Pharmacometrics of dolutegravir and tenofovir: a quantitative approach to characterise drug-drug interactions, pharmacogenetics and optimise treatment

Africa houses more than 50% of the 37 million people estimated to be living with HIV (PLWH). Although great strides have been made in increasing access to antiretroviral therapy, the number of new HIV infections remains high. In sub-Saharan Africa, co-infections of HIV, tuberculosis, and malaria are common because the three pandemics overlap considerably. Treatment of these co-infections is often challenging because of the potential for drug-drug interactions. Dolutegravir-based regimens are now the preferred first-line option for the management of HIV. Therefore, many African countries have transitioned most PLWH from efavirenz- to dolutegravir-based regimens. A fixed-dose combination containing dolutegravir, tenofovir, and lamivudine taken daily constitutes one of the most widely used regimens in Africa. In this thesis, we employ population pharmacokinetic modelling to optimise HIV treatment using data from healthy volunteers or PLWH, some of whom also have tuberculosis. We characterise dolutegravir pharmacokinetics, pharmacogenetics, and its drug-drug interaction with the antituberculosis drugs rifampicin and rifabutin and with the antimalarial drugs artemether-lumefantrine and artesunate-amodiaquine. We also describe the pharmacokinetics of tenofovir when dosed as either tenofovir disoproxil fumarate or tenofovir alafenamide in South Africans living with HIV. We found that rifampicin increases dolutegravir clearance more than twofold, leading to a reduction in its exposure. We confirmed that this interaction can be overcome with twice-daily dosing of 50-mg dolutegravir. We also demonstrate that a simpler regimen of 100 mg once daily may be sufficient. We also found that rifabutin decreases dolutegravir volume of distribution, but without an overall change in exposure. The interaction between dolutegravir and artemether-lumefantrine or artesunate-amodiaquine was not clinically significant, and no dose adjustment is required when these are co-administered. Lastly, we demonstrate that polymorphisms within the UGT1A locus affect dolutegravir exposure among Africans. For tenofovir, we created a joint model that describes its disposition when given either as tenofovir disoproxil fumarate or tenofovir alafenamide. In conclusion, by employing pharmacometric techniques, we were able to analyze and pool data from different studies, including sparsely sampled data, and run simulations to test and inform alternative dosing scenarios

A systematic review on maternal-to-infant transfer of drugs through breast milk during the treatment of malaria, tuberculosis, and neglected tropical diseases

BackgroundExclusive breastfeeding of infants under 6 months of age is recommended by the World Health Organization. In 2021, over 300 million combined incident cases of malaria, tuberculosis, and neglected tropical diseases (NTDs) were reported, predominantly in low-income countries. For many of the drugs used as first-line treatments for these conditions, there is limited knowledge on infant exposure through breastfeeding with poorly understood consequences. This review summarized available knowledge on mother-to-infant transfer of these drugs to inform future lactation pharmacokinetic studies.MethodologyA list of first-line drugs was generated from the latest WHO treatment guidelines. Using standard online databases, 2 independent reviewers searched for eligible articles reporting lactation pharmacokinetics studies and extracted information on study design, participant characteristics, and the mathematical approach used for parameter estimation. A third reviewer settled any disagreements between the 2 reviewers. All studies were scored against the standardized "ClinPK" checklist for conformity to best practices for reporting clinical pharmacokinetic studies. Simple proportions were used to summarize different study characteristics.FindingsThe most remarkable finding was the scarcity of lactation pharmacokinetic data. Only 15 of the 69 drugs we listed had lactation pharmacokinetics fully characterized. Most studies enrolled few mothers, and only one evaluated infant drug concentrations. Up to 66% of the studies used non-compartmental analysis to estimate pharmacokinetic parameters rather than model-based compartmental analysis. Unlike non-compartmental approaches, model-based compartmental analysis provides for dynamic characterization of individual plasma and breast milk concentration-time profiles and adequately characterizes variability within and between individuals, using sparsely sampled data. The "ClinPK" checklist inadequately appraised the studies with variability in the number of relevant criteria across different studies.Conclusions/significanceA consensus is required on best practices for conducting and reporting lactation pharmacokinetic studies, especially in neglected diseases such as malaria, tuberculosis, and NTDs, to optimize treatment of mother-infant pairs

Population pharmacokinetics of tenofovir given as either tenofovir disoproxil fumarate or tenofovir alafenamide in an African population

Abstract Tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are prodrugs of the nucleotide analogue tenofovir, which acts intracellularly to inhibit HIV replication. Whereas TDF converts to tenofovir in plasma and may cause kidney and bone toxicity, TAF mostly converts to tenofovir intracellularly, so it can be administered at lower doses. TAF leads to lower tenofovir plasma concentrations and lower toxicity, but there are limited data on its use in Africa. We used data from 41 South African adults living with HIV from the ADVANCE trial and described, with a joint model, the population pharmacokinetics of tenofovir given as TAF or TDF. The TDF was modeled to appear in plasma as tenofovir with a simple first‐order process. Instead, two parallel pathways were used for a TAF dose: an estimated 32.4% quickly appeared as tenofovir into the systemic circulation with first‐order absorption, whereas the rest was sequestered intracellularly and released into the systemic circulation as tenofovir slowly. Once in plasma (from either TAF or TDF), tenofovir disposition followed two‐compartment kinetics and had a clearance of 44.7 L/h (40.2–49.5), for a typical 70‐kg individual. This semimechanistic model describes the population pharmacokinetics of tenofovir when dosed as either TDF or TAF in an African population living with HIV and can be used as a tool for exposure prediction in patients, and to simulate alternative regimes to inform further clinical trials

­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

­Pharmacokinetics of 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 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