Subcutaneous infusions of benzathine penicillin G (SCIP) in healthy adults
Safety, tolerability and pharmacokinetics of high dose, subcutaneous infusions of benzathine penicillin G (Bicillin® L-A) in healthy adults
Telethon Kids Institute
24 participants
Mar 19, 2021
Interventional
Conditions
Summary
The associated morbidity from rheumatic heart disease (RHD) is the leading driver of cardiovascular inequality for Indigenous Australians. Across the Tasman, its precursor acute rheumatic fever (ARF) and RHD almost exclusively affect Maori and Pacific children and young adults living in socio-economically deprived areas of the North Island of New Zealand. For 70 years, the only proven way to prevent ARF progression has been benzathine penicillin G (BPG), given as a monthly intramuscular (IM) injection. The effectiveness of this approach is limited by pain and the frequency of injection which leads to sub- optimal adherence in these vulnerable groups. There is an urgent need to improve penicillin formulations for all children living with ARF/RHD. Based on a randomised cross-over trial conducted by our team, we hypothesise that BPG could be repurposed as an ‘implant’ if given as a high-dose subcutaneous (SC) infusion of penicillin (SCIP). By providing sustained penicillin concentrations for >3 months, this approach would fulfil the ideal product characteristics for the next generation of long-acting penicillins. This 3-year multiphase program begins with a phase 1 study, assessing the safety, tolerability and pharmacokinetics of SCIP in healthy adults (SCIP-I). If SCIP appears tolerable and provides sustained penicillin concentrations, we will perform an observational study of SCIP in children living with ARF (SCIP-II). Concurrently, we will implement mixed-methods studies to identify acceptability, barriers and benefits of SCIP RHD, both from consumer and health care provider perspectives (SCIP-IIa).
Eligibility
Inclusion Criteria7
- (a) Male and females aged 18 - 65 years at the time of screening.
- (b) BMI between 20kg/m2 and 34.9kg/m2.
- (c) No history of chronic renal impairment or significant liver dysfunction.
- (d) No prior documented allergy to penicillin, cephalosporin antibiotics.
- (e) Participants who are considered likely to adhere to the trial guidelines for the duration of the trial.
- (f) Sign and dated informed consent in accordance with Good Clinical Practice (GCP)/Declaration of Helsinki.
- (g) Participants must be in good state of health in the opinion of the investigator as indicated by a comprehensive clinical assessment (medical history and physical exam) and laboratory investigations (haematology, clinical chemistry, and urinalysis).
Exclusion Criteria19
- (a) Currently taking penicillins or use of any penicillin-based antibiotics from screening through to the final study visit. The use of probenecid, NSAIDs, or other medications which may significantly alter the Bicillin® L-A PK will also not be permitted within 14 days prior to study drug administration until completion of the final follow-up visit. Sporadic NSAID use (<5 occasions) in the 14 days prior to drug administration will be allowed, but the need for ongoing regular NSAIDS will render the person ineligible due to NSAIDS effects on proximal tubular penicillin excretion. Hormonal contraceptives for females and occasional paracetamol and ibuprofen use is permitted while on study.
- (b) Known soy allergy.
- (c) History of adverse drug reaction or hypersensitivity.
- (d) History of seizure disorder
- (e) Receipt of an investigational product within 3 months of Dosing.
- (f) Planned participation in another clinical trial concurrently.
- (g) Pregnant or breastfeeding females.
- (h) Existing dermatological conditions that may affect skin integrity at the site of injection.
- (i) Planned operation/absence from the study site during the duration of the study.
- (j) History within the last 12 months of intramuscular, or subcutaneous injection of the abdominal wall, or history of surgery to the buttocks, abdomen or abdominal wall within the last 12 months.
- (k) History of radiotherapy.
- (l) Use of any prescription medication or over-the-counter medication, herbal products, vitamins or minerals, within 7 days prior to study drug administration until completion of the final follow-up visit, unless in the opinion of the Principal Investigator or delegate the medication will not compromise participant safety or interfere with study procedures or data validity.
- (m) Participants who are smokers must abstain from using tobacco products during the confinement period.
- (n) Laboratory tests that fail to meet the following thresholds: one repeat will be allowed at discretion of the investigator to confirm eligibility.
- i. Haematology: complete blood count (Haemoglobin, total white cell count and platelet count) – parameters within gender-specific reference intervals from PathWest unless deemed not clinically significant by the investigator.
- ii. Clinical chemistry within gender-specific reference intervals from PathWest unless deemed not clinically significant by the investigator: urea, glucose, creatinine, sodium, potassium, chloride and bicarbonate, lactate dehydrogenase, calcium, total protein, magnesium, phosphate, albumin, cholesterol, and uric acid. For renal function an eGFR >90ml/min/m2 will be considered normal using the CKD-EPI without albuminuria on dipstick].
- iii. Liver function tests (only at screening): aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin, gamma-glutamyl transferase [<1.5 x ULN (ALT, GGT; PathWest gender-specific reference ranges) will be considered not clinically significant].
- iv. Negative HIV, Hepatitis B and C serology.
- v. Negative pregnancy test at screening and check-in (females).
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Interventions
Administration of high dose (6.9mL, 13.8mL or 20.7mL [3.6MIU, 7.2MIU or 10.8MIU]) Bicillin® L-A by a single subcutaneous infusion up to 30 minutes. Determination of the dosage participants will be receiving will be according to their enrollment number in the study and their weight group. There will be 3 administration periods. In Cohort 1, 2 participants in each weight group (ideal and overweight BMI, 4 participants total) will receive a 6.9ml (3.6 MIU) dose of Bicillin® L-A by a single subcutaneous infusion up to 30 minutes. In Cohort 2, five participants in each weight group (ideal and overweight BMI, 10 participants total) will receive a 13.8ml (7.2 MIU) dose of Bicillin® L-A by a single subcutaneous infusion up to 30 minutes. In Cohort 3, five participants in each weight group (ideal and overweight BMI, 10 participants total) will receive a 20.7ml (10.8 MIU) dose of Bicillin® L-A by a single subcutaneous infusion up to 30 minutes. Progression to the next Administration period is dependent upon no SAEs and will be determined by a Safety Monitoring Committee.
Locations(1)
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ACTRN12621000135819