{"doi":"10.1111/bcp.15410","title":"Long‐acting injectable Cabotegravir: How drug concentrations could help guide patient management","abstract":"With the introduction of long-acting (LA) injectable antiretrovirals, a new paradigm for HIV prevention and treatment is upon us. In the last 15 months, the Food and Drug Administration-approved LA cabotegravir/rilpivirine (CAB-LA/RPV-LA) intramuscular (IM) injections every 4 weeks (or 8 weeks (Q8W) for the treatment of HIV infection,1 as well as CAB-LA injections (Q8W) for pre-exposure prophylaxis (PrEP).2 Currently, a 1-size-fits-all dose and frequency are being proposed for LA injectables based on strong efficacy in tightly controlled clinical trials, where study visits were fixed, participants were highly-selected (e.g., those with long-term suppression and treatment naïve patients without history of adherence barriers), and study personnel provided active follow up. However, these idealized settings are not like the real world, where patient management problems are common and include missed/late appointments, changing providers and leaving/re-entering care.3, 4 This makes it of utmost importance to understand CAB-LA pharmacokinetics and injection-to-injection variability so that clinicians can appropriately manage patients in the real world. In this issue of the British Journal of Clinical Pharmacology, Yu et al. and Han et al. present population pharmacokinetic (PK) models for CAB-LA using data from the HPTN 077 (Yu et al.), and 16 studies that collected CAB concentrations including HPTN 077 (Han et al.). HPTN 077 was a tightly controlled phase 2a study that characterized safety and PK of IM CAB-LA in 199 healthy adults using 2 different doses: 800 mg IM every 8 week and 600 mg IM Q8W.5 In their study, Yu and colleagues analysed data from 133 participants (67% female; 41% Black) using a nonlinear mixed-effects model, ultimately fitting a 2-compartment model with a first-order absorption rate (Ka) to the concentration–time data. The first order Ka is the basis for the long-acting formulation and critical to the dose frequency and duration of action. Therefore, factors that influence the absorption rate and injection-to-injection variability are clinically relevant and important to understand. To this end, Yu and colleagues modelled between occasion variability and quantified a 38.5% unexplained variability in absorption rate within-person, from injection to injection. The source of this variability remains unclear, but some is presumably due to injecting into fat and/or lean muscle from injection to injection. Other possibilities include muscle/fat gains or losses, hot vs. cold months (influencing blood flow), and/or other yet-to-be-identified factors. Covariates such as age, sex, body weight and body mass index (BMI), were evaluated as predictors of PK parameters including Ka. Sex was most influential on Ka with a ~40% slower Ka for women compared with men, and weight was significant for oral clearance, which is consistent with previous reports.5 The study from Han et al. was even more comprehensive and included data from 1647 individuals (23 926 concentrations) including persons with and without HIV, injections with various needle lengths, and several doses for both oral and injections. Sex, BMI, needle length and split injections influenced Ka. For example, females had a ~51% lower Ka compared with males; those in the 90th percentile of weight had ~29% lower Ka vs. those in the 10th percentile; split injections resulted in 48% higher Ka; and longer needles increased the Ka. All these findings are consistent with faster Ka when drug is injected into lean muscle, and slower Ka when injected into fat. BMI and smoking (potential UGT1A1 induction) were associated with oral clearance and BMI was associated with volumes. The interindividual variability for Ka was ~58%, which was lower than the ~83% reported by Yu et al. The clinical implications of these studies are important. First, they show that, even in a tightly controlled settings such as clinical trials, PK variability in CAB-LA is substantial and not always predictabl","journal":"British Journal of Clinical Pharmacology","year":2022,"id":287585,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9593,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":279022,"name":"Peter L. Anderson","orcid":"0000-0002-1200-8494","position":1,"is_corresponding":false},{"id":395985,"name":"José Castillo‐Mancilla","orcid":"0000-0003-1242-1745","position":0,"is_corresponding":true}],"reference_count":8,"raw_metadata":null,"created_at":"2026-07-19T00:30:01.051685Z","pmid":"35971819","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":[]}