CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

429

Evaluation of a Protocol for Managing Cyclosporine and Nirmatrelvir/ Ritonavir Drug- Drug Interaction Pierre Giguere 1 , Kyla Agtarap 2 , Marie-Josée Deschênes 1 , Lacey DeVreese 1 , Jessica McDougall 1 , Stephanie Hoar 3 , Swapnil Hiremath 3 1 The Ottawa Hospital, Ottawa, Canada, 2 Hôpital Montfort, Ottawa, Canada, 3 University of Ottawa, Ottawa, Canada Background: Morbidity and mortality of COVID-19 is higher in immunocompromised people including kidney transplant recipients (KTR). Nirmatrelvir/ritonavir (NRMr) interacts with many medications, in particular calcineurin inhibitors (CNI). Limited evidence exists for reinitiating CNIs post-NRMr. We created a protocol to manage the NRMr-cyclosporine (CsA) interaction. This study aims to describe the application of the protocol and deviations, evaluate its impact on cyclosporine levels, and analyze safety outcomes. Methods: This is a retrospective study between May 2022 and Nov 2023. As per protocol, CsA dose was reduced by 80% at NRMr start and up to 2 days post-NRMr. CsA levels were drawn 2 days post-NRMr. If the 1st level was sub/ therapeutic, CsA was resumed at 100% and level repeated 1 week later. If supratherapeutic, the dose reduction was maintained for another 2 days, then reinitiated at 100% pre-NRMr dose. Acute kidney injury (AKI), hospitalization and death were collected through 30-days post-NRMr therapy. Results: Forty-two KTR were identified, of which 35 started NRMr and met eligibility criteria and were analyzed. Nine KTR did not follow the protocol instructions. At baseline, 83% of patients were in therapeutic range, with a mean CsA level of 258 μg/L. Median dose reduction at initiation of NRMr was 80% [IQR 76-83]. At the first follow-up (FU) 2 days post-NRMr, the average CsA level was higher by 23 μg/L (P=0.51). There was a greater proportion of patients with sub and supratherapeutic levels compared to baseline (20% vs 9% and 31% vs 9%). Nonadherence to the protocol was observed in 5/18 levels outside therapeutic range. At the second FU, there was a correction of sub and supratherapeutic levels (14% and 14%) as patients shifted to therapeutic range. Of the 16 patients requiring additional monitoring, levels returned to baseline values within 30 days. Two KTR experienced AKI for unrelated reasons to COVID-19 treatment (unstable atrial flutter, gastroenteritis) and one that resolved with increased fluid intake. There were 4 hospitalizations, but none related to the initial COVID-19 treatment management. There was no graft rejection or death 30 days post-NRMr. Conclusion: Though CsA levels outside therapeutic range were common immediately post-NRMr treatment, levels were restored rapidly. No clinically relevant safety events related to NRMr treatment occurred within the 30-days. Adherence to the protocol is crucial.

428

Pharmacokinetics of Tecovirimat in Persons With Mpox: Results From ACTG 5418 Zixuan Wei 1 , Grace Aldrovandi 2 , Judith S. Currier 2 , Joseph J. Eron 3 , William Fischer 3 , Rajesh T. Gandhi 4 , Matthew M. Hamill 5 , Lara Hosey 6 , Arzhang C. Javan 7 , Sharon Nachman 8 , Davey M. Smith 9 , Timothy J. Wilkin 10 , Jason E. Zucker 11 , Edmund Capparelli 9 , Kristina M. Brooks 1 1 University of Colorado Anschutz Medical Campus, Aurora, CO, USA, 2 University of California Los Angeles, Los Angeles, CA, USA, 3 University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, 4 Massachusetts General Hospital, Boston, MA, USA, 5 The Johns Hopkins University School of Medicine, Baltimore, MD, USA, 6 DLH Corporation, Atlanta, GA, USA, 7 National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA, 8 Stony Brook University, Stony Brook, NY, USA, 9 University of California San Diego, La Jolla, CA, USA, 10 Weill Cornell Medicine, New York, NY, USA, 11 Columbia University Medical Center, New York, NY, USA Background: Tecovirimat is an FDA-approved oral antiviral medication for human smallpox and is being used widely for mpox treatment. The pharmacokinetics (PK) of tecovirimat has been assessed in animal models and healthy human volunteers, but data in people with mpox are limited. Methods: The Study of Tecovirimat for mpox (STOMP/ACTG 5418, NCT05534984) is an ongoing international randomized (2:1) clinical trial of the efficacy of tecovirimat for mpox. STOMP includes an open-label arm of participants with severe disease, immunosuppression, pregnancy and those aged <18 years, which is the focus of this report. Intensive PK assessments were conducted in a subset of participants on study day 8 (steady-state) following an observed dose of tecovirimat with a meal. All received 600 mg twice daily. Blood samples were collected pre-dose (time 0), 1, 2, 3, 4, 6, 8, and 10 hours post-dose. Tecovirimat concentrations were quantified by LC-MS/MS. PK were analyzed via noncompartmental analysis with predicted AUC0-12h and C12h determined from the terminal phase of the post-dose curve. AUC0-12h and C12h were compared to predicted exposures in fed healthy adults receiving the same doses (data from the U.S. FDA) and mean Cmin values associated with survival and clinical/virologic response in non-human primates (NHP) (minimum and maximum effective doses of 3 and 10 mg/kg/day, respectively). Results: PK data were generated in 13 participants (11 non-pregnant adults; 1 adolescent; 1 pregnant female adult). Of 12 non-pregnant participants, 11 were male, 5 were Black; 7 were persons with HIV of whom 4 had HIV-1 RNA <200 copies/mL, 2 were not on ART, and 2/6 had CD4 counts <200 cells/mm 3 ; median (range) age and weight were 35 (<18-51) years and 77 (57-103) kg, respectively. Comparable PK was observed between non-pregnant participants and the pregnant participant and by HIV status (Table). Median tecovirimat AUC0-12h and C12h in non-pregnant adults were 38% and 72% lower than 50th percentile exposures in healthy adults. Despite lower tecovirimat exposures, C12h across all participants exceeded mean effective Cmin values in NHPs receiving 3 and 10 mg/kg/day. Conclusion: Persons with mpox had lower tecovirimat exposures vs. healthy adults, although concentrations remained above the minimally effective Cmin in NHPs. Future work will explore factors associated with tecovirimat PK and assess relationships with clinical and virologic outcomes to evaluate the clinical relevance of these PK differences.

Poster Abstracts

CROI 2024 106