Pharmacogenetics and pharmacokinetics of CNS penetration of efavirenz and its metabolites

Decloedt, Eric H.; Sinxadi, Phumla; Zyl, Gert van; Wiesner, Lubbe; Khoo, Saye; Joska, John A.; Haas, David W.; Maartens, Gary

doi:10.1093/jac/dky481

Cited by 15 publications

(19 citation statements)

References 45 publications

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“…Several clinical studies on African populations ( Table 1 ) have demonstrated the potential for PGx testing and dose adjustments in HIV patients receiving Efavirenz [ 26 , 27 , 28 , 30 , 41 , 42 ]. Other clinical studies have identified PGx biomarkers for African patients receiving rosuvastatin [ 43 ], imatinib [ 44 ], anti-retroviral (ARV) therapy, TB, and antimalarial comedication [ 25 , 45 , 46 , 47 ].…”

Section: Paucity Of Clinical Pharmacogenetics Studies In Ssamentioning

confidence: 99%

“…Distinct and highly diverse alleles of the Cytochrome P450 family have been recorded in African populations relative to other populations, highlighting the need for further dedicated PGx and functional studies on these unique variants [ 21 ]. For instance, the loss-of-function CYP2B6*6 allele which accounts for low efavirenz plasma levels and an increased risk of neurotoxicity, is highly prevalent in African populations relative to Europeans and Asians [ 30 ].…”

Section: Challenges In Genotyping Pharmacogene Variantsmentioning

confidence: 99%

“…This has led to clinical and non-clinical PGx research on African populations that has characterised some unique PGx biomarkers, thereby demonstrating the potential benefits of integrating PGx testing in clinical practice in SSA [ 24 , 25 , 26 , 27 , 28 , 29 ]. A classic example is the characterisation of highly prevalent CYP2B6*6 genetic variants in African populations associated with central nervous system toxicities in HIV patients on efavirenz treatment, which has led to specific drug dosage recommendations for African cohorts, relative to European populations [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

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Barriers to Implementing Clinical Pharmacogenetics Testing in Sub-Saharan Africa. A Critical Review

Tata

Ambele

2020

Pharmaceutics

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Clinical research in high-income countries is increasingly demonstrating the cost- effectiveness of clinical pharmacogenetic (PGx) testing in reducing the incidence of adverse drug reactions and improving overall patient care. Medications are prescribed based on an individual’s genotype (pharmacogenes), which underlies a specific phenotypic drug response. The advent of cost-effective high-throughput genotyping techniques coupled with the existence of Clinical Pharmacogenetics Implementation Consortium (CPIC) dosing guidelines for pharmacogenetic “actionable variants” have increased the clinical applicability of PGx testing. The implementation of clinical PGx testing in sub-Saharan African (SSA) countries can significantly improve health care delivery, considering the high incidence of communicable diseases, the increasing incidence of non-communicable diseases, and the high degree of genetic diversity in these populations. However, the implementation of PGx testing has been sluggish in SSA, prompting this review, the aim of which is to document the existing barriers. These include under-resourced clinical care logistics, a paucity of pharmacogenetics clinical trials, scientific and technical barriers to genotyping pharmacogene variants, and socio-cultural as well as ethical issues regarding health-care stakeholders, among other barriers. Investing in large-scale SSA PGx research and governance, establishing biobanks/bio-databases coupled with clinical electronic health systems, and encouraging the uptake of PGx knowledge by health-care stakeholders, will ensure the successful implementation of pharmacogenetically guided treatment in SSA.

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Section: Paucity Of Clinical Pharmacogenetics Studies In Ssamentioning

confidence: 99%

Section: Challenges In Genotyping Pharmacogene Variantsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Barriers to Implementing Clinical Pharmacogenetics Testing in Sub-Saharan Africa. A Critical Review

Tata

Ambele

2020

Pharmaceutics

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“…We previously reported LD plots for these polymorphisms. 18 …”

Section: Methodsmentioning

confidence: 99%

“…17 We previously reported on the pharmacogenetics of CSF penetration of efavirenz in black South Africans. 18 Here, we characterise the associations between transporter gene polymorphisms and CSF penetration of tenofovir and emtricitabine in the same cohort.…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenetics of tenofovir and emtricitabine penetration into cerebrospinal fluid

Decloedt

Sinxadi

Wiesner

et al. 2021

Southern African Journal of HIV Medicine

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Background: Blood-cerebrospinal fluid (CSF) barrier transporters affect the influx and efflux of drugs. The antiretrovirals tenofovir and emtricitabine may be substrates of blood-brain barrier (BBB) and blood-CSF barrier transporters, but data are limited regarding the pharmacogenetics and pharmacokinetics of their central nervous system (CNS) penetration.Objectives: We investigated genetic polymorphisms associated with CSF disposition of tenofovir and emtricitabine.Method: We collected paired plasma and CSF samples from 47 HIV-positive black South African adults who were virologically suppressed on efavirenz, tenofovir and emtricitabine. We considered 1846 single-nucleotide polymorphisms from seven relevant transporter genes (ABCC5, ABCG2, ABCB1, SLCO2B1, SCLO1A2, SLCO1B1 and ABCC4) and 782 met a linkage disequilibrium (LD)-pruning threshold.Results: The geometric mean (95% confidence interval [CI]) values for tenofovir and emtricitabine CSF-to-plasma concentration ratios were 0.023 (0.021–0.026) and 0.528 (0.460–0.605), respectively. In linear regression models, the lowest p-value for association with the tenofovir CSF-to-plasma ratio was ABCB1 rs1989830 (p = 1.2 × 10−3) and for emtricitabine, it was ABCC5 rs11921035 (p = 1.4 × 10−3). None withstood correction for multiple testing.Conclusion: No genetic polymorphisms were associated with plasma, CSF concentrations or CSF-to-plasma ratios for either tenofovir or emtricitabine.

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Blood and cerebrospinal fluid biomarker changes in patients with HIV-associated neurocognitive impairment treated with lithium: analysis from a randomised placebo-controlled trial

et al. 2023

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HIV-associated neurocognitive disorders (HAND) persist in the era of antiretroviral therapy (ART). Thus, ART does not completely halt or reverse the pathological processes behind HAND. Adjuvant mitigating treatments are, therefore, prudent. Lithium treatment is known to promote neuronal brain–derived neurotrophic factors (BDNF). Lithium is also an inhibitor of glycogen synthase kinase-3 beta (GSK-3-β). We analyzed biomarkers obtained from participants in a randomized placebo-controlled trial of lithium in ART-treated individuals with moderate or severe HAND. We assayed markers at baseline and 24 weeks across several pathways hypothesized to be affected by HIV, inflammation, or degeneration. Investigated biomarkers included dopamine, BDNF, neurofilament light chain, and CD8 + lymphocyte activation (CD38 + HLADR +). Alzheimer’s Disease (AD) biomarkers included soluble amyloid precursor protein alpha and beta (sAPPα/β), Aβ38, 40, 42, and ten other biomarkers validated as predictors of mild cognitive impairment and progression in previous studies. These include apolipoprotein C3, pre-albumin, α1-acid glycoprotein, α1-antitrypsin, PEDF, CC4, ICAM-1, RANTES, clusterin, and cystatin c. We recruited 61 participants (placebo = 31; lithium = 30). The age baseline mean was 40 (± 8.35) years and the median CD4 + T-cell count was 498 (IQR: 389–651) cells/μL. Biomarker concentrations between groups did not differ at baseline. However, both groups’ blood dopamine levels decreased significantly after 24 weeks (adj. p < 002). No other marker was significantly different between groups, and we concluded that lithium did not confer neuroprotection following 24 weeks of treatment. However, the study was limited in duration and sample size.

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Pharmacogenetics and pharmacokinetics of CNS penetration of efavirenz and its metabolites

Cited by 15 publications

References 45 publications

Barriers to Implementing Clinical Pharmacogenetics Testing in Sub-Saharan Africa. A Critical Review

Barriers to Implementing Clinical Pharmacogenetics Testing in Sub-Saharan Africa. A Critical Review

Pharmacogenetics of tenofovir and emtricitabine penetration into cerebrospinal fluid

Blood and cerebrospinal fluid biomarker changes in patients with HIV-associated neurocognitive impairment treated with lithium: analysis from a randomised placebo-controlled trial

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