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.

Abstract

Since 1955, the recommended strategy for rheumatic heart disease (RHD) secondary prophylaxis has been benzathine penicillin G [BPG; 1.2 MU (900 mg)] injections administered intramuscularly every 4 weeks. 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 (t1/2 = 12 days) absorption pharmacokinetic model. In simulations, time above the conventionally accepted target concentration of 20 ng/mL (0.02 µg/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.

• Authors: Joseph Kado, Sam Salman, Thel K Hla, Stephanie Enkel, Robert Henderson, Robert M Hand, Adam Hort, Madhu Page-Sharp, Kevin Batty, Brioni R Moore, Julie Bennett, Anneka Anderson, Jonathan Carapetis, Laurens Manning
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 67 Issue 12 Pg. e0096223 (12 14 2023) ISSN: 1098-6596 [Electronic] United States
• PMID: 37971244 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Penicillin G Benzathine

Topics

• Adult
• Humans
• Anti-Bacterial Agents (pharmacokinetics)
• Infusions, Subcutaneous
• Pain (drug therapy)
• Penicillin G Benzathine (adverse effects)
• Rheumatic Fever (prevention & control)
• Rheumatic Heart Disease (drug therapy, prevention & control)