{"doi":"10.17615/cf2t-6846","title":"Pharmacokinetic Modeling to Guide Preclinical Development of an Islatravir-Eluting Reservoir-Style Biodegradable Implant for Long-Acting HIV PrEP","abstract":"Long-acting injectable cabotegravir is more effective than daily oral PrEP at preventing HIV transmission due to improved adherence, but requires bi-monthly large-volume intramuscular injections. Subcutaneous (SC) contraceptive implants can be formulated with antiretrovirals for extended-duration HIV PrEP. Islatravir (ISL) is a first-in-class, investigational antiretroviral with pharmacologic properties well-suited for implant delivery. We performed preclinical studies for the development of a reservoir-style, poly(ε-caprolactone) ISL-eluting implant by conducting a single-dose SC ISL dose-ranging pharmacokinetic (PK) study of 0.1, 0.3, and 1 mg/kg in adult Wistar rats. Non-compartmental analysis was conducted, and dose proportionality assessed for ISL plasma and intracellular islatravir-triphosphate (ISL-tp). Population PK models estimated ISL's unit impulse response to deconvolve ISL-implant in vivo absorption rate (mg/day) and cumulative mass (mg) from published rat plasma PK (n> = 10). Drug release was interpreted using four kinetic models. Dose proportionality was affirmed for ISL and ISL-tp. A first-order, two-compartment model fitted the SC ISL bolus data. Mean (SD) absorption rate from 0 to 154 days was 0.072 ± 0.024 mg/day, and cumulative mass at 154 days was 8.67 ± 3.22 mg. ISL absorption was well-described by zero-order (r2 = 0.95) and Ritger-Peppas (r2 = 0.98). Our zero-order ISL-release poly(ε-caprolactone) implant is projected to achieve clinical PK above ISL-tp's PrEP efficacy threshold. Continued development for HIV PrEP applications is warranted.","journal":"UNC Libraries","year":2024,"id":505230,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9515,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":473720,"name":"Ariane van der Straten","orcid":"0000-0001-8536-648X","position":1,"is_corresponding":false},{"id":600001,"name":"Sai Archana Krovi","orcid":"0000-0003-1546-9955","position":2,"is_corresponding":false},{"id":1313492,"name":"Talisa S. Kinsale","orcid":"0000-0002-3102-3040","position":3,"is_corresponding":false},{"id":1313845,"name":"Greg Gatto","orcid":null,"position":4,"is_corresponding":false},{"id":372555,"name":"Brian Van Horne","orcid":null,"position":5,"is_corresponding":false},{"id":1101621,"name":"Chasity Norton","orcid":"0000-0001-6730-5181","position":6,"is_corresponding":false},{"id":1313493,"name":"Linying Li","orcid":"0000-0002-0373-5905","position":7,"is_corresponding":false},{"id":370695,"name":"Angela D. M. Kashuba","orcid":"0000-0002-9171-8493","position":8,"is_corresponding":false},{"id":536629,"name":"Julie B. Dumond","orcid":"0000-0002-3500-5819","position":9,"is_corresponding":false},{"id":446538,"name":"Rhonda M. Brand","orcid":null,"position":10,"is_corresponding":false},{"id":1148501,"name":"Shekhar Yeshwante","orcid":"0009-0003-5968-1007","position":11,"is_corresponding":false},{"id":919880,"name":"Leah M. Johnson","orcid":"0000-0002-3258-8713","position":12,"is_corresponding":false},{"id":772643,"name":"Ellen Luecke","orcid":"0000-0003-1509-5092","position":13,"is_corresponding":false},{"id":40493,"name":"Gauri G. Rao","orcid":"0000-0002-8704-7770","position":14,"is_corresponding":false},{"id":370688,"name":"Mackenzie L. Cottrell","orcid":"0000-0002-0291-5111","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:10:43.302033Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}