title: A population pharmacokinetic modeling approach shows that serum penicillin G concentrations are below inhibitory concentrations by two weeks after benzathine penicillin G injection in the majority of young adults.
abstract: Serum penicillin G falls to low levels 2 weeks after injection as benzathine penicillin G (BPG) in young adults. Using Pmetrics and previously reported penicillin G pharmacokinetic data after 1.2 million units were given as BPG to 329 male military recruits, here we develop the first reported population pharmacokinetic model of penicillin G after BPG injection. We simulated time-concentration profiles over a broad range of pediatric and adult weights after alternative doses and dose frequencies to predict the probability of maintaining serum penicillin G concentrations of >0.02 mg/liter, a proposed protective threshold against group A Streptococcus pyogenes (GAS). The final population model included linear absorption into a central compartment, distribution to and from a peripheral compartment, and linear elimination from the central compartment, with allometrically scaled volumes and rate constants. With 1.2 million units of BPG given intramuscularly every 4 weeks in four total doses, only 23.2% of 5,000 simulated patients maintained serum penicillin G trough concentrations of >0.02 mg/liter 4 weeks after the last dose. When the doses were 1.8 million units and 2.4 million units, the percentages were 30.2% and 40.7%, respectively. With repeated dosing of 1.2 million units every 3 weeks and every 2 weeks for 4 doses, the percentages of simulated patients with a penicillin G trough concentration of >0.02 mg/liter were 37.8% and 65.2%, respectively. Our simulations support recommendations for more frequent rather than higher BPG doses to prevent recurrent rheumatic heart disease in areas of high GAS prevalence or during outbreaks.
authors.affiliation: Laboratory of Applied Pharmacokinetics and Bioinformatics, Children's Hospital of Los Angeles, and Keck School of Medicine of USC, Los Angeles, California, USA mneely@usc.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Neely
authors.affiliation: Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
authors.forename: Edward L
authors.initials: EL
authors.lastname: Kaplan
authors.affiliation: Departments of Pediatrics and Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Blumer
authors.affiliation: Operational Infectious Diseases Department, Naval Health Research Center, San Diego, California, USA.
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Faix
authors.affiliation: Operational Infectious Diseases Department, Naval Health Research Center, San Diego, California, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Broderick
mesh_terms: D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D010401:Penicillin G Benzathine / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D012141:Respiratory Tract Infections / Q000188:drug therapy / Q000382:microbiology; D012214:Rheumatic Heart Disease / Q000382:microbiology / Q000517:prevention & control; D013297:Streptococcus pyogenes / Q000187:drug effects*; D013587:Syphilis / Q000188:drug therapy / Q000382:microbiology; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D010401:Penicillin G Benzathine