Genetic and non‐genetic factors influencing efavirenz population pharmacokinetics among human immunodeficiency virus‐1‐infected children in Ethiopia
Abstract Despite the potential for efavirenz (EFV) to be an effective alternative antiretroviral agent, its sources of wide inter‐ and intra‐individual pharmacokinetic (PK) variability are not well‐characterized in children. We investigated the effects of genetic and non‐genetic factors, including d...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-06-01
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| Series: | CPT: Pharmacometrics & Systems Pharmacology |
| Online Access: | https://doi.org/10.1002/psp4.12951 |
| _version_ | 1827924612734779392 |
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| author | Adugna Chala Eliford Ngaimisi Kitabi Jemal Hussien Ahmed Birkneh Tilahun Tadesse Tolossa Eticha Chaka Eyasu Makonnen Eleni Aklillu |
| author_facet | Adugna Chala Eliford Ngaimisi Kitabi Jemal Hussien Ahmed Birkneh Tilahun Tadesse Tolossa Eticha Chaka Eyasu Makonnen Eleni Aklillu |
| author_sort | Adugna Chala |
| collection | DOAJ |
| description | Abstract Despite the potential for efavirenz (EFV) to be an effective alternative antiretroviral agent, its sources of wide inter‐ and intra‐individual pharmacokinetic (PK) variability are not well‐characterized in children. We investigated the effects of genetic and non‐genetic factors, including demographic, treatment duration, baseline clinical, and biochemical characteristics, on the PKs of EFV through population‐PK modeling. Antiretroviral therapy (ART) naïve HIV infected children, 3–16 years (n = 100), were enrolled in Ethiopia and received EFV‐based combination ART. EFV concentrations after the first dose and at steady‐state collected over a span of 1 year were modeled using population‐based methods. A one‐compartment model with first‐order absorption kinetics described the observed EFV data adequately. The CYP2B6*6 and ABCB1c.4036A>G genotypes were identified as major factors influencing EFV clearance. The typical estimates of oral clearance, volume of distribution, and absorption rate constant for typical 22 kg children with CYP2B6 *1/*1 and ABCB1c.4036G/G genotypes were 4.3 L/h, 124 L, and 0.776/h, respectively. Clearance was reduced by 28% and 72% in CYP2B6*1/*6 and CYP2B6*6/*6 genotypes, respectively. Compared to week 1, clearance was higher from weeks 8 and 12 in CYP2B6*1/*6 and CYP2B6*1/*1 genotypes, respectively. Simulations indicated that EFV 12‐h concentrations were comparable across weight bands, but more than 80% of subjects with CYP2B6*6/*6 had EFV concentrations greater than 4 μg/mL. EFV PK variability among children is partly explained by body weight, treatment duration, CYP2B6*6, and ABCB1 rs3842 genotypes. Therefore, in addition to body weight, pediatric dosing of EFV should consider pharmacogenetic variability, duration of therapy, and individual treatment outcomes. |
| first_indexed | 2024-03-13T05:13:08Z |
| format | Article |
| id | doaj.art-7cf022a5a3bd475c8fc6c38a045b754a |
| institution | Directory Open Access Journal |
| issn | 2163-8306 |
| language | English |
| last_indexed | 2024-03-13T05:13:08Z |
| publishDate | 2023-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | CPT: Pharmacometrics & Systems Pharmacology |
| spelling | doaj.art-7cf022a5a3bd475c8fc6c38a045b754a2023-06-16T04:18:33ZengWileyCPT: Pharmacometrics & Systems Pharmacology2163-83062023-06-0112678379410.1002/psp4.12951Genetic and non‐genetic factors influencing efavirenz population pharmacokinetics among human immunodeficiency virus‐1‐infected children in EthiopiaAdugna Chala0Eliford Ngaimisi Kitabi1Jemal Hussien Ahmed2Birkneh Tilahun Tadesse3Tolossa Eticha Chaka4Eyasu Makonnen5Eleni Aklillu6Department of Pharmacology and Clinical Pharmacy, College of Health Sciences Addis Ababa University Addis Ababa EthiopiaDivision of Pharmacometrics Office of Clinical Pharmacology, Food and Drugs Administration Silver Spring Maryland USADepartment of Pharmacy Jimma University Jimma EthiopiaDepartment of Global Public Health Karolinska Institutet, Widerströmska Huset Stockholm SwedenDepartment of Pediatrics and Child Health Adama Hospital Medical College Adama EthiopiaDepartment of Pharmacology and Clinical Pharmacy, College of Health Sciences Addis Ababa University Addis Ababa EthiopiaDepartment of Global Public Health Karolinska Institutet, Widerströmska Huset Stockholm SwedenAbstract Despite the potential for efavirenz (EFV) to be an effective alternative antiretroviral agent, its sources of wide inter‐ and intra‐individual pharmacokinetic (PK) variability are not well‐characterized in children. We investigated the effects of genetic and non‐genetic factors, including demographic, treatment duration, baseline clinical, and biochemical characteristics, on the PKs of EFV through population‐PK modeling. Antiretroviral therapy (ART) naïve HIV infected children, 3–16 years (n = 100), were enrolled in Ethiopia and received EFV‐based combination ART. EFV concentrations after the first dose and at steady‐state collected over a span of 1 year were modeled using population‐based methods. A one‐compartment model with first‐order absorption kinetics described the observed EFV data adequately. The CYP2B6*6 and ABCB1c.4036A>G genotypes were identified as major factors influencing EFV clearance. The typical estimates of oral clearance, volume of distribution, and absorption rate constant for typical 22 kg children with CYP2B6 *1/*1 and ABCB1c.4036G/G genotypes were 4.3 L/h, 124 L, and 0.776/h, respectively. Clearance was reduced by 28% and 72% in CYP2B6*1/*6 and CYP2B6*6/*6 genotypes, respectively. Compared to week 1, clearance was higher from weeks 8 and 12 in CYP2B6*1/*6 and CYP2B6*1/*1 genotypes, respectively. Simulations indicated that EFV 12‐h concentrations were comparable across weight bands, but more than 80% of subjects with CYP2B6*6/*6 had EFV concentrations greater than 4 μg/mL. EFV PK variability among children is partly explained by body weight, treatment duration, CYP2B6*6, and ABCB1 rs3842 genotypes. Therefore, in addition to body weight, pediatric dosing of EFV should consider pharmacogenetic variability, duration of therapy, and individual treatment outcomes.https://doi.org/10.1002/psp4.12951 |
| spellingShingle | Adugna Chala Eliford Ngaimisi Kitabi Jemal Hussien Ahmed Birkneh Tilahun Tadesse Tolossa Eticha Chaka Eyasu Makonnen Eleni Aklillu Genetic and non‐genetic factors influencing efavirenz population pharmacokinetics among human immunodeficiency virus‐1‐infected children in Ethiopia CPT: Pharmacometrics & Systems Pharmacology |
| title | Genetic and non‐genetic factors influencing efavirenz population pharmacokinetics among human immunodeficiency virus‐1‐infected children in Ethiopia |
| title_full | Genetic and non‐genetic factors influencing efavirenz population pharmacokinetics among human immunodeficiency virus‐1‐infected children in Ethiopia |
| title_fullStr | Genetic and non‐genetic factors influencing efavirenz population pharmacokinetics among human immunodeficiency virus‐1‐infected children in Ethiopia |
| title_full_unstemmed | Genetic and non‐genetic factors influencing efavirenz population pharmacokinetics among human immunodeficiency virus‐1‐infected children in Ethiopia |
| title_short | Genetic and non‐genetic factors influencing efavirenz population pharmacokinetics among human immunodeficiency virus‐1‐infected children in Ethiopia |
| title_sort | genetic and non genetic factors influencing efavirenz population pharmacokinetics among human immunodeficiency virus 1 infected children in ethiopia |
| url | https://doi.org/10.1002/psp4.12951 |
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