The Influence of Pharmacogenetic Variants in HIV/Tuberculosis Coinfected Patients in Uganda in the SOUTH Study

Calcagno, Andrea; Cusato, Jessica; Sekaggya-Wiltshire, Christine; Braun, Amrei von; Motta, Ilaria; Turyasingura, Grace; Castelnuovo, Barbara; Fehr, Jan; Perri, Giovanni Di; Lamorde, Mohammed

doi:10.1002/cpt.1403

Cited by 15 publications

(11 citation statements)

References 38 publications

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“…The proposed dosing strategy is restricted by resources to determine acetylator status. However, genotype‐based tailoring of antitubercular therapy could be used in hard‐to‐treat patients even if resources are limited …”

Section: Discussionmentioning

confidence: 99%

Model‐Based Assessment of Variability in Isoniazid Pharmacokinetics and Metabolism in Patients Co‐Infected With Tuberculosis and HIV: Implications for a Novel Dosing Strategy

Sundell

Bienvenu

Janzén

et al. 2020

Clin Pharma and Therapeutics

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Tuberculosis is the most common cause of death in HIV‐infected patients. Isoniazid is used as a first‐line drug to treat tuberculosis infection. However, variability in isoniazid pharmacokinetics can result in hepatotoxicity or treatment failure. Determination of clinical factors affecting isoniazid pharmacokinetics and metabolic pathways in HIV co‐infected patients is therefore critical. Plasma levels of isoniazid, acetyl‐isoniazid, and isonicotinic acid from 63 patients co‐infected with tuberculosis and HIV were analyzed by liquid chromatography with tandem mass spectrometry followed by nonlinear mixed‐effects modeling. Patients were genotyped to determine acetylator status. Patients were either on concomitant efavirenz‐based antiretroviral therapy or HIV treatment naïve. Clearances of isoniazid were 1.3‐fold and 2.3‐fold higher in intermediate and rapid acetylators, respectively, compared with slow acetylators. Patients on concomitant efavirenz‐based antiretroviral therapy had 64% and 80% higher population predicted clearances of acetyl‐isoniazid and isonicotinic acid, respectively, compared with patients who were HIV treatment naïve. Both sex and CD4 cell count affected the bioavailability of isoniazid. Variability in isoniazid exposure could be reduced by dose adaptions based on acetylator type and sex in addition to the currently used weight bands. A novel dosing strategy that has the potential to reduce isoniazid‐related toxicity and treatment failure is presented.

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Section: Discussionmentioning

confidence: 99%

Model‐Based Assessment of Variability in Isoniazid Pharmacokinetics and Metabolism in Patients Co‐Infected With Tuberculosis and HIV: Implications for a Novel Dosing Strategy

Sundell

Bienvenu

Janzén

et al. 2020

Clin Pharma and Therapeutics

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“…The association of SLCO1B1 rs4149056, rs2306283, rs4149032 and rs11045819 polymorphisms with rifampicin PK reported in certain studies were not replicated in other studies. Recent studies from the African population have not found any association with SLCO1B1 polymorphisms and rifampicin exposures among TB patients 22,26,27 . Similarly, studies conducted by Ramesh et al 28 and Jeremiah et al 29 in the Indian and Tanzanian population, respectively, did not report any association of SLCO1B1 polymorphisms with plasma rifampicin exposures.…”

Section: Discussionmentioning

confidence: 89%

“…Recent studies from the African population have not found any association with SLCO1B1 polymorphisms and rifampicin exposures among TB patients. 22,26,27 Similarly, studies conducted by Ramesh et al 28 and Jeremiah et al 29…”

Section: Allegra Et Al Reported Higher Plasma Rifampicin Concentrations In Tbmentioning

confidence: 92%

Relationship among genetic polymorphism of SLCO1B1, rifampicin exposure and clinical outcomes in patients with active pulmonary tuberculosis

Kim

Kwon

Chung

et al. 2021

Brit J Clinical Pharma

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Aims: Rifampicin is a key drug for the treatment of tuberculosis (TB). Little is known for the relationship between the rifampicin pharmacokinetics and genetic polymorphisms in the Asian population. We aimed to investigate relationship between genetic polymorphism of SLCO1B1 and rifampicin exposure and its impact on clinical outcomes in Korean patients with active pulmonary TB.Methods: From February 2016 to December 2019, patients with active pulmonary TB who were taking rifampicin for >1 week were prospectively enrolled. Serial or 1-time blood sampling was conducted to determine rifampicin concentrations. The genotype of 4 single nucleotide polymorphisms of SLCO1B1 was determined. To estimate the drug clearance and exposure, population pharmacokinetics analysis was conducted. Clinical outcomes such as time to acid-fast bacteria culture conversion, chest radiograph score changes from baseline, and all-cause mortality were also evaluated. The exposure among different SLCO1B1 genotype was compared and relationship between drug exposure and clinical outcomes were explored.Results: A total of 105 patients (70 males and 35 females) were included in the final analysis. The mean age of patients was 55.4 years. The mean drug clearance and exposure were 13.6 L/h and 57.9 mg h/L, respectively. The genetic polymorphisms of SLCO1B1 were not related to rifampicin clearance or exposure. As the rifampicin exposure increased, the chest radiographs improved significantly, but the duration of acid-fast bacteria culture conversion was not related to the drug exposure.Conclusion: SLCO1B1 gene polymorphisms did not influence rifampicin concentrations and clinical outcomes in Korean patients with active pulmonary TB.

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“…However, recent studies from the African population have not found any association with SLCO1B1 polymorphisms and RF exposures among TB patients [48,51,52]. Similarly, studies conducted by Ramesh et al and Jeremiah et al in the Indian and Tanzanian population, respectively, did not report any association of SLCO1B1 polymorphisms with plasma RF exposures (Table 1) [53,54].…”

Section: Slco1b1mentioning

confidence: 90%

“…Reports from the Brazilian population revealed the frequencies of FokI TT, TC and CC genotypes to be 44.6%, 41.4% and 14%, respectively [80]. Calcagno et al reported that the VDR regulatory region Cdx2 variant was not associated with any significant changes in the plasma RF concentration [52].…”

Section: Vitamin D Pathway Gene Polymorphismsmentioning

confidence: 99%

Influence of Single Nucleotide Polymorphisms on Rifampin Pharmacokinetics in Tuberculosis Patients

et al. 2020

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Rifampin (RF) is metabolized in the liver into an active metabolite 25-desacetylrifampin and excreted almost equally via biliary and renal routes. Various influx and efflux transporters influence RF disposition during hepatic uptake and biliary excretion. Evidence has also shown that Vitamin D deficiency (VDD) and Vitamin D receptor (VDR) polymorphisms are associated with tuberculosis (TB). Hence, genetic polymorphisms of metabolizing enzymes, drug transporters and/or their transcriptional regulators and VDR and its pathway regulators may affect the pharmacokinetics of RF. In this narrative review, we aim to identify literature that has explored the influence of single nucleotide polymorphisms (SNPs) of genes encoding drug transporters and their transcriptional regulators (SLCO1B1, ABCB1, PXR and CAR), metabolizing enzymes (CES1, CES2 and AADAC) and VDR and its pathway regulators (VDR, CYP27B1 and CYP24A1) on plasma RF concentrations in TB patients on antitubercular therapy. Available reports to date have shown that there is a lack of any association of ABCB1, PXR, CAR, CES1 and AADAC genetic variants with plasma concentrations of RF. Further evidence is required from a more comprehensive exploration of the association of SLCO1B1, CES2 and Vitamin D pathway gene variants with RF pharmacokinetics in distinct ethnic groups and a larger population to reach conclusive information.

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The Influence of Pharmacogenetic Variants in HIV/Tuberculosis Coinfected Patients in Uganda in the SOUTH Study

Cited by 15 publications

References 38 publications

Model‐Based Assessment of Variability in Isoniazid Pharmacokinetics and Metabolism in Patients Co‐Infected With Tuberculosis and HIV: Implications for a Novel Dosing Strategy

Model‐Based Assessment of Variability in Isoniazid Pharmacokinetics and Metabolism in Patients Co‐Infected With Tuberculosis and HIV: Implications for a Novel Dosing Strategy

Relationship among genetic polymorphism of SLCO1B1, rifampicin exposure and clinical outcomes in patients with active pulmonary tuberculosis

Influence of Single Nucleotide Polymorphisms on Rifampin Pharmacokinetics in Tuberculosis Patients

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