<i>MRP2/ABCC2 C1515Y</i>
            Polymorphism Modulates Exposure to Lumefantrine During Artemether-Lumefantrine Antimalarial Therapy

Vos, Karin; Sciuto, Carlotta Lo; Piedade, Rita; Ashton, Michael; Björkman, Anders; Ngasala, Billy; Mårtensson, Andreas; Gil, José Pedro

doi:10.2217/pgs-2017-0032

Cited by 9 publications

(11 citation statements)

References 15 publications

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“…In HIV patients' cohort study, it was observed that patients receiving Efavirenz-based antiretoviral therapy (ART) (CYP3A inducer) had lower LF concentration compared with those receiving nevirapine-based ART and ART naive control group . Previous studies showed absence of CYP3A5*1 influence on LF concentration in nonpregnant population Vos et al, 2017), which could not be ascertained in this study due to a small sample size of nonpregnant women.…”

Section: Discussioncontrasting

confidence: 63%

“…The main findings include the following: 1) significantly lower day 7 LF plasma concentration in pregnant compared with nonpregnant women, 2) significant association of CYP3A5*1/*1 genotype and low body weight with low day 7 LF plasma concentration, and 3) low day 7 LF plasma concentration as a significant predictor of treatment failure. To date, there are limited studies investigating the effect of CYP3A and ABCB1 genotype on LF concentration and malaria treatment outcome Vos et al, 2017), and only one small sample size study reported effect of genotype on LF plasma concentration in pregnant women (Mutagonda et al, 2017). Therefore, the present study described the effect of pregnancy and CYP3A genotype on day 7 LF plasma concentration and malaria treatment outcome.…”

Section: Discussionmentioning

confidence: 89%

“…LF is a substrate of P-glycoprotein, and the effect of different transporters on LF concentration has been reported. The role of ABCB1c.3435 (Multi-Drug Resistance -MDR1) in HIV patients receiving Nevirapine-based ART and that of ABCC2 ( MDR2) in children under ,5 years has been described Vos et al, 2017). It has been reported that ABCB1 is highly expressed during pregnancy as a defense mechanism to protect the fetus from toxicity starting from the first trimester to term (Sun et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, few studies highlighted relevance of pharmacogenetics variations in determining patient variability in plasma LF exposure Mutagonda et al, 2017;Vos et al, 2017). In a small sample size study, it was reported that pregnant women who were carriers of functional CYP3A5 and CYP3A4*1B allele had lower day 7 LF concentrations and recrudescence, respectively, compared with the carriers of defective alleles (Mutagonda et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Pregnancy andCYP3A5Genotype Affect Day 7 Plasma Lumefantrine Concentrations

et al. 2019

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Pregnancy and pharmacogenetics variation alter drug disposition and treatment outcome. The objective of this study was to investigate the effect of pregnancy and pharmacogenetics variation on day 7 lumefantrine (LF) plasma concentration and therapeutic responses in malaria-infected women treated with artemetherlumefantrine (ALu) in Tanzania. A total of 277 (205 pregnant and 72 nonpregnant) women with uncomplicated Plasmodium falciparum malaria were enrolled. Patients were treated with ALu and followed up for 28 days. CYP3A4, CYP3A5, and ABCB1 genotyping were done. Day 7 plasma LF concentration and the polymerase chain reaction (PCR)corrected adequate clinical and parasitological response (ACPR) at day 28 were determined. The mean day 7 plasma LF concentrations were significantly lower in pregnant women than nonpregnant women [geometric mean ratio 5 1.40; 95% confidence interval (CI) of geometric mean ratio (1.119-1.1745), P < 0.003]. Pregnancy, low body weight, and CYP3A5*1/*1 genotype were significantly associated with low day 7 LF plasma concentration (P < 0.01). PCR-corrected ACPR was 93% (95% CI 5 89.4-96.6) in pregnant women and 95.7% (95% CI 5 90.7-100) in nonpregnant women. Patients with lower day 7 LF concentration had a high risk of treatment failure (mean 652 vs. 232 ng/ml, P < 0.001). In conclusion, pregnancy, low body weight, and CYP3A5*1 allele are significant predictors of low day 7 LF plasma exposure. In turn, lower day 7 LF concentration is associated with a higher risk of recrudescence. SIGNIFICANCE STATEMENTThis study reports a number of factors contributing to the lower day 7 lumefantrine (LF) concentration in women, which includes pregnancy, body weight, and CYP3A5*1/*1 genotype. It also shows that day 7 LF concentration is a main predictor of malaria treatment. These findings highlight the need to look into artemether-LF dosage adjustment in pregnant women so as to be able to maintain adequate drug concentration, which is required to reduce treatment failure rates in pregnant women.

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Section: Discussioncontrasting

confidence: 63%

Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pregnancy andCYP3A5Genotype Affect Day 7 Plasma Lumefantrine Concentrations

et al. 2019

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“…No significant associations between artemether‐lumefantrine treatment outcome and CYP3A4*1B and CYP3A5*3 are observed in patients with uncomplicated malaria in Angola 192 . The MRP2/ABCC2 1515YY polymorphism but not MDR1/ABCB1 C3435T was significantly associated with higher lumefantrine day 7 concentrations 193 . Genetic polymorphisms of both drug‐metabolizing enzymes and transport proteins could pose a high risk of interactions when antimalarial drugs and antiretroviral therapies are coadministered.…”

Section: Antimalarial Dose Optimization In Special Conditionsmentioning

confidence: 90%

The Role of Clinical Pharmacology in Chemotherapy of Multidrug‐Resistant Plasmodium falciparum

Karbwang

Na‐Bangchang

2020

The Journal of Clinical Pharma

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Malaria remains one of the major global public health problems due to the emergence and spread of multidrug‐resistant Plasmodium falciparum. In recent years, clinical pharmacology has significantly contributed to the optimal dosing regimens of antimalarial drugs. The application of pharmacometric modeling and simulation has assisted in the accurate characterization of pharmacokinetic‐pharmacodynamic relationships and the optimization of the dosage regimens of existing antimalarial drugs, including new antimalarial candidates for multidrug‐resistant P falciparum in different populations.

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*CYP2B6**6 Genotype Specific Differences in Artemether‐Lumefantrine Disposition in Healthy Volunteers

Abdullahi

Soyinka

Olagunju

et al. 2019

The Journal of Clinical Pharma

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Cytochrome P450 2B6 (CYP2B6) is involved in the metabolism of the antimalarial drugs artemether and lumefantrine. Here we investigated the effect of CYP2B6*6 on the plasma pharmacokinetics of artemether, lumefantrine, and their metabolites in healthy volunteers. Thirty healthy and previously genotyped adult volunteers—15 noncarriers (CYP2B6*1/*1) and 15 homozygote carriers (CYP2B6*6/*6)—selected from a cohort of 150 subjects from the Ilorin metropolitan area were administered the complete 3‐day course of artemether and lumefantrine (80 and 480 mg twice daily, respectively). Intensive pharmacokinetic sampling was conducted at different time points before and after the last dose. Plasma concentrations of artemether, lumefantrine, dihydroartemisinin, and desbutyllumefantrine were quantified using validated liquid chromatography–mass spectrometric methods. Pharmacokinetic parameters were evaluated using noncompartmental analysis. Artemether clearance of CYP2B6*6/*6 volunteers was nonsignificantly lower by 26% (ratios of geometric mean [90% CI]; 0.74 [0.52‐1.05]), and total exposure (the area under the plasma concentration‐time curve from time 0 to infinity [AUC0‐∞]) was greater by 35% (1.35 [0.95‐1.93]) when compared with those of *1/*1 volunteers. Similarly, assuming complete bioconversion from artemether, the dihydroartemisinin AUC0‐∞ was 22% lower. On the contrary, artemether‐to‐dihydroartemisinin AUC0‐∞ ratio was 73% significantly higher (1.73 [1.27‐2.37]). Comparison of lumefantrine exposure and lumefantrine‐to‐desbutyllumefantrine metabolic ratio of *6/*6 with corresponding data from *1/*1 volunteers showed no differences. The increased artemether‐to‐dihydroartemisinin metabolic ratio of *6/*6 volunteers is unlikely to result in differences in artemether‐lumefantrine efficacy and treatment outcomes. This is the first study in humans to associate CYP2B6*6 genotype with artemether disposition.

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MRP2/ABCC2 C1515Y Polymorphism Modulates Exposure to Lumefantrine During Artemether-Lumefantrine Antimalarial Therapy

Abstract: LUM body disposition may be influenced by MRP2/ABCC2 genotype.

Cited by 9 publications

References 15 publications

Pregnancy andCYP3A5Genotype Affect Day 7 Plasma Lumefantrine Concentrations

Pregnancy andCYP3A5Genotype Affect Day 7 Plasma Lumefantrine Concentrations

The Role of Clinical Pharmacology in Chemotherapy of Multidrug‐Resistant Plasmodium falciparum

*CYP2B6**6 Genotype Specific Differences in Artemether‐Lumefantrine Disposition in Healthy Volunteers

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MRP2/ABCC2 C1515Y Polymorphism Modulates Exposure to Lumefantrine During Artemether-Lumefantrine Antimalarial Therapy

Abstract: LUM body disposition may be influenced by MRP2/ABCC2 genotype.

Cited by 9 publications

References 15 publications

Pregnancy andCYP3A5Genotype Affect Day 7 Plasma Lumefantrine Concentrations

Pregnancy andCYP3A5Genotype Affect Day 7 Plasma Lumefantrine Concentrations

The Role of Clinical Pharmacology in Chemotherapy of Multidrug‐Resistant Plasmodium falciparum

CYP2B6*6 Genotype Specific Differences in Artemether‐Lumefantrine Disposition in Healthy Volunteers

Contact Info

Product

Resources

About

*CYP2B6**6 Genotype Specific Differences in Artemether‐Lumefantrine Disposition in Healthy Volunteers