Pregnancy andCYP3A5Genotype Affect Day 7 Plasma Lumefantrine Concentrations

Abstract

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.

Early or deferred initiation of efavirenz during rifampicin‐based TB therapy has no significant effect on CYP3A induction in TB‐HIV infected patients

“…CYP3A5 is not expressed in most white populations due to the high frequency of a defective variant allele, CYP3A5*3 . In contrast, about 70% of the black African populations are CYP3A5 expressors as they carry the functional CYP3A5*1 allele (Kuehl et al, 2001 ; Mutagonda et al, 2019 ; Quaranta et al, 2006 ). Although CYP3A4 is genetically polymorphic, no clear link between genotype and variability in enzyme activity has been reported yet.…”

“…Although CYP3A4 is genetically polymorphic, no clear link between genotype and variability in enzyme activity has been reported yet. On the other hand, CYP3A5 genotype is the most important contributor to inter‐individual differences in CYP3A‐dependent drug disposition particularly in black African populations (Diczfalusy et al, 2008 ; Gebeyehu et al, 2011 ; Mukonzo, Waako, Ogwal‐Okeng, Gustafsson, & Aklillu, 2010 ; Mutagonda et al, 2019 ). We previously reported a significant influence of sex on CYP3A activity in healthy Ethiopian volunteers using the 4β‐OHC/Chol ratio as a marker (Gebeyehu et al, 2011 ) and also in healthy Ugandans using quinine as a CYP3A probe drug (Mukonzo, Waako, Ogwal‐Okeng, Gustafsson, & Aklillu, 2010 ).…”

Anti‐Infective Dosing in Special Populations: Pregnancy

“…Six studies published following this meta‐analysis were identified 15–20 . Out of these, five were inconclusive regarding need for dose adjustments but rather commented that the clinical relevance of statistically significant differences in pharmacokinetic parameters warrants further evaluation.…”

“…Six studies published following this meta-analysis were identified. [15][16][17][18][19][20] Out of these, five were inconclusive regarding need for dose adjustments but rather commented that the clinical relevance of statistically significant differences in pharmacokinetic parameters warrants further evaluation. All the studies used day-7 lumefantrine concentrations of either >175 ng/mL or >280 ng/mL as a proxy for adequate dosing to avoid treatment failure, based on the demonstrated correlation between concentrations below these targets and risk of recrudescent malaria.…”

Pregnancy Increases CYP3A Enzymes Activity as Measured by the 4β-Hydroxycholesterol/Cholesterol Ratio

“…A functional CYP3A5 enzyme is expressed in about 70% of the black African population [ 15 ], in contrast to European populations, where 80–90% of the individuals are homozygous for the non-functional CYP3A5*3 allele [ 16 ]. Studies involving non-pregnant populations reported contrasting effects of CYP3A5 genetic variations on the plasma 4β-OHC/Chol ratio.…”