SYMPOSIUM 11: Neglected tropical diseases: Getting the dose right
Tracks
Track 3
| Tuesday, September 23, 2025 |
| 10:30 AM - 12:00 PM |
| Grand Copthorne Waterfront Hotel - Waterfront Ballroom II |
Details
Neglected Tropical Diseases (NTDs) affect predominantly marginalized and impoverished communities and receive insufficient funding and research into prevention and treatment. NTDs pose significant public health challenges, affecting over a billion people worldwide. They cause substantial morbidity and mortality, leading to long-term disabilities, economic losses, and hindering of socioeconomic development.
Many NTDs have limited effective drugs available, and these are often used at suboptimal doses. This can cause treatment failures and development of drug resistance. Determining the optimal dose in a population requires quantification of the dose –exposure – therapeutic efficacy relationship. This can be achieved through pre-clinical and clinical studies in combination with pharmacokinetic and pharmacodynamic modelling.
This symposium provides an overview of the importance, impact and use of pharmacokinetic and pharmacodynamic tools in optimizing treatments of NTDs.
Speaker
Prof Julie Simpson
Biostatistics Unit, University of Melbourne
Modelling of red blood cell turnover to determine safe dosing strategies for treatment of vivax malaria patients
Abstract
Background
Primaquine is the only widely available drug that targets Plasmodium vivax malaria parasites in the liver. However, primaquine is underused because of concerns that this drug can cause dose-dependent haemolysis in glucose-6-phosphate dehydrogenase (G6PD) deficient individuals. We developed and calibrated a within-host Bayesian pharmacodynamic model of red blood cell (RBC) production and turnover to explore the safety of primaquine regimens for individuals with G6PD deficiency.
Methods
The within-host RBC model captured deviations from the RBC normal process by assuming a dose-dependent effect of primaquine on the lifespan of circulating erythrocytes and the compensatory response of precursor cells and reticulocytes. The compartmental mechanistic RBC model was fitted to data from a regimen-adaptive trial of ascending primaquine doses in 23 G6PD hemizygote deficient volunteers using a Bayesian hierarchical framework. Detailed serial haemoglobin and reticulocyte count data were available, 1523 individual measurements over 656 unique time points.
Results
Our model estimated that primaquine doses of ~0.75 mg base/kg reduce the circulating lifespan of deficient erythrocytes by ~30 days in individuals with common Southeast Asian G6PD variants. We predict that a total dose of 5 mg/kg of primaquine can be administered safely to G6PD deficient individuals over 14 days with expected drops in haemoglobin of 2.7 to 6.5 g/dL from a baseline of 15 g/dL.
Discussion
Our within-host RBC model captured the effect of primaquine on G6PD deficient volunteers’ haemoglobin and reticulocyte profiles. This mechanistic model suggests safe and effective primaquine dosing schemes can be administered within two weeks to G6PD deficient individuals.
Primaquine is the only widely available drug that targets Plasmodium vivax malaria parasites in the liver. However, primaquine is underused because of concerns that this drug can cause dose-dependent haemolysis in glucose-6-phosphate dehydrogenase (G6PD) deficient individuals. We developed and calibrated a within-host Bayesian pharmacodynamic model of red blood cell (RBC) production and turnover to explore the safety of primaquine regimens for individuals with G6PD deficiency.
Methods
The within-host RBC model captured deviations from the RBC normal process by assuming a dose-dependent effect of primaquine on the lifespan of circulating erythrocytes and the compensatory response of precursor cells and reticulocytes. The compartmental mechanistic RBC model was fitted to data from a regimen-adaptive trial of ascending primaquine doses in 23 G6PD hemizygote deficient volunteers using a Bayesian hierarchical framework. Detailed serial haemoglobin and reticulocyte count data were available, 1523 individual measurements over 656 unique time points.
Results
Our model estimated that primaquine doses of ~0.75 mg base/kg reduce the circulating lifespan of deficient erythrocytes by ~30 days in individuals with common Southeast Asian G6PD variants. We predict that a total dose of 5 mg/kg of primaquine can be administered safely to G6PD deficient individuals over 14 days with expected drops in haemoglobin of 2.7 to 6.5 g/dL from a baseline of 15 g/dL.
Discussion
Our within-host RBC model captured the effect of primaquine on G6PD deficient volunteers’ haemoglobin and reticulocyte profiles. This mechanistic model suggests safe and effective primaquine dosing schemes can be administered within two weeks to G6PD deficient individuals.
Biography
Professor Julie Simpson is Head of Biostatistics at the Melbourne School of Population and Global Health and Director of the Methods and Implementation Support for Clinical and Health research (MISCH) Hub at the University of Melbourne, and a Visiting Professor of the University of Oxford. She has 30 years’ experience collaborating on multidisciplinary research projects with clinicians, laboratory scientists, epidemiologists and health policy-makers at universities and hospitals worldwide. Her main area of research is the integration of biostatistics and mathematical modelling to improve the treatment of malaria.
Meg Tully
The University of Melbourne
In silico modelling of triple artemisinin-based combination therapies to inform dosing in areas with emerging antimalarial drug resistance
Abstract
Declining antimalarial drug efficacy poses a significant threat to malaria control worldwide. The firstline treatment for P. falciparum malaria combines artemisinin derivatives with a long-acting partner drug. These artemisinin-based combination therapies (ACT) have proven very successful in maintaining high cure-rates. However, recent decreases in ACT efficacy have led to the necessary development and testing of new drugs and therapies, such as triple ACTs (TACT), where the ACT is administered alongside a third antimalarial drug.
Some promising candidate TACTs are currently in clinical trials; and whilst essential, clinical trials are an extremely time and resource intensive way to learn more about candidate regimens. Mathematical modelling of the underlying drug-parasite dynamics can be a cost-effective and ethical way to simulate efficacy of novel regimens, informing effects in varied scenarios.
We have developed an in silico pharmacokinetic-pharmacodynamic model that incorporates parent-metabolite profiles, drug-drug interactions, parasite life-cycle and age-specific killing effects. It was previously applied to dihydroartemisinin-piperaquine-mefloquine and was able to accurately estimate efficacy in the populations where clinical trials were conducted. We have performed a simulation study of the TACT artemether-lumefantrine-amodiaquine, using published pharmacokinetic and pharmacodynamic parameters to explore treatment outcomes in a variety of settings.
This flexible model allows for evaluation of potential cure rates at different levels of resistance to each of the three antimalarials, and for a variety of possible interaction scenarios. This model framework can be used to explore likely efficacy in different populations and inform TACT dosing schedules and local treatment policy.
Some promising candidate TACTs are currently in clinical trials; and whilst essential, clinical trials are an extremely time and resource intensive way to learn more about candidate regimens. Mathematical modelling of the underlying drug-parasite dynamics can be a cost-effective and ethical way to simulate efficacy of novel regimens, informing effects in varied scenarios.
We have developed an in silico pharmacokinetic-pharmacodynamic model that incorporates parent-metabolite profiles, drug-drug interactions, parasite life-cycle and age-specific killing effects. It was previously applied to dihydroartemisinin-piperaquine-mefloquine and was able to accurately estimate efficacy in the populations where clinical trials were conducted. We have performed a simulation study of the TACT artemether-lumefantrine-amodiaquine, using published pharmacokinetic and pharmacodynamic parameters to explore treatment outcomes in a variety of settings.
This flexible model allows for evaluation of potential cure rates at different levels of resistance to each of the three antimalarials, and for a variety of possible interaction scenarios. This model framework can be used to explore likely efficacy in different populations and inform TACT dosing schedules and local treatment policy.
Biography
Meg Tully has a Masters of Biostatistics from the University of Melbourne and is currently undertaking a PhD specialising in novel antimalarial combination therapies to combat the ongoing threat of drug resistance. She is based in the Centre for Epidemiology and Biostatistics within the Melbourne School of Population and Global Health and supervised by Prof Julie Simpson, A/Prof David Price and Dr Robert Commons. Her research is currently focused on pharmacokinetic-pharmacodynamic modelling of the within-host dynamics of novel malaria treatments.
Prof Joel Tarning
Mahidol Oxford Research Unit, Bangkok
Dose-optimisation of a novel co-formulated triple combination antimalarial therapy: Artemether-lumefantrine-amodiaquine
Abstract
There were an estimated 263 million cases of malaria worldwide, leading to 597,000 deaths, in 2023. Children under the age of five accounted for 74% of all malaria-related deaths. Artemisinin-based combination therapy (ACT) is the first-line therapy for uncomplicated falciparum malaria, but artemisinin resistance in Asia and now sub-Saharan Africa is threatening our ability to control and eliminate malaria. Triple-ACTs have emerged as a viable alternative treatment to combat declining ACT efficacy due to drug-resistant malaria. In this study, we developed and evaluated an optimal fixed-dose regimen of artemether-lumefantrine-amodiaquine through population pharmacokinetic modeling and simulation. Three published population-based pharmacometric models and two large cohorts of observed adult subjects and pediatric malaria patients were used to simulate pharmacokinetic profiles of different dosing strategies. Based on simulated total exposure and peak concentrations, an optimal dose regimen was developed resulting in an extension of the current 4 weight bands to a total of 5 weight bands to generate equivalent exposures in all body weight groups and minimize the fluctuation in exposure between patients. The proposed drug-to-drug ratio of artemether-lumefantrine-amodiaquine (20:120:40 mg) was kept constant throughout the dosing bands in order to simplify manufacturing, implementation, and further development of a fixed-dose co-formulated product.
Key words: malaria, resistance, dose-optimisation, triple combination therapy, pharmacokinetics, pharmacometrics
Key words: malaria, resistance, dose-optimisation, triple combination therapy, pharmacokinetics, pharmacometrics
Biography
Professor Joel Tarning leads a large and diverse team of 30 people studying clinical pharmacology at the Mahidol Oxford Tropical Medicine Research Unit (MORU) in Thailand. The main scientific directions within the department are pharmacometric data analysis, bioanalytical method development, drug quantification of clinical study samples, omics-based research, falsified/substandard medicine, and basic pharmacology. He is a Professor of Clinical Pharmacology at the University of Oxford, UK and a visiting Professor at the Faculty of Tropical Medicine, Mahidol University, Thailand. Professor Tarning has published >250 peer-reviewed articles resulting in >18,000 citations. His main research is focused on dose-optimisation of drugs used to treat neglected tropical diseases in under-served populations at risk of treatment failure and resistance development, such as children and pregnant women. His work on antimalarial drugs has already had a global impact.
www.ndm.ox.ac.uk/principal-investigators/researcher/joel-tarning
Dr Thanaporn Wattanakul
Mahidol Oxford Tropical Medicine Research Unit (MORU), Bangkok
Mechanistic pharmacokinetic modelling of primaquine in lactating women and breastfed infants for the radical treatment of maternal P. vivax malaria
Abstract
Introduction: Primaquine is one of two drugs available for the radical cure of vivax malaria. Lactating women are excluded from receiving primaquine due to a perceived risk of haemolysis in breastfeeding infants with glucose-6-phosphate-dehydrogenase(G6PD)-deficiency.
Methods: Twenty-one lactating women who received a standard dose of primaquine (0.5mg/kg/day) for 14 days were included in this analysis. Primaquine and its metabolite (carboxyprimaquine) concentrations were measured in maternal venous plasma, capillary plasma, breastmilk, and in breastfeeding infant capillary plasma. Population pharmacokinetic analysis was performed using nonlinear mixed-effects modelling (NONMEMv7.4). A mother-to-infant model incorporating feeding pattern observed in the studied population was developed to predict infant drug exposure. Maternal exposure after a single low dose of primaquine (0.25mg/kg) served as a safety reference that does not cause clinically significant haemolysis in G6PD-deficient individuals.
Results: A one-compartment disposition models for both primaquine and carboxyprimaquine accurately described the maternal concentration data across all measurement matrices. Primaquine absorption followed a transit absorption model with first-pass metabolism. Primaquine and its metabolite were excreted into breastmilk, but the estimated infant dose and total drug exposure were <1% of maternal levels. The predicted infant exposures were also well below the safety reference for G6PD-deficient individuals in all evaluated dosing scenarios.
Conclusion: Modelling and simulations demonstrated negligible infant drug exposure, suggesting that even in infants with the most severe G6PD-deficient variants, standard primaquine doses given to mothers are unlikely to cause clinically significant haemolysis in infants through milk consumption. Thus, lactating women should not be excluded from radical cure for vivax malaria.
Methods: Twenty-one lactating women who received a standard dose of primaquine (0.5mg/kg/day) for 14 days were included in this analysis. Primaquine and its metabolite (carboxyprimaquine) concentrations were measured in maternal venous plasma, capillary plasma, breastmilk, and in breastfeeding infant capillary plasma. Population pharmacokinetic analysis was performed using nonlinear mixed-effects modelling (NONMEMv7.4). A mother-to-infant model incorporating feeding pattern observed in the studied population was developed to predict infant drug exposure. Maternal exposure after a single low dose of primaquine (0.25mg/kg) served as a safety reference that does not cause clinically significant haemolysis in G6PD-deficient individuals.
Results: A one-compartment disposition models for both primaquine and carboxyprimaquine accurately described the maternal concentration data across all measurement matrices. Primaquine absorption followed a transit absorption model with first-pass metabolism. Primaquine and its metabolite were excreted into breastmilk, but the estimated infant dose and total drug exposure were <1% of maternal levels. The predicted infant exposures were also well below the safety reference for G6PD-deficient individuals in all evaluated dosing scenarios.
Conclusion: Modelling and simulations demonstrated negligible infant drug exposure, suggesting that even in infants with the most severe G6PD-deficient variants, standard primaquine doses given to mothers are unlikely to cause clinically significant haemolysis in infants through milk consumption. Thus, lactating women should not be excluded from radical cure for vivax malaria.
Biography
Dr. Wattanakul is an experienced pharmacometrics researcher specializing in tropical diseases, particularly malaria. Currently, she serves as the Deputy Head of the Pharmacometrics Group in the Department of Clinical Pharmacology at the Mahidol Oxford Tropical Medicine Research Unit, Bangkok, Thailand. Her research focuses on malaria and aim to optimize treatments for underserved populations, including children, lactating women, and pregnant women, through pharmacokinetic/pharmacodynamic (PK/PD) modelling.
Dr Francis Williams Oraja
Gulu University, Gulu, Uganda & The Infectious Diseases Institute, Kampala, Uganda
Role of TDM in model-based individual predictions for treatment of NTDs in breastfeeding mothers
Abstract
Introduction: Breast milk offers health benefits to both the mother and infant but also poses a threat for infant exposure to maternal drugs. Only 22% of first-line drugs used for treating malaria, tuberculosis and neglected tropical diseases (NTDs) have breastmilk data [1], limiting informed treatment and potentiating negative efficacy and safety outcomes. We explore the opportunity for Therapeutic Drug Monitoring (TDM) in breastfeeding mothers based on the Maternal to Infant Lactation pharmacoKinetic (MILK) program.
Methods: Breastfeeding mothers plus their infants were enrolled across different observational studies in Kampala, Uganda. Maternal blood and breastmilk, and infant blood were sampled across time within dosing intervals. Bioanalysis of blood and breastmilk used validated liquid chromatography-tandem mass spectrometry. Plasma and breastmilk concentration data were jointly modelled to characterize milk-to plasma ratios, quantify inter-individual variability and identify influential patient/treatment factors, using the population approach in NONMEM 7.4.1.
Results: Overall 200 mothers-infant pairs have been recruited, representing therapeutic areas of HIV (n=152) [2, 3], tuberculosis (n=20) [4] and malaria (n=30) [5]. Workflows for bioanalysis and population pharmacokinetic analysis have fully been developed for lamivudine, a first-line antiretroviral agent, reporting a milk-to-plasma ratio of 1.77 and infant exposure of 179.3 μg/kg/day (range: 125.8, 282.3). Bioanalytical methods for quantification of antituberculosis and antimalarial plasma and breastmilk drug concentrations are under development.
Conclusions: The lactation pharmacokinetic workflows can be leveraged for TDM for the reported antiinfectives, and drugs for NTDs, possessing high milk-to-plasma ratios and high interindividual pharmacokinetic variability to support treatment optimization in breastfeeding mother-infant pairs.
Methods: Breastfeeding mothers plus their infants were enrolled across different observational studies in Kampala, Uganda. Maternal blood and breastmilk, and infant blood were sampled across time within dosing intervals. Bioanalysis of blood and breastmilk used validated liquid chromatography-tandem mass spectrometry. Plasma and breastmilk concentration data were jointly modelled to characterize milk-to plasma ratios, quantify inter-individual variability and identify influential patient/treatment factors, using the population approach in NONMEM 7.4.1.
Results: Overall 200 mothers-infant pairs have been recruited, representing therapeutic areas of HIV (n=152) [2, 3], tuberculosis (n=20) [4] and malaria (n=30) [5]. Workflows for bioanalysis and population pharmacokinetic analysis have fully been developed for lamivudine, a first-line antiretroviral agent, reporting a milk-to-plasma ratio of 1.77 and infant exposure of 179.3 μg/kg/day (range: 125.8, 282.3). Bioanalytical methods for quantification of antituberculosis and antimalarial plasma and breastmilk drug concentrations are under development.
Conclusions: The lactation pharmacokinetic workflows can be leveraged for TDM for the reported antiinfectives, and drugs for NTDs, possessing high milk-to-plasma ratios and high interindividual pharmacokinetic variability to support treatment optimization in breastfeeding mother-infant pairs.
Biography
Francis is a Lecturer of pharmacology at Gulu University (Uganda) and currently a Postdoc at the Infectious Diseases Institute (Uganda).
He holds a Bachelors of Science degree in Biochemistry and a Masters of Science degree in pharmacology, both from Makerere University, and a Doctoral degree in pharmacometrics from the Freie Universitaet Berlin (Germany). Francis’s research has applied pharmacometrics in different therapeutic areas, including paediatrics and adult oncology, and infectious diseases such as malaria and HIV, characterising the relationship between treatment and treatment outcome (safety and efficacy).
His current research focuses on pharmacometrics-based optimisation of treatment in special populations including pregnant and breastfeeding mother-infant pairs. He is passionate about teaching and mentoring junior scientists into pharmacometrics and increasing the role of pharmacometrics in clinical pharmacology research in Uganda and Africa.
https://www.linkedin.com/in/ojara-williams-francis-38993822
https://twitter.com/fwojara
https://scholar.google.com/citations?use
Session chair
Jacqueline Hannam
The University Of Auckland
Richard Hoglund
Mahidol Oxford Research Unit, Bangkok
