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Background: Coadministration of artemether-lumefantrine and efavirenz has been shown to result in significant interactions. The influence of functional genetic polymorphisms in selected CYPs on the magnitude of this interaction was investigated in pregnant and nonpregnant adults., Method: A standard 3-day regimen of artemether-lumefantrine was administered to each patient on steady-state efavirenz-based antiretroviral therapy (ART). Pharmacokinetic parameters were obtained from intensive plasma concentration-time data. Genotyping data were tested for compliance with Hardy-Weinberg equilibrium by Chi-square test. Linear regressions, Mann-Whitney U-test or Kruskal-Wallis tests were conducted to examine the association of lumefantrine plasma level with CYP2B6 c.516G>T, NR1I3 152c-1089T>C, CYP2B6 c.983T>C, CYP3A5*3 and CYP3A4*22., Results: Among a total of 69 malaria-HIV coinfected patients (34 nonpregnant and 35 pregnant), median (interquartile range) age was 33 (27-36.5) years and body weight was 59.5 (50-67.5) kg. In nonpregnant group, CYP2B6 c.516G>T was significantly associated with lower log Cday 7 of lumefantrine using multivariate linear regressions (β = -0.239; P = 0.013). In 59% of women with CYP2B6 c.516T, Cday 7 of lumefantrine was below the target of 280 ng/mL compared to 47% in the noncarriers. CYP2B6 c.983T>C significantly associated with higher log Cday 7 of desbutyl lumefantrine in both pregnant (β = 0.383; P = 0.033) and nonpregnant (β = 0.395; P = 0.023) groups. Composite genotypes for both CYP2B6 Single-nucleotide polymorphisms strongly associated with lumefantrine plasma concentration. An associative trend between lumefantrine pharmacokinetics and NR1I3 152c-1089T>C genotypes indicated that 70% of the Cday 7 of lumefantrine in those with NR1I3 152c-1089TT genotype was below 280 ng/mL compared to 53% in those with NR1I3 152c-1089CC or CT genotype., Conclusion: The findings revealed that the efavirenz-lumefantrine interaction was accentuated in the group with CYP2B6 c.516T, c.983C and NR1I3 152c-1089T alleles. This warrants further investigations of other drug-drug interactions for optimising dosing in genetically defined subgroups, particularly during drug development.

Background and Objective: MAMA decoction (MD) is an antimalarial product prepared from the leaves of Mangifera indica L. (Anacardiaceae), Alstonia boonei De Wild (Apocynaceae), Morinda lucida Benth (Rubiaceae) and Azadirachta indica A. Juss (Meliaceae). A previous report showed that MD enhanced the efficacy of amodiaquine (AQ) in malaria-infected mice, thus suggesting a herb-drug interaction. The present study hence evaluated the effect of MD on the disposition of AQ in mice with a view to investigating a possible pharmacokinetic interaction., Methods: In a 3-period study design, three groups of mice (n = 72) were administered oral doses of AQ (10 mg/kg/day) alone, concurrently with MD (120 mg/kg/day), and in the 3rd period, mice were given AQ after a 3-day pre-treatment with MD. Blood samples were collected between 0 and 96 h for quantification of AQ and its major metabolite, desethylamodiaquine, by a validated high-performance liquid chromatography method., Results: Maximum concentrations of AQ increased by 12% with the concurrent dosing of MD and by 85% in the group of mice pre-treated with MD. The exposure and half-life of desethylamodiaquine increased by approximately 11% and 21%, respectively, with concurrent administration. Corresponding increases of approximately 20% and 33% of desethylamodiaquine were also observed in mice pre-treated with MD., Conclusion: MD influenced the pharmacokinetics of AQ and desethylamodiaquine, its major metabolite. The increase in the half-life and systemic exposure of AQ following its co-administration with MD may provide a basis for the enhanced pharmacological effect of the combination in an earlier study in Plasmodium-infected mice.

Abstract: Amodiaquine (AQ) and pioglitazone (PGZ) are both metabolized by CYP2C8, an enzyme also inhibited by PGZ. These drugs are likely to be administered in instances of comorbidity of malaria with type 2 diabetes. This study, hence, evaluated the possibility of a drug interaction resulting from the concurrent use of both drugs. A 3‐period crossover design in 10 healthy subjects, that assessed the disposition of AQ and PGZ alone and when coadministered, was implemented with the administration of single oral doses of AQ and PGZ. Whole‐blood samples collected between 0 and 24 hours on protein saver cards across the study periods were processed and analyzed for AQ and PGZ contents. Pharmacokinetic parameters were derived by a noncompartmental analysis. Geometric mean ratios for the Cmax, area under the concentration‐time curve for 24 hours (AUC0‐24h), and AUC0‐∞, alongside their corresponding 90%CIs, were compared across the study periods to infer clinically significant changes in disposition. The coadministration of AQ and PGZ resulted in decreases of about 38% and 54% in the Cmax and AUC0‐24h of AQ, respectively. For PGZ, the Cmax increased by about 50%, and AUC0‐24 rose by 48%. The 90%CIs of geometric mean ratios for the Cmax, AUC0‐24h, and AUC0‐∞ were all outside the expected bioequivalence interval of 80% to 125% for both drugs, implying significant interactions. These findings suggest that a bidirectional interaction between AQ and PGZ, with likely implications for the therapy and toxicity of both drugs, may occur in the event of their coadministration. [ABSTRACT FROM AUTHOR]

Background: Artemisinin combination therapy is first-line therapy for treatment of malaria, which is one of the most significant public health problems in Nigeria. With the increasing level of use of these drugs coupled with the emergence of resistance, there is a need for regular post-market surveillance. Method: Twenty different brands of artesunate-containing antimalarial drugs and 10 brands of artemether–lumefantrine were multi-sourced in the south western part of Nigeria and were subjected to identification, weight uniformity test, and assay using United State pharmacopoeia and International Pharmacopoeia monographs. In vitro-dissolution test of the artemether tablets was also investigated. Results: All 10 brands (100%) of the artemether-lumefantrine tablets met the assay requirement for artemether and 8 (80%) met the assay requirement for lumefantrine, but only 4 brands (40%) met the requirement for artemether dissolution. One of these brands failed the weight uniformity test. Of the 20 brands of artesunate-containing brands included in this study, 15 (75%) met the standard assay requirement for artesunate and two failed the weight uniformity test. Conclusions: There is evidence of the presence of substandard artemisinin products in the Nigerian market. [ABSTRACT FROM AUTHOR]