Norah Mwebaza

Pharmacovigilance of antimalarial treatment in Uganda: community perceptions and suggestions for reporting adverse events

Objectives  The deployment of new antimalarials in Africa provides an important opportunity to develop systems for pharmacovigilance. To inform strategies for reporting adverse events in Uganda, we investigated local perceptions and experiences with antimalarial treatment, and evaluated existing and potential systems for pharmacovigilance.

Antiretroviral Therapy With Efavirenz Accentuates Pregnancy‐Associated Reduction of Dihydroartemisinin‐Piperaquine Exposure During Malaria Chemoprevention

Dihydroartemisinin (DHA)‐piperaquine is promising for malaria chemoprevention in pregnancy. We assessed the impacts of pregnancy and efavirenz‐based antiretroviral therapy on exposure to DHA and piperaquine in pregnant Ugandan women. Intensive sampling was performed at 28 weeks gestation in 31 HIV‐uninfected pregnant women, in 27 HIV‐infected pregnant women receiving efavirenz, and in 30 HIV‐uninfected nonpregnant women. DHA peak concentration and area under the concentration time curve (AUC0‐8hr) were 50% and 47% lower, respectively, and piperaquine AUC0‐21d was 40% lower in pregnant women compared to nonpregnant women. DHA AUC0‐8hr and piperaquine AUC0‐21d were 27% and 38% lower, respectively, in pregnant women receiving efavirenz compared to HIV‐uninfected pregnant women. Exposure to DHA and piperaquine were lower among pregnant women and particularly in women on efavirenz, suggesting a need for dose modifications. The study of modified dosing strategies for these populations is urgently needed.

Antiretroviral Choice for HIV Impacts Antimalarial Exposure and Treatment Outcomes in Ugandan Children

Pharmacokinetic/pharmacodynamic studies of artemether-lumefantrine and 3 antiretroviral regimens were conducted in malaria-infected Ugandan children. Efavirenz-based treatment was associated with significant reductions in antimalarial exposure and higher risks of recurrent malaria. Caution in their concurrent use is warranted.

Artemether-Lumefantrine Pharmacokinetics and Clinical Response Are Minimally Altered in Pregnant Ugandan Women Treated for Uncomplicated Falciparum Malaria

ABSTRACT Artemether-lumefantrine is a first-line regimen for the treatment of uncomplicated malaria during the second and third trimesters of pregnancy. Previous studies have reported changes in the pharmacokinetics and clinical outcomes following treatment with artemether-lumefantrine in pregnant women compared to nonpregnant adults; however, the results are inconclusive. We conducted a study in rural Uganda to compare the pharmacokinetics of artemether-lumefantrine and the treatment responses between 30 pregnant women and 30 nonpregnant adults with uncomplicated Plasmodium falciparum malaria. All participants were uninfected with HIV, treated with a six-dose regimen of artemether-lumefantrine, and monitored clinically for 42 days. The pharmacokinetics of artemether, its metabolite dihydroartemisinin, and lumefantrine were evaluated for 21 days following treatment. We found no significant differences in the overall pharmacokinetics of artemether, dihydroartemisinin, or lumefantrine in a direct comparison of pregnant women to nonpregnant adults, except for a statistically significant but small difference in the terminal elimination half-lives of both dihydroartemisinin and lumefantrine. There were seven PCR-confirmed reinfections (5 pregnant and 2 nonpregnant participants). The observation of a shorter terminal half-life for lumefantrine may have contributed to a higher frequency of reinfection or a shorter posttreatment prophylactic period in pregnant women than in nonpregnant adults. While the comparable overall pharmacokinetic exposure is reassuring, studies are needed to further optimize antimalarial efficacy in pregnant women, particularly in high-transmission settings and because of emerging drug resistance. (This study is registered at ClinicalTrials.gov under registration no. NCT01717885.)

Parasite Clearance and Artemether Pharmacokinetics Parameters Over the Course of Artemether-Lumefantrine Treatment for Malaria in Human Immunodeficiency Virus (HIV)-Infected and HIV-Uninfected Ugandan Children

Background. Artemisinins are primarily responsible for initial parasite clearance. Antimalarial pharmacokinetics (PK), human immunodeficiency virus (HIV) infection, and antiretroviral therapy have been shown to impact treatment outcomes, although their impact on early parasite clearance in children has not been well characterized. Methods. Parasite clearance parameters were generated from twice-daily blood smears in HIV-infected and HIV-uninfected Ugandan children treated with artemether-lumefantrine (AL). Artemether and dihydroartemisinin (DHA) area-under-the-curve from 0–8 hours (AUC0-8hr) after the 1st AL dose was compared with AUC0-8hr after the last (6th) dose in a concurrently enrolled cohort. The association between post-1st dose artemisinin AUC0-8hr and parasite clearance was assessed. Results. Parasite clearance was longer in HIV-infected versus HIV-uninfected children (median, 3.5 vs 2.8 hours; P = .003). Artemether AUC0-8hr was 3- to 4-fold lower after the 6th dose versus the 1st dose of AL in HIV-infected children on nevirapine- or lopinavir/ritionavir-based regimens and in HIV-uninfected children (P ≤ .002, 1st vs 6th-dose comparisons). Children on efavirenz exhibited combined post-1st dose artemether/DHA exposure that was significantly lower than those on lopinavir/ritonavir and HIV-uninfected children. Multiple regression analysis supported that the effect of artemether/DHA exposure on parasite clearance was significantly moderated by HIV status. Conclusions. Parasite clearance rates remain rapid in Uganda and were not found to associate with PK exposure. However, significant decreases in artemisinin PK with repeated dosing in nearly all children, coupled with small, but significant increase in parasite clearance half-life in those with HIV, may have important implications for AL efficacy, particularly because reports of artemisinin resistance are increasing.

Oil-Fortified Maize Porridge Increases Absorption of Lumefantrine in Children with Uncomplicated Falciparum Malaria.

Artemether‐lumefantrine (AL) is a first‐line treatment for uncomplicated malaria. Absorption of lumefantrine (LUM) is fat dependent, and in children, intake is recommended with milk. We investigated whether oil‐fortified maize porridge can be an alternative when milk is not available. In an open‐label pharmacokinetic study, Ugandan children <5 years with uncomplicated Plasmodium falciparum malaria were randomized to receive standard six‐dose AL treatment [one tablet (20 mgA/120 mg LUM) if <15 kg and two tablets if >15 kg] with milk (A) or maize porridge plus oil (B). Parametric two‐sample t‐test was used to compare relative oral LUM bioavailability. The primary end‐point was LUM exposure till 8 hr after the first dose (AUC0–8 hr). Secondary outcome included day 7 concentrations (d7LUM), LUM exposure between days 7 and 28 (AUCd7–28) and day 28 PCR‐adjusted parasitological response. Evaluable children (n = 33) included 16 in arm A and 17 in arm B. The AUC0–8 hr was comparable between A and B [geometric mean (95% CI): 6.01 (3.26–11.1) versus 6.26 (4.5–8.43) hr*μg/mL, p = 0.9]. Less interindividual variability in AUC0–8 hr was observed in B (p = 0.01), but d7LUM and AUCd7–28 were comparable. Children receiving two tablets had significantly higher exposure than those receiving one tablet [median d7LUM (505 versus 289 ng/mL, p = 0.02) and AUCd7–28 (108 versus 41 hr*μg/mL, p = 0.006)]. One parasitological failure (d28 recrudescence) was observed. Our findings suggest that oil‐fortified maize porridge can be an alternative to milk in augmenting absorption of LUM. The lower LUM exposure observed in children dosed with one AL tablet needs further attention.

Strong correlation of lumefantrine concentrations in capillary and venous plasma from malaria patients

Background Lumefantrine is a long-acting antimalarial drug with an elimination half-life of over 3 days and protein binding of 99 percent. Correlation of lumefantrine concentrations from capillary plasma via fingerprick (Cc) versus venous plasma (Cv) remains to be defined. Methods Venous and capillary plasma samples were collected simultaneously from children, pregnant women, and non-pregnant adults at 2, 24, 120hr post last dose of a standard 3-day artemether-lumefantrine regimen they received for uncomplicated malaria. Some of the enrolled children and pregnant women were also HIV-infected. Samples were analyzed via liquid chromatography tandem mass spectrometry. Linear regression analysis was performed using the program Stata® SE12.1. Results In children, the linear regression equations for Cc vs Cv at 2, 24, and 120hr (day 7) post dose are [Cc] = 1.05*[Cv]+95.0 (n = 142, R2 = 0.977), [Cc] = 0.995*[Cv]+56.7 (n = 147, R2 = 0.990) and [Cc] = 0.958*[Cv]+18.6 (n = 139, R2 = 0.994), respectively. For pregnant women, the equations are [Cc] = 1.04*[Cv]+68.1 (n = 43, R2 = 0.990), [Cc] = 0.997*[Cv]+37.3 (n = 43, R2 = 0.993) and [Cc] = 0.941*[Cv]+11.1 (n = 41, R2 = 0.941), respectively. For non-pregnant adults, the equations are [Cc] = 1.05*[Cv]-117 (n = 32, R2 = 0.958), [Cc] = 0.962*[Cv]+9.21 (n = 32, R2 = 0.964) and [Cc] = 1.04*[Cv]-40.1 (n = 32, R2 = 0.988), respectively. In summary, a linear relationship with a slope of ~1 was found for capillary and venous lumefantrine levels in children, pregnant women and non-pregnant adults at 2hr, 24hr and 120hr post last dose, representing absorption, distribution, and elimination phases. Conclusions Capillary and venous plasma concentration of lumefantrine can be used interchangeably at 1:1 ratio. Capillary sampling method via finger prick is a suitable alternative for sample collection in clinical studies.