2023 - A Coruña - Spain

PAGE 2023: Clinical Applications
Paul Thoueille

Pharmacometrics-based analysis of long-acting cabotegravir over 6 months in real-life people living with HIV in Switzerland

Paul Thoueille 1, Laurent A. Decosterd 1, Thierry Buclin 1, Monia Guidi 1,2,3, The Swiss HIV Cohort Study

1 Service and Laboratory of Clinical Pharmacology, Department of Laboratory Medicine and Pathology, Lausanne University Hospital and University of Lausanne, Switzerland 2 Centre for Research and Innovation in Clinical Pharmaceutical Sciences, Lausanne University Hospital and University of Lausanne, Switzerland 3 Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, University of Lausanne, Switzerland

Introduction: The present study is part of an ongoing nationwide multicenter observational study within the Swiss HIV Cohort Study for the prospective therapeutic drug monitoring of people living with HIV (PLWH) on long-acting injectable cabotegravir plus rilpivirine (SHCS-879). After an optional 1-month oral lead-in period, loading doses of cabotegravir and rilpivirine are separately injected intramuscularly (i.m.). Maintenance therapy is then administered every 2 or 1 months [1-3]. Results from Phase III clinical trials showed extensive pharmacokinetics (PK) variability in carefully selected PLWH and indicated that low drug exposure, in combination with other risk factors, could be associated with virological failure [4-7].

Objectives: The present analysis aims to develop a population PK (popPK) model of cabotegravir in PLWH, while characterizing patient-related factors that could affect cabotegravir exposure, outside the clinical trial stringent settings.

Methods: A total of 622 cabotegravir concentrations, of which 501 obtained during the long-acting dosing period, measured in 154 PLWH were available for the popPK analysis (NONMEM). A stepwise procedure allowed identifying the model best fitting the concentrations after oral and i.m. administrations. The following covariates were available and tested for significance on the base model parameters: age, gender, ethnicity, bodyweight, body mass index, height, eGFR (CKD-EPI equations [8]), liver cirrhosis, and heart failure. The latter were classified according to the Child-Pugh score [9] and NYHA scale [10], respectively. Finally, model-based simulations allowed comparing cabotegravir trough concentrations (Cmin) and PK profiles over 24 weeks.

Results: A one-compartment model with distinct first order-absorption constants and volumes of distribution for oral and i.m. administrations, and identical clearances (CL) to depict drug linear elimination, best described cabotegravir data. I.m.-administered cabotegravir exhibited flip-flop kinetics (i.e., absorption rate constant k12 < elimination rate constant k20) consistent with reported data [11, 12]. Parameter estimates of the base popPK model with interindividual variability (CV%) were: k12 of 2.76 h-1 and 0.0011 h-1 (39%) and volumes of distribution of 10.6 L and 19 L (73%) for oral and i.m. administrations, respectively, and an identical CL of 0.199 L/h (26%). The base model allowed estimating a Tmax of 1.8 h and a half-life of 37 h after oral administration, slightly lower than the values found in literature [2, 13]. Covariate analyses revealed a significant association between gender and k12, with a 43% slower k12 in women compared to men, resulting in lower Cmax but higher Cmin due to the flip-flop kinetics of cabotegravir after i.m. injection. Model-based simulations showed that the median Cmin at steady-state was 5044 ng/mL [95% confidence interval (CI95): 2584 – 9071] after oral administration, consistent with previously reported values [2, 13]. On the other hand, cabotegravir concentrations were 25% lower in women at week 8 (i.e., Cmin 4 weeks after loading dose) compared to men, with median Cmin of 1349 [CI95: 687 – 2731] ng/mL and 1788 [CI95: 945 – 3432] ng/mL, respectively. However, the difference in cabotegravir Cmin between the two groups then reversed, reaching trough levels 27% higher in women at week 24, where median Cmin of 1436 [CI95: 771 – 2575] ng/mL was predicted in women, and of 1131 [CI95: 389 – 2366] ng/mL in men.  

Conclusion: More rapid absorption and a larger volume of distribution are observed for long-acting cabotegravir after i.m. injection in our study compared to the data reported in the Phase III clinical trials [11]. Drug flip-flop kinetics, implying that the rate of absorption is the limiting factor of cabotegravir elimination, combined with a larger volume of distribution, leads to a lower Cmin than previously described. Further observations are warranted to evaluate the clinical relevance of these findings in real-life PLWH.



References:

  1. U.S. Food and Drug Administration. Cabenuva product label. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/212888s005s006lbl.pdf. Accessed February 2023.
  2. European Medicines Agency (EMA). Vocabria Product Information. https://www.ema.europa.eu/en/documents/product-information/vocabria-epar-product-information_en.pdf. Accessed February 2023.
  3. European Medicines Agency (EMA). Rekambys Product Information. https://www.ema.europa.eu/en/documents/product-information/rekambys-epar-product-information_en.pdf. Accessed February 2023.
  4. Orkin, C., et al., Initiation of long-acting cabotegravir plus rilpivirine as direct-to-injection or with an oral lead-in in adults with HIV-1 infection: week 124 results of the open-label phase 3 FLAIR study. Lancet HIV, 2021. 8(11): p. e668-e678.
  5. Overton, E.T., et al., Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection: 152-week results from ATLAS-2M, a randomized, open-label, Phase 3b, noninferiority study. Clinical Infectious Diseases, 2023.
  6. European Medicines Agency (EMA). Assessment report Vocabria. https://www.ema.europa.eu/en/documents/assessment-report/vocabria-epar-public-assessment-report_en.pdf Accessed February 2023.
  7. Cutrell, A.G., et al., Exploring predictors of HIV-1 virologic failure to long-acting cabotegravir and rilpivirine: a multivariable analysis. Aids, 2021. 35(9): p. 1333-1342.
  8. Levey, A.S., et al., A new equation to estimate glomerular filtration rate. Ann Intern Med, 2009. 150(9): p. 604-12.
  9. Child, C.G. and J.G. Turcotte, Surgery and portal hypertension. Major Probl Clin Surg, 1964. 1: p. 1-85.
  10. Dolgin M, Association NYH, Fox AC, Gorlin R, Levin RI, New York Heart Association. Criteria Committee. Nomenclature and criteria for diagnosis of diseases of the heart and great vessels. 9th ed. Boston, MA: Lippincott Williams and Wilkins; March 1, 1994.
  11. Han, K., et al., Population pharmacokinetics of cabotegravir following administration of oral tablet and long-acting intramuscular injection in adult HIV-1-infected and uninfected subjects. Br J Clin Pharmacol, 2022.
  12. Yu, Y., et al., A population pharmacokinetic model based on HPTN 077 of long-acting injectable cabotegravir for HIV PrEP. Br J Clin Pharmacol, 2022.
  13. Cabotegravir (oral) PK Fact Sheet. University of Liverpool. Produced February 2021.

Reference: PAGE 31 (2023) Abstr 10475 [www.page-meeting.org/?abstract=10475]
Poster: Clinical Applications
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