Piyawat Chaivichacharn (1), Anchalee Avihingsanon (2,3), Sivaporn Gatechompol (2,3), Sasiwimol Ubolyam (2), Baralee Punyawudho (1,*)
(1) Department of Pharmaceutical Care, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand, (2) The HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT), Thai Red Cross AIDS Research Centre, Bangkok, Thailand, (3) Tuberculosis Research Unit, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand, (*) Author for correspondence
Introduction/Objectives: Lopinavir/Ritonavir (LPV/r) is an alternative drug in HIV-1 treatment when the first-line drugs cannot be used [1]. Currently, the standard doses of LPV/r are 400/100 mg and 800/200 mg twice daily in Thai HIV mono-infected and HIV/tuberculosis (TB) co-infected patients, respectively [1]. Several studies showed the possibility of dose reduction of protease inhibitors in Thai patients [2-4]. Nevertheless, the optimal dose reduction of LPV/r in the Thai population has not been suggested. This study aimed to develop the population pharmacokinetic model of LPV/r and investigate the possibility of LPV/r dose reduction Thai HIV mono-infection and HIV/TB co-infection.
Methods: The steady-state plasma lopinavir (LPV) and ritonavir (RTV) concentrations were obtained from 206 Thai HIV-infected patients. Blood samples were collected before the next dose. Additionally, intensive data with blood samples collected at pre-dose and 1, 2, 4, 6, 8, 10, and 12 h post-dose from the previous pharmacokinetic studies of LPV/r in 32 patients were included in the analysis [5,6]. The population pharmacokinetic analysis was performed using NONMEM®. The model describing the interaction between LPV and RTV was explored. The simulations were conducted to investigate different dose reduction regimens and determine the optimal dose of LPV/r. The percentage of in silico patients having LPV plasma concentrations within the therapeutic range of 1 to 8 mg/L was compared across the dosage regimens [7].
Results: One hundred and four patients were male (50.5%), and 20 (9.7%) were HIV/TB co-infected patients receiving rifampin (RIF) as co-medication. The medians ± IQR [min, max] of age and weight were 40 ± 11 [19, 78] years and 57.0 ± 14.5 [31.0, 99.4] kg, respectively. A one-compartment model with the transit-compartmental absorption best described the pharmacokinetics of both drugs. The maximum inhibition model best described the drug-drug interaction, explaining the impact of RTV plasma concentration on the apparent clearance (CL/F) of LPV. The IC50 was estimated to be 0.207 mg/L when Imax was fixed to 1. The CL/F of LPV in the absence and presence of RTV was 15.4 L/h and 4.69 L/h, respectively. The RIF use was the significant covariate affecting CL/F of LPV and RTV and increased LPV and RTV CL/F by 1.74-fold and 1.99-fold, respectively. The simulation results showed that the reduced LPV/r doses of 300/75 mg or 200/150 mg twice daily for HIV mono-infected patients provided a comparable percentage (87% or 84%, respectively) of patients having LPV plasma concentrations within the therapeutic range to the standard doses (88%). Moreover, patients receiving RIF as co-medication who do not tolerate the standard dose of LPV/r could use the reduced LPV/r dose of 600/150 mg twice daily.
Conclusions: This study is the first population pharmacokinetics of LPV/r integrating LPV and RTV interaction model in Thai and Asian patients. The reduced doses of LPV/r in Thai HIV-infected patients with and without RIF provide adequate LPV exposure. These could reduce the short and long-term toxicity for those who use LPV/r.
References:
[1] Ruxrungtham K, et al. Thailand National Guidelines on HIV/AIDS Diagnosis, Treatment and Prevention 2020/2021. Department of Disease Control. Thailand ministry of public Health; 2020 August 2020.
[2] Bunupuradah T, et al. Low-dose versus standard-dose ritonavir-boosted atazanavir in virologically suppressed Thai adults with HIV (LASA): a randomised, open-label, non-inferiority trial. Lancet HIV. 2016;3(8):e343-e50.
[3] Avihingsanon A, et al. A low dose of ritonavir-boosted atazanavir provides adequate pharmacokinetic parameters in HIV-1-infected Thai adults. Clin Pharmacol Ther. 2009;85(4):402-8.
[4] van der Lugt J, et al. Pharmacokinetics and short-term efficacy of a double-boosted protease inhibitor regimen in treatment-naive HIV-1-infected adults. J Antimicrob Chemother. 2008;61(5):1145-53.
[5] https://clinicaltrials.gov/ct2/show/NCT01138202
[6] https://clinicaltrials.gov/ct2/show/NCT01138241
[7] Breilh D, et al. Virological, intracellular and plasma pharmacological parameters predicting response to lopinavir/ritonavir (KALEPHAR study). AIDS. 2004;18(9):1305-10.
Reference: PAGE 30 (2022) Abstr 9957 [www.page-meeting.org/?abstract=9957]
Poster: Drug/Disease Modelling - Infection