-Pharmacokinetics of antimalarial drugs used to treat uncomplicated malaria in breastfeeding mother-infant pairs: An observational pharmacokinetic study.

Background: Data surrounding the exposure of the breastfed infant to drugs and any associated risks are sparse. Drugs usually are transferred to milk in small quantities, and many have been used without obviously noticeable infant toxicity for many years - this lack of a 'safety signal' has further reduced the interest in studying mother-to-infant transfer of the drugs. In sub-Saharan Africa, pregnant women are at risk of  Plasmodium falciparum infection, and one in four women have evidence of placental infection at the time of delivery. Artemisinin-based combination therapies (ACTs), primarily artemether-lumefantrine (AL), are the current first-line treatment for uncomplicated Plasmodium falciparum malaria, with the same dosing recommendations in breastfeeding women as those in the adult population. Dihydroartemisinin-piperaquine (DP) is routinely used as an alternative to AL in Uganda. However, lactation pharmacokinetics (PK) of ACTs are unknown. Pharmacokinetic characterization of anti-malarial transfer to breast milk and breastfed infants is crucial in understanding the potential consequences to the infant, in terms of therapeutic- and prophylactic effects as well as potential toxicity.   Methods: This observational study will enroll 30 mother-infant pairs, and aims to characterize the breastmilk transfer of antimalarial medications (AL and DP) to infants when these ACTs are administered to mothers as part of treatment for uncomplicated malaria. In addition, we will assess the mental health of the breastfeeding mothers enrolled as well as the well-being of their children. PK samples of maternal blood, breastmilk and breastfeeding infant's blood will be obtained at specific times points. Pharmacokinetic data will be analyzed using a population pharmacokinetic approach. Conclusions: We anticipate that findings from this research will guide to develop a PK model describing lumefantrine and piperaquine disposition and will provide a framework to foster other lactation pharmacokinetic studies in different disease areas.

Association between HIV and treatment-resistant hypertension in Malawian adults: a protocol for a case-control study.

INTRODUCTION: Treatment-resistant hypertension (RH), defined as uncontrolled blood pressure (≥140/90 mm Hg) despite treatment with ≥3 medications of different classes (including diuretics) at optimal doses, is associated with poor prognosis and an elevated risk of end-organ damage. In areas where HIV is endemic, such as sub-Saharan Africa, the risk of hypertension is high in people living with HIV. It remains unknown if HIV infection further increases the risk of RH. This study seeks to determine the association between HIV and RH as well as investigate other factors associated with RH in hypertensive Malawian adults. METHODS AND ANALYSIS: A case-control study will be conducted among adult hypertensive patients attending a clinic at a referral hospital in Malawi. The cases will be hypertensive patients with a confirmed diagnosis of RH. For each case, two controls (hypertensive patients without RH), frequency matched for age group and sex, will be selected from among hospital clients attending the same hypertension clinic as the case. In both groups, HIV status will be ascertained. Additionally, information on other potential risk factors of RH, such as chronic kidney disease, obesity, hypercholesteraemia, diabetes, smoking, alcohol use, antiretroviral therapy regimen and duration, will be collected in both cases and controls. For each of the potential risk factors, ORs will be calculated to quantify the strength of their association with RH. In a multivariate analysis, conditional logistic regression will be used to assess the independent association between HIV and RH as well as the influence of the other potential drivers of RH. ETHICS AND DISSEMINATION: This protocol has been approved by the College of Medicine Research Ethics Committee (COMREC) in Malawi (P.05/22/3637). Findings from this study will be disseminated through a peer-reviewed publication in an open-access international journal. Furthermore, anonymised data will be available on request from the authors.

Modelling the therapeutic dose range of single low dose primaquine to reduce malaria transmission through age-based dosing.

BACKGROUND: Low-dose primaquine is a key candidate for use in malaria transmission reduction and elimination campaigns such as mass drug administration (MDA). Uncertainty about the therapeutic dose range (TDR) required for general and paediatric populations challenge the implementation of the World Health Organisation's recommendation to add 0.25 mg/kg to current standard antimalarial treatment in such settings. Modelling work shows that for low-dose primaquine to have an impact, high efficacy and extensive population coverage are needed. In practice, age-based dose regimens, often used in MDA, could lead to safety concerns and a different effectiveness profile. We aimed to define TDRs for primaquine and to assess dosing accuracy of age-based dose regimens. METHODS: Optimised regional age-based dosing regimens for low-dose primaquine were developed in steps. First, we identified potential TDR options based on suggested published efficacy and safety thresholds (i.e. 0.1-0.4, 0.125-0.375, 0.15-0.35 mg/kg). We then used our previously defined weight-for-age growth references and age-based dose optimisation tool to model predicted regimen accuracies for Africa, Asia and Latin America based on low-dose primaquine tablets (3.75 mg and 7.5 mg) currently under development by Sanofi while employing the identified dose range options and pre-specified regimen characteristics. RESULTS: Dose regimens employing TDRs of 0.1-0.4 and 0.125-0.375 mg/kg had the highest average predicted dose accuracies in all regions with the widest dose range of 0.1-0.4 mg/kg resulting in ≥99% dose accuracy in all three regions. The narrower 0.15-0.35 mg/kg range was on average predicted to correctly dose 91.4% of the population in Africa, 93.2% in Asia and 92.6% in Latin America. This range would prescribe ≥20% of 3-year-olds doses below 0.15 mg/kg and ≥20% of 11-year-olds doses above 0.35 mg/kg. Widening the TDR from 0.15-0.35 to 0.1-0.4 mg/kg increased the dose accuracy by ≥20% in Africa, ≥15% in Asia and ≥10% in Latin America. CONCLUSION: Optimised age-based dose regimens derived from wider TDRs are predicted to attain the dose accuracies required for effective MDA in malaria transmission reduction and elimination settings. We highlight the need for a clearly defined TDR and for safety and efficacy trials to focus on doses compatible with age-based dosing often employed in such settings.