 weeks compared with 9 days of every 4-weekly dosing interval for the standard 1.2 MU intramuscular dose (i.e., 63% and 32% of the dosing interval, respectively). High-dose SCIP (BPG) is safe, has acceptable tolerability, and may be suitable for up to 3 monthly dosing intervals for secondary prophylaxis of RHD.\n                  <\/jats:p>","DOI":"10.1128\/aac.00962-23","type":"journal-article","created":{"date-parts":[[2023,11,16]],"date-time":"2023-11-16T09:00:35Z","timestamp":1700125235000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":23,"title":["Subcutaneous infusion of high-dose benzathine penicillin G is safe, tolerable, and suitable for less-frequent dosing for rheumatic heart disease secondary prophylaxis: a phase 1 open-label population pharmacokinetic study"],"prefix":"10.1128","volume":"67","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3121-4397","authenticated-orcid":true,"given":"Joseph","family":"Kado","sequence":"first","affiliation":[{"name":"Wesfarmers Centre for Vaccines and Infectious Diseases, Telethon Kids Institute, University of Western 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