Yu-Wei Lin1,2, Amy S. Y. Cheung1,2, Isabelle Deprez1,2, Susan Ford2, Jon Collins3, Rashmi Mehta2, Mark Bush3, Kelong Han2, Cindy McCoig4, Conn M. Harrington3, Lionel Tan5, Aditya Gaur6, Carolyn Bolton7, Lynda Stranix-Chibanda8, Sybil Hosek9, Mark Marzinke10, Brookie Best11, Edmund Capparelli11, . for IMPAACT 2017 Team12, . for HPTN 084-01 Study Team13, . for HPTN 083-01 Study Team13
1Certara, 2GlaxoSmithKline, 3ViiV Healthcare, 4ViiV Healthcare, Madrid, Spain, 5ViiV Healthcare, 6St Jude Children's Research Hospital, 7Centre for Infectious Disease Research in Zambia, 8University of Zimbabwe, 9Department of Psychiatry, Stroger Hospital of Cook County, 10Department of Pathology, The Johns Hopkins University, 11University of California San Diego, 12International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network , 13HIV Prevention Trials Network (HPTN)
Introduction: Cabotegravir (CAB) is an integrase strand transfer inhibitor approved in adults and adolescents (12 to <18 years) weighing =35 kg as long-acting injectable (LAI) HIV-1 prevention, and for treatment in combination with rilpivirine. An existing CAB population pharmacokinetic (PopPK) model was limited to adult PK [1]. We set out to extend and optimize that existing PopPK model for adolescents (12 to <18 years) by incorporating available adolescent PK data from the IMPAACT2017/MOCHA (NCT03497676) and HPTN 083/084-01(NCT04824131/ NCT02720094) clinical trials. Method: The existing adult PopPK model was refined based on a new dataset, including intensive and sparse concentration, dosing, demographic, and covariate data, from adolescent participants in IMPAACT 2017, HPTN 083-01, and HPTN 084-01. All drug concentrations were measured via LC-MS/MS by a single laboratory (Clinical Pharmacology Analytical Laboratory). The PopPK model parameters were re-estimated based on this pooled dataset using NONMEM 7.3 using the Laplacian method. Individual steady-state exposure metrics (e.g. Ctau,ss) were derived using empirical Bayes estimates and compared between adolescents and adults. Subsequently, Monte Carlo simulation was performed using the updated PopPK model to simulate plasma concentration versus time profiles of CAB for every four weeks dosing (Q4W) and every eight weeks dosing (Q8W) regimens in adult and adolescent participants over an observation period of approximately 1 year. Results: PK data following oral lead-in (30mg once daily, QD for at least 4 weeks) and LAI treatment (an initial 600mg 4-week loading dose followed by 400mg Q4W or 600mg Q8W) from 147 adolescents with HIV (IMPAACT 2017) and 62 HIV-negative adolescents (HPTN 083/084-01) with weight of 35.2-168 kg, body mass index (BMI) of 15.8-51.6 kg/m2 and 12 to 17 years were added to adult data (n=1647). The PK of CAB following oral and LAI administration in adults and adolescents was adequately described by a 2-compartment model with first-order absorption and first-order elimination. All parameters were estimated with good precision, with the % RSE consistently =30%. No new covariates were identified as compared to the adult PopPK model. Weight and smoking status were significant determinants of CL/F (L/h), and only weight was a determinant of Vc/F (L), Vp/F (L), and Q/F (L/h). Needle length, female sex, splitting of the injection, and Body Mass Index (BMI) were significant determinants of absorption rate constant for LAI intramuscular (IM) formulation, Ka2, in the pooled model. All adolescents were non-smokers and the majority of the adolescent participants received non-split injections. Their impact on adolescent PK were assumed to be the same as the adult population. For the weight range 35.2-168.3 kg, CL/F and Q/F ranged from approximately 40.0% lower to 73.3% higher than for a 74.8 kg participant, and Vc/F and Vp/F ranged from approximately 43.3% lower to 84.3% higher than for a 74.8 kg participant. Females had 50.8% lower Ka2 values than males. In various dosing scenarios (Q4W and Q8W dosing regimens), simulated concentrations were compared against the efficacy threshold of 0.45 µg/mL and the safety threshold of 22.5 µg/mL. The CAB PK profiles across the entire treatment period for the CAB long-acting IM Q4W and Q8W dosing regimens were predicted to remain above the Phase 3 efficacy threshold and below the safety threshold in =95% of the virtual adolescent population. Adolescents had CAB LA exposure at steady state (Ctau,ss median, 5th-95th: 2.36, 0.849-4.13 µg/mL for 600mg Q8W) comparable to that of adults (Ctau,ss : 1.91, 0.786-3.33 µg/mL for Q8W), with their exposure levels falling within the same range across all dosing phases, and contained within the established efficacy and safety thresholds of 0.45 and 22.5 µg/mL [2]. Conclusions: The addition of adolescent data to the adult PopPK dataset allowed expansion of the prior PopPK model down to adolescents weighing 35 kg and optimization of predictions in adolescents. Given the similarity of CAB PK across adolescents and adults, the same dosing regimens apply for adults and adolescents. The slightly higher exposure in the adolescent participants is clinically insignificant. No dose adjustment is recommended for adolescent participants (12 to <18 years of age) weighing at least 35 kg in accordance with the current label for CAB.
1. Han et al. Br J Clin Pharmacol. 2022;88(10):4607-4622. 2. Integrated review. Page 86. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/212887Orig1s000,212888Orig1s000IntegratedR.pdf.
Reference: PAGE 33 (2025) Abstr 11371 [www.page-meeting.org/?abstract=11371]
Poster: Drug/Disease Modelling - Paediatrics