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Dosage Optimization of Efavirenz Based on a Population Pharmacokinetic-Pharmacogenetic Model of HIV-infected Patients in Thailand.
Clin Ther. 2020 May 22 [Online ahead of print]CT

Abstract

PURPOSE

Efavirenz exhibits high interindividual variability in plasma concentrations, leading to unpredictable efficacy and toxicity. Polymorphism of CYP2B6 516G > T has been found to predominantly contribute to efavirenz variability. However, dosage recommendations incorporating CYP2B6 516G > T polymorphism have not been investigated in the Thai population. This study aimed to develop a population model of the pharmacokinetic properties of efavirenz, and to investigate the impact of patients' characteristics and CYP2B6 516G > T polymorphism on the pharmacokinetic properties of efavirenz. Model-based simulations were performed to provide genotype-based dosage optimization in a Thai population.

METHODS

Plasma efavirenz concentrations measured at 12 h post-dose in 360 Thai HIV-infected patients with and without tuberculosis were analyzed by the nonlinear mixed-effects modeling approach. A 1-compartment model with first-order absorption and elimination was used for describing the pharmacokinetic properties of efavirenz.

FINDINGS

The allele frequency of CYP2B6 516G > T was 34.17%. The efavirenz oral clearance were 11.9, 8.0, and 2.8 L/h in patients weighing 57 kg and having the CYP2B6 516 GG, 516 GT, and 516 TT genotypes, respectively. The use of rifampicin increased efavirenz oral clearance by 28%. The results from the simulations suggest that efavirenz dosages of 400, 300, and 100 mg once daily in Thai HIV mono-infected patients, and 800, 600, and 200 mg once daily in HIV/tuberculosis co-infected patients carrying CYP2B6 516 GG, 516 GT, and 516 TT, respectively.

IMPLICATION

The results from this study provide a rationale for efavirenz dose adjustment based on CYP2B6 516G > T polymorphism in Thai HIV-infected patients, which could help to improve treatment outcomes in this population. ClinicalTrials.gov identifier: NCT01138267. (Clin Ther. 2020; 42:XXX-XXX) © 2020 Elsevier Inc.

Authors+Show Affiliations

Department of Pharmaceutical Care, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand.HIV-NAT, Thai Red Cross AIDS Research Centre, Bangkok, Thailand; Tuberculosis Research Unit, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.Bamrasnaradura Infectious Diseases Institute, Ministry of Public Health, Mueang Nonthaburi, Thailand.HIV-NAT, Thai Red Cross AIDS Research Centre, Bangkok, Thailand.Center of Excellence for Medical Genomics, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Center of Excellence for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand.Center of Excellence for Medical Genomics, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Center of Excellence for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand.Department of Pharmaceutical Care, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand. Electronic address: Baralee.p@cmu.ac.th.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32451120

Citation

Chaivichacharn, Piyawat, et al. "Dosage Optimization of Efavirenz Based On a Population Pharmacokinetic-Pharmacogenetic Model of HIV-infected Patients in Thailand." Clinical Therapeutics, 2020.
Chaivichacharn P, Avihingsanon A, Manosuthi W, et al. Dosage Optimization of Efavirenz Based on a Population Pharmacokinetic-Pharmacogenetic Model of HIV-infected Patients in Thailand. Clin Ther. 2020.
Chaivichacharn, P., Avihingsanon, A., Manosuthi, W., Ubolyam, S., Tongkobpetch, S., Shotelersuk, V., & Punyawudho, B. (2020). Dosage Optimization of Efavirenz Based on a Population Pharmacokinetic-Pharmacogenetic Model of HIV-infected Patients in Thailand. Clinical Therapeutics. https://doi.org/10.1016/j.clinthera.2020.04.013
Chaivichacharn P, et al. Dosage Optimization of Efavirenz Based On a Population Pharmacokinetic-Pharmacogenetic Model of HIV-infected Patients in Thailand. Clin Ther. 2020 May 22; PubMed PMID: 32451120.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dosage Optimization of Efavirenz Based on a Population Pharmacokinetic-Pharmacogenetic Model of HIV-infected Patients in Thailand. AU - Chaivichacharn,Piyawat, AU - Avihingsanon,Anchalee, AU - Manosuthi,Weerawat, AU - Ubolyam,Sasiwimol, AU - Tongkobpetch,Siraprapa, AU - Shotelersuk,Vorasuk, AU - Punyawudho,Baralee, Y1 - 2020/05/22/ PY - 2019/10/30/received PY - 2020/04/21/revised PY - 2020/04/22/accepted PY - 2020/5/27/entrez KW - CYP2B6 516G>T KW - Dose optimization KW - Efavirenz KW - HIV KW - Population pharmacokinetics–pharmacogenetics KW - Thailand JF - Clinical therapeutics JO - Clin Ther N2 - PURPOSE: Efavirenz exhibits high interindividual variability in plasma concentrations, leading to unpredictable efficacy and toxicity. Polymorphism of CYP2B6 516G > T has been found to predominantly contribute to efavirenz variability. However, dosage recommendations incorporating CYP2B6 516G > T polymorphism have not been investigated in the Thai population. This study aimed to develop a population model of the pharmacokinetic properties of efavirenz, and to investigate the impact of patients' characteristics and CYP2B6 516G > T polymorphism on the pharmacokinetic properties of efavirenz. Model-based simulations were performed to provide genotype-based dosage optimization in a Thai population. METHODS: Plasma efavirenz concentrations measured at 12 h post-dose in 360 Thai HIV-infected patients with and without tuberculosis were analyzed by the nonlinear mixed-effects modeling approach. A 1-compartment model with first-order absorption and elimination was used for describing the pharmacokinetic properties of efavirenz. FINDINGS: The allele frequency of CYP2B6 516G > T was 34.17%. The efavirenz oral clearance were 11.9, 8.0, and 2.8 L/h in patients weighing 57 kg and having the CYP2B6 516 GG, 516 GT, and 516 TT genotypes, respectively. The use of rifampicin increased efavirenz oral clearance by 28%. The results from the simulations suggest that efavirenz dosages of 400, 300, and 100 mg once daily in Thai HIV mono-infected patients, and 800, 600, and 200 mg once daily in HIV/tuberculosis co-infected patients carrying CYP2B6 516 GG, 516 GT, and 516 TT, respectively. IMPLICATION: The results from this study provide a rationale for efavirenz dose adjustment based on CYP2B6 516G > T polymorphism in Thai HIV-infected patients, which could help to improve treatment outcomes in this population. ClinicalTrials.gov identifier: NCT01138267. (Clin Ther. 2020; 42:XXX-XXX) © 2020 Elsevier Inc. SN - 1879-114X UR - https://www.unboundmedicine.com/medline/citation/32451120/Dosage_Optimization_of_Efavirenz_Based_on_a_Population_Pharmacokinetic-Pharmacogenetic_Model_of_HIV-infected_Patients_in_Thailand L2 - https://linkinghub.elsevier.com/retrieve/pii/S0149-2918(20)30231-9 DB - PRIME DP - Unbound Medicine ER -