scholarly journals Prediction of Improved Antimalarial Chemoprevention with Weekly Dosing of Dihydroartemisinin-Piperaquine

2017 ◽  
Vol 61 (5) ◽  
Author(s):  
Jesmin Permala ◽  
Joel Tarning ◽  
François Nosten ◽  
Nicholas J. White ◽  
Mats O. Karlsson ◽  
...  
Keyword(s):  
Peak Plasma ◽  
Malaria Incidence ◽  
Plasma Concentrations ◽  
Intermittent Preventive Treatment ◽  
Preventive Treatment ◽  
Vulnerable Groups ◽  
Fixed Dose ◽  
Dosing Regimen ◽  
Dosing Regimens ◽  
Dose Combination

ABSTRACT Intermittent preventive treatment (IPT) is used to reduce malaria morbidity and mortality, especially in vulnerable groups such as children and pregnant women. IPT with the fixed dose combination of piperaquine (PQ) and dihydroartemisinin (DHA) is being evaluated as a potential mass treatment to control and eliminate artemisinin-resistant falciparum malaria. This study explored alternative DHA-PQ adult dosing regimens compared to the monthly adult dosing regimen currently being studied in clinical trials. A time-to-event model describing the concentration-effect relationship of preventive DHA-PQ administration was used to explore the potential clinical efficacy of once-weekly adult dosing regimens. Loading dose strategies were evaluated and the advantage of weekly dosing regimen was tested against different degrees of adherence. Assuming perfect adherence, three tablets weekly dosing regimen scenarios maintained malaria incidence of 0.2 to 0.3% per year compared to 2.1 to 2.6% for all monthly dosing regimen scenarios and 52% for the placebo. The three tablets weekly dosing regimen was also more forgiving (i.e., less sensitive to poor adherence), resulting in a predicted ∼4% malaria incidence per year compared to ∼8% for dosing regimen of two tablets weekly and ∼10% for monthly regimens (assuming 60% adherence and 35% interindividual variability). These results suggest that weekly dosing of DHA-PQ for malaria chemoprevention would improve treatment outcomes compared to monthly administration by lowering the incidence of malaria infections, reducing safety concerns about high PQ peak plasma concentrations and being more forgiving. In addition, weekly dosing is expected to reduce the selection pressure for PQ resistance.

scholarly journals Identifying an optimal dihydroartemisinin-piperaquine dosing regimen for malaria prevention in young Ugandan children

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Erika Wallender ◽  
Ali Mohamed Ali ◽  
Emma Hughes ◽  
Abel Kakuru ◽  
Prasanna Jagannathan ◽  
...  
Keyword(s):  
Malaria Incidence ◽  
Protective Efficacy ◽  
Intermittent Preventive Treatment ◽  
Preventive Treatment ◽  
Malaria Prevention ◽  
Incidence Data ◽  
Resistance Selection ◽  
Mixed Effects Modeling ◽  
Malnourished Children ◽  
Dosing Regimens

AbstractIntermittent preventive treatment (IPT) with dihydroartemisinin-piperaquine (DP) is highly protective against malaria in children, but is not standard in malaria-endemic countries. Optimal DP dosing regimens will maximize efficacy and reduce toxicity and resistance selection. We analyze piperaquine (PPQ) concentrations (n = 4573), malaria incidence data (n = 326), and P. falciparum drug resistance markers from a trial of children randomized to IPT with DP every 12 weeks (n = 184) or every 4 weeks (n = 96) from 2 to 24 months of age (NCT02163447). We use nonlinear mixed effects modeling to establish malaria protective PPQ levels and risk factors for suboptimal protection. Compared to DP every 12 weeks, DP every 4 weeks is associated with 95% protective efficacy (95% CI: 84–99%). A PPQ level of 15.4 ng/mL reduces the malaria hazard by 95%. Malnutrition reduces PPQ exposure. In simulations, we show that DP every 4 weeks is optimal across a range of transmission intensities, and age-based dosing improves malaria protection in young or malnourished children.

scholarly journals Infant sex modifies associations between placental malaria and risk of malaria in infancy

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Abel Kakuru ◽  
Michelle E. Roh ◽  
Richard Kajubi ◽  
Teddy Ochieng ◽  
John Ategeka ◽  
...  
Keyword(s):  
Malaria Incidence ◽  
Placental Malaria ◽  
Intermittent Preventive Treatment ◽  
Preventive Treatment ◽  
Adverse Outcomes ◽  
Adjusted Incidence Rate ◽  
Causal Mediation Analysis ◽  
Infant Sex ◽  
Adjusted Incidence

Abstract Background Placental malaria (PM) has been associated with a higher risk of malaria during infancy. However, it is unclear whether this association is causal, and is modified by infant sex, and whether intermittent preventive treatment in pregnancy (IPTp) can reduce infant malaria by preventing PM. Methods Data from a birth cohort of 656 infants born to HIV-uninfected mothers randomised to IPTp with dihydroartemisinin–piperaquine (DP) or Sulfadoxine–pyrimethamine (SP) was analysed. PM was categorized as no PM, active PM (presence of parasites), mild-moderate past PM (> 0–20% high powered fields [HPFs] with pigment), or severe past PM (> 20% HPFs with pigment). The association between PM and incidence of malaria in infants stratified by infant sex was examined. Causal mediation analysis was used to test whether IPTp can impact infant malaria incidence via preventing PM. Results There were 1088 malaria episodes diagnosed among infants during 596.6 person years of follow-up. Compared to infants born to mothers with no PM, the incidence of malaria was higher among infants born to mothers with active PM (adjusted incidence rate ratio [aIRR] 1.30, 95% CI 1.00–1.71, p = 0.05) and those born to mothers with severe past PM (aIRR 1.28, 95% CI 0.89–1.83, p = 0.18), but the differences were not statistically significant. However, when stratifying by infant sex, compared to no PM, severe past PM was associated a higher malaria incidence in male (aIRR 2.17, 95% CI 1.45–3.25, p < 0.001), but not female infants (aIRR 0.74, 95% CI 0.46–1.20, p = 0.22). There were no significant associations between active PM or mild-moderate past PM and malaria incidence in male or female infants. Male infants born to mothers given IPTp with DP had significantly less malaria in infancy than males born to mothers given SP, and 89.7% of this effect was mediated through prevention of PM. Conclusion PM may have more severe consequences for male infants, and interventions which reduce PM could mitigate these sex-specific adverse outcomes. More research is needed to better understand this sex-bias between PM and infant malaria risk. Trial registration ClinicalTrials.gov, NCT02793622. Registered 8 June 2016, https://clinicaltrials.gov/ct2/show/NCT02793622

scholarly journals Infant sex modifies associations between placental malaria and risk of malaria in infancy

2020 ◽  
Author(s):  
Abel Kakuru ◽  
Michelle E. Roh ◽  
Richard Kajubi ◽  
Teddy Ochieng ◽  
John Ategeka ◽  
...  
Keyword(s):  
Malaria Incidence ◽  
Placental Malaria ◽  
Intermittent Preventive Treatment ◽  
Preventive Treatment ◽  
Adverse Outcomes ◽  
Trial Registration ◽  
Adjusted Incidence Rate ◽  
Infant Sex ◽  
Adjusted Incidence

Abstract BackgroundPlacental malaria (PM) has been associated with a higher risk of malaria during infancy. However, it is unclear whether this association is causal, and is modified by infant sex, and whether intermittent preventive treatment in pregnancy (IPTp) can reduce infant malaria by preventing PM. MethodsData from a birth cohort of 656 infants born to HIV-uninfected mothers randomized to IPTp with dihydroartemisinin-piperaquine (DP) or sulfadoxine-pyrimethamine (SP) was analyzed. PM was categorized as no PM, active PM (presence of parasites), mild-moderate past PM (>0-20% high powered fields [HPFs] with pigment), or severe past PM (>20% HPFs with pigment). The association between PM and incidence of malaria in infants stratified by infant sex was examined. Causal mediation analysis was used to test whether IPTp can impact infant malaria incidence via preventing PM. ResultsThere were 1088 malaria episodes diagnosed among infants during 596.6 person years of follow-up. Compared to infants born to mothers with no PM, the incidence of malaria was higher among infants born to mothers with active PM (adjusted incidence rate ratio [aIRR] 1.30, 95% CI 1.00-1.71, p=0.05) and those born to mothers with severe past PM (aIRR 1.28, 95% CI 0.89-1.83, p=0.18), but the differences were not statistically significant. However, when stratifying by infant sex, compared to no PM, severe past PM was associated a higher malaria incidence in male (aIRR 2.17, 95% CI 1.45-3.25, p<0.001), but not female infants (aIRR 0.74, 95% CI 0.46-1.20, p=0.22). There were no significant associations between active PM or mild-moderate past PM and malaria incidence in male or female infants. Male infants born to mothers given IPTp with DP had significantly less malaria in infancy than males born to mothers given SP, and 89.7% of this effect was mediated through prevention of PM.ConclusionPM may have more severe consequences for male infants, and interventions which reduce PM could mitigate these sex-specific adverse outcomes. More research is needed to better understand this sex-bias between PM and infant malaria risk.Trial registrationTrial registration: ClinicalTrials.gov, NCT02793622. Registered 8 June 2016, https://clinicaltrials.gov/ct2/show/NCT02793622

scholarly journals Infant sex modifies associations between placental malaria and risk of malaria in infancy

2020 ◽  
Author(s):  
Abel Kakuru ◽  
Michelle E. Roh ◽  
Richard Kajubi ◽  
Teddy Ochieng ◽  
John Ategeka ◽  
...  
Keyword(s):  
Malaria Incidence ◽  
Placental Malaria ◽  
Intermittent Preventive Treatment ◽  
Preventive Treatment ◽  
Adverse Outcomes ◽  
Adjusted Incidence Rate ◽  
Causal Mediation Analysis ◽  
Infant Sex ◽  
Adjusted Incidence

Abstract Background Placental malaria (PM) has been associated with a higher risk of malaria during infancy. However, it is unclear whether this association is causal, and is modified by infant sex, and whether intermittent preventive treatment in pregnancy (IPTp) can reduce infant malaria by preventing PM. Methods Data from a birth cohort of 656 infants born to HIV-uninfected mothers randomised to IPTp with dihydroartemisinin-piperaquine (DP) or sulfadoxine-pyrimethamine (SP) was analysed. PM was categorized as no PM, active PM (presence of parasites), mild-moderate past PM (>0-20% high powered fields [HPFs] with pigment), or severe past PM (>20% HPFs with pigment). The association between PM and incidence of malaria in infants stratified by infant sex was examined. Causal mediation analysis was used to test whether IPTp can impact infant malaria incidence via preventing PM. Results There were 1088 malaria episodes diagnosed among infants during 596.6 person years of follow-up. Compared to infants born to mothers with no PM, the incidence of malaria was higher among infants born to mothers with active PM (adjusted incidence rate ratio [aIRR] 1.30, 95% CI 1.00-1.71, p=0.05) and those born to mothers with severe past PM (aIRR 1.28, 95% CI 0.89-1.83, p=0.18), but the differences were not statistically significant. However, when stratifying by infant sex, compared to no PM, severe past PM was associated a higher malaria incidence in male (aIRR 2.17, 95% CI 1.45-3.25, p<0.001), but not female infants (aIRR 0.74, 95% CI 0.46-1.20, p=0.22). There were no significant associations between active PM or mild-moderate past PM and malaria incidence in male or female infants. Male infants born to mothers given IPTp with DP had significantly less malaria in infancy than males born to mothers given SP, and 89.7% of this effect was mediated through prevention of PM. Conclusion PM may have more severe consequences for male infants, and interventions which reduce PM could mitigate these sex-specific adverse outcomes. More research is needed to better understand this sex-bias between PM and infant malaria risk. Trial registration: ClinicalTrials.gov, NCT02793622. Registered 8 June 2016, https://clinicaltrials.gov/ct2/show/NCT02793622

scholarly journals Population Pharmacokinetics of Mefloquine Intermittent Preventive Treatment for Malaria in Pregnancy in Gabon

2018 ◽  
Vol 63 (2) ◽  
pp. e01113-18 ◽  
Author(s):  
Michael Ramharter ◽  
Matthias Schwab ◽  
Ghyslain Mombo-Ngoma ◽  
Rella Zoleko Manego ◽  
Daisy Akerey-Diop ◽  
...  
Keyword(s):  
Pregnant Women ◽  
Intermittent Preventive Treatment ◽  
Preventive Treatment ◽  
Malaria In Pregnancy ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Blood Concentrations ◽  
Split Dose ◽  
Dosing Regimens ◽  
In Pregnancy

ABSTRACT Mefloquine was evaluated as an alternative for intermittent preventive treatment of malaria in pregnancy (IPTp) due to increasing resistance against the first-line drug sulfadoxine-pyrimethamine (SP). This study determined the pharmacokinetic characteristics of the mefloquine stereoisomers and the metabolite carboxymefloquine (CMQ) when given as IPTp in pregnant women. Also, the relationship between plasma concentrations of the three analytes and cord samples was evaluated, and potential covariates influencing the pharmacokinetic properties were assessed. A population pharmacokinetic analysis was performed with 264 pregnant women from a randomized controlled trial evaluating a single and a split-dose regimen of two 15-mg/kg mefloquine doses at least 1 month apart versus SP-IPTp. Both enantiomers of mefloquine and its carboxy-metabolite (CMQ), measured in plasma and cord samples, were applied for pharmacokinetic modelling using NONMEM 7.3. Both enantiomers and CMQ were described simultaneously by two-compartment models. In the split-dose group, mefloquine bioavailability was significantly increased by 5%. CMQ induced its own metabolism significantly. Maternal and cord blood concentrations were significantly correlated (r2 = 0.84) at delivery. With the dosing regimens investigated, prophylactic levels are not constantly achieved. A modeling tool for simulation of the pharmacokinetics of alternative mefloquine regimens is presented. This first pharmacokinetic characterization of mefloquine IPTp indicates adequate exposure in both mefloquine regimens; however, concentrations at delivery were below previously suggested threshold levels. Our model can serve as a valuable tool for researchers and clinicians to develop and optimize alternative dosing regimens for IPTp in pregnant women.

scholarly journals Pharmacokinetics and Bioequivalence Evaluation of Two Fixed-Dose Tablet Formulations of Dihydroartemisinin and Piperaquine in Vietnamese Subjects

2008 ◽  
Vol 53 (2) ◽  
pp. 828-831 ◽  
Author(s):  
Nguyen Trong Chinh ◽  
Nguyen Ngoc Quang ◽  
Nguyen Xuan Thanh ◽  
Bui Dai ◽  
Jason P. Geue ◽  
...  
Keyword(s):  
Peak Plasma ◽  
Plasma Concentrations ◽  
Fixed Dose ◽  
Concentration Time ◽  
Tablet Formulations ◽  
Dose Tablet

ABSTRACT The two fixed-dose combinations of dihydroartemisinin and piperaquine (Artekin and Arterakine) were found to be bioinequivalent in healthy Vietnamese subjects. However, because the peak plasma concentrations and areas under the concentration-time curves of dihydroartemisinin and piperaquine were only marginally different between the two formulations, similar therapeutic efficacies are expected in the treatment of malaria infections.

scholarly journals Evaluating artesunate-amodiaquine deployment, efficacy and safety: an in silico pharmacological model

2019 ◽  
Author(s):  
Ki Bae Hong ◽  
Ian Hastings ◽  
Katherine Kay ◽  
Eva Maria Hodel
Keyword(s):  
Patient Adherence ◽  
Real Life ◽  
World Health ◽  
Fixed Dose ◽  
Multiple Treatment ◽  
Increased Risk ◽  
Dosing Regimens ◽  
Dose Combination ◽  
Health Organization ◽  
Pharmacological Model

AbstractBackgroundThe World Health Organization currently recommends artesunate-amodiaquine (AS-AQ) as a first-line treatment for uncomplicated falciparum malaria. The clinical efficacy of AS-AQ is very high but its effectiveness in the field varies considerably. This study aimed at comparing the efficacy, effectiveness and safety of AS-AQ fixed dose combination (FDC) and non-fixed formulation (non-FDC) in controlled and real-life settings using a pharmacological model of antimalarial treatment.MethodsThe effectiveness and safety of different drug formulations in different treatment scenarios were investigated using a pharmacological model of AS-AQ treatment. The model simulated multiple treatment scenarios to assess the effects of age-or weight-based dosing bands in three geographically distinct patient populations, and poor patient adherence.ResultsThe model output was consistent with clinical trials in terms of cure rates, recrudescence rates and the pattern of AQ overdosing with age- and weight-based dosing regimens. AS-AQ treatment has good efficacy and effectiveness in fully adherent patients but monotherapy of AS or AQ lead to treatment failure. The weight-based dosing regimen with FDC was the best option for patients in terms of drug safety and had similar efficacies to the other regimens. Asians were more likely to be overdosed with AQ when using age-based dosing regimens.ConclusionsWeight-based dosing is optimal but not always feasible, so age-based dosing regimens are often used as an alternative. The model outputs highlight the importance of optimising these age-based dosing regimens for specific regions, and identify an increased risk of overdosing in young children.

scholarly journals Infant Sex Modifies Associations Between Placental Malaria and Risk of Malaria in Infancy

2020 ◽  
Author(s):  
Abel kakuru ◽  
Michelle E. Roh ◽  
Richard Kajubi ◽  
Teddy Ochieng ◽  
John Ategeka ◽  
...  
Keyword(s):  
Malaria Incidence ◽  
Placental Malaria ◽  
Intermittent Preventive Treatment ◽  
Preventive Treatment ◽  
Adverse Outcomes ◽  
Trial Registration ◽  
Adjusted Incidence Rate ◽  
Infant Sex ◽  
Adjusted Incidence

Abstract Background Placental malaria (PM) has been associated with a higher risk of malaria during infancy. However, it is unclear whether this association is causal, and is modified by infant sex, and whether intermittent preventive treatment in pregnancy (IPTp) can reduce infant malaria by preventing PM.MethodsData from a birth cohort of 656 infants born to HIV-uninfected mothers randomized to IPTp with dihydroartemisinin-piperaquine (DP) or sulfadoxine-pyrimethamine (SP) was analyzed. PM was categorized as no PM, active PM (presence of parasites), mild-moderate past PM (>0-20% high powered fields [HPFs] with pigment), or severe past PM (>20% HPFs with pigment). The association between PM and incidence of malaria in infants stratified by infant sex was examined. Causal mediation analysis was used to test whether IPTp can impact infant malaria incidence via preventing PM. ResultsThere were 1088 malaria episodes diagnosed among infants during 596.6 person years of follow-up. Compared to infants born to mothers with no PM, the incidence of malaria was higher among infants born to mothers with active PM (adjusted incidence rate ratio [aIRR] 1.30, 95% CI 1.00-1.71, p=0.05) and those born to mothers with severe past PM (aIRR 1.28, 95% CI 0.89-1.83, p=0.18), but the differences were not statistically significant. However, when stratifying by infant sex, compared to no PM, severe past PM was associated a higher malaria incidence in male (aIRR 2.17, 95% CI 1.45-3.25, p<0.001), but not female infants (aIRR 0.74, 95% CI 0.46-1.20, p=0.22). There were no significant associations between active PM or mild-moderate past PM and malaria incidence in male or female infants. Male infants born to mothers given IPTp with DP had significantly less malaria in infancy than males born to mothers given SP, and 89.7% of this effect was mediated through prevention of PM.ConclusionPM may have more severe consequences for male infants, and interventions which reduce PM could mitigate these sex-specific adverse outcomes. More research is needed to better understand this sex-bias between PM and infant malaria risk.Trial registrationTrial registration: ClinicalTrials.gov, NCT02793622. Registered 8 June 2016, https://clinicaltrials.gov/ct2/show/NCT02793622

A New Fixed-Dose Combination for Added Blood Pressure Control: Telmisartan Plus Hydrochlorothiazide

2002 ◽  
Vol 30 (4) ◽  
pp. 366-379 ◽  
Author(s):  
Y Lacourcière
Keyword(s):  
Blood Pressure ◽  
Cost Effective ◽  
Pressure Control ◽  
Fixed Dose Combination ◽  
Fixed Dose ◽  
Angiotensin Ii Receptor Blocker ◽  
Angiotensin Ii Receptor ◽  
Wide Range ◽  
Dosing Regimens ◽  
Dose Combination

Population surveys on hypertension management reveal worrying deficiencies in the awareness and treatment of high blood pressure. Many patients with hypertension will require two or more drugs with complementary mechanisms of action (which generally have additive effects, producing greater blood pressure reductions than either agent alone) to attain the blood pressure goals specified in internationally accepted guidelines. Nevertheless, physicians are often reluctant to prescribe multiple anti-hypertensive drugs due to concerns over side-effects, inconvenient dosing regimens and costs. Fixed-dose formulations combining two agents from different classes in a single tablet should help to allay these concerns. A fixed-dose combination containing telmisartan (an angiotensin II receptor blocker) and hydrochlorothiazide (a thiazide diuretic) has recently been developed. Telmisartan/hydrochlorothiazide provides additional anti-hypertensive efficacy compared with the respective monotherapies in a wide range of patients, including black patients, requires once-daily dosing, is cost-effective, well tolerated and is associated with less potassium depletion than hydrochlorothiazide administered alone.

Sign in / Sign up

Export Citation Format

Share Document