Noppaket Singkham (1,2), Richard C Brundage (3), Angela K Birnbaum (3), Anchalee Avihingsanon (4, 5), Narukjaporn Thammajaruk (4), Kiat Ruxrungtham (4, 5), Torsak Bunupuradah (4), Sasisopin Kiertiburanakul (6), Ploenchan Chetchotisak (7), Baralee Punyawudho (1) and LASA study team
(1) Department of Pharmaceutical Care, Faculty of Pharmacy, Chiang Mai University, Thailand, (2) Graduate School, Chiang Mai University, Thailand, (3) Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, USA, (4) HIV-NAT, Thai Red Cross AIDS Research Centre, Thailand, (5) Department of Medicine, Faculty of Medicine, Chulalongkorn University, Thailand, (6) Faculty of Medicine Ramathibodi Hospital, Mahidol University, Thailand, (7) Department of Medicine, Faculty of Medicine, KhonKaen University, Thailand
Objectives:
In Thailand, Ritonavir-Boosted Atazanavir (ATV/RTV) is a preferred protease inhibitor based-regimen for the treatment of HIV infection. The pharmacokinetics (PK) of ATV exhibit high interindividual variability that are influenced by patient characteristics and genetic factors. Single nucleotide polymorphisms (SNPs) of metabolizing enzymes, protein transporters, and gene regulation were found to be associated with PK of ATV/RTV.1–4 There is evidence that Thai HIV-infected patients have a lower oral clearance of ATV (CL/FATV) compared to other ethnicities, leading to higher drug exposure.5 Although non-genetic and genetic factors including CYP3A5 and NR1I2 polymorphisms had significant effect on CL/FATV in Caucasian, this information in Thai patients is limited. Thus, we aimed to characterize the population PK of ATV and RTV and identify potential factors influencing their disposition, taking into account the inhibition effect of RTV on ATV. Additionally, optimal dosage regimens for Thai HIV-infected patient were investigated.
Methods:
A total of 544 patients with 1464 concentrations of ATV and RTV were obtained from two clinical studies.6–7 Thai adult HIV-infected patients receiving ATV/RTV-based regimen for their therapy (300/100 or 200/100 mg, once daily) were included in the analysis. Among all patients, 27 patients had intensive PK data (0, 1, 2, 4, 6, 8, 10, 12 and 24 h after dosing) and 517 patients had plasma trough concentrations. Genetic polymorphisms of CYP3A5 6986A>G, ABCB1 3435C>T, ABCB1 2677G>T, SLCO1B1 521T>C and NR1I2 63396C>T were genotyped. A population PK model was developed using the nonlinear mixed-effect modelling software (NONMEMâ). The model of ATV and RTV was developed separately and then were incorporated to describe an interaction between drugs using sequential approach. One- and two-compartment models with the first-order absorption and elimination and a delay absorption with lag time or transit model were explored. The influence of covariates on PK parameters were analyzed using stepwise forward inclusion and backward deletion. The covariates included genetic factors (CYP3A5 6986A>G, ABCB1 3435C>T, ABCB1 2677G>T, SLCO1B1 521T>C and NR1I2 63396C>T) and clinical factors (age, sex, body weight, liver function test and using of tenofovir disoproxil fumarate). An effect of RTV concentrations on CL/FATV was determined with different inhibitory models. Monte Carlo simulations were conducted based on the final model to compare the probability of achieving the therapeutic range of ATV (Ctrough 0.15-0.85 mg/L) under different dosing regimens and various covariates.
Results:
The PK of ATV and RTV were described by a one-compartment model with first-order absorption. The CL/FATV in the absence RTV was 7.39 L/h with interindividual variability (IIV) of 27.98%, apparent volume of distribution (V/FATV) was 76 L and absorption rate constant (ka ATV) was 1.64 h–1. The significant covariates for CL/FATV were CYP3A5 6986A>G and sex. Patients with CYP3A5 6986 GG (non-expressors) had a 7.3% lower CL/FATV than those with AA/AG genotype (expressors). The CL/FATV decreased by 10.5% for female compared with male patients. For RTV, the estimates of CL/FRTV (IIV), V/FRTV and kaRTV were 8.46 L/h (30.3%), 58.3 L and 1.23 h–1, respectively. The CL/FRTV was influenced by body weight using allometric scaling and CYP3A5 6986A>G. The inhibition effect of RTV trough concentration on CL/FATV can be described by maximum effect model. The maximum inhibitory effect (Imax) of RTV was 66.7% and RTV concentration producing half of the maximal inhibition effect (IC50) was 0.561 mg/L. The simulation results showed that, more patients in the low dose of ATV/RTV (200/100 mg) group achieved target concentration (67.98%), whereas 36.21% of patients in the standard dose of ATV/RTV (300/100 mg) group had concentration exceed the target concentration (ATV Ctrough>0.85 mg/L). For CYP3A5 non-expressor patients receiving ATV/RTV 200/100 mg, the probabilities of achieving ATV target concentration were 62.74% and 71.31% in female and male patients, respectively.
Conclusions:
The population model was developed to describe PK of ATV/RTV in Thai adult HIV-infected patients. The results suggest an influence of CYP3A5 6986A>G and sex on CL/FATV. Simulations confirmed that a reduction of ATV dosage from 300 to 200 mg in combination with RTV 100 mg, once-daily was sufficient to achieve target concentration.
References:
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Reference: PAGE 28 (2019) Abstr 8811 [www.page-meeting.org/?abstract=8811]
Poster: Clinical Applications