Population pharmacokinetics and cardiovascular safety of piperaquine in African patients with uncomplicated malaria
Thanaporn Wattanakul (1,2), Rita Baiden (3), Abraham Oduro(4), Tinto Halidou(5), Margaret Gyapong (6), Ali Sie (7), Eusebio Macete (8) , Salim Abdulla (9), Seth Owusu-Agyei (10), Abdunoor Mulokozi (9), Alex Adjei (6), Esperanca Sevene (8), Guillaume Compaoré (7), Innocent Valea (5), Isaac Osei (4), Abena Yawson (10), Martin Adjuik (3), Raymond Akparibo (3), Bernhards Ogutu (3), Gabriel Leonard Upunda (11), Peter Smith (12) and Fred Binka (3,13), Markus Winterberg (1,2), Joel Tarning (1,2)
(1) Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand, (2) Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK, (3) INDEPTH Network, Accra, Ghana, (4) Navrongo Health Research Centre, Navrongo, Ghana, (5) Nanoro Health Research Centre, Nanoro, Burkina Faso, (6) Dodowa Health Research Centre, Dodowa, Ghana, (7) Nouna Health Research Centre, Nouna, Burkina Faso, (8) Centro de InvestigaçãoemSaúde de Manhiça, CISM, Manhiça, Mozambique, (9) Ifakara Health Institute, Ifakara, Tanzania, (10) Kintampo Health Research Centre, Kintampo, Ghana, (11) Ministry of Health, Dar es Salaam, Tanzania, (12) London School of Hygiene & Tropical Medicine,London, UK, (13) University for Health and Allied Sciences, Ho, Ghana.
Objectives: Develop a PK/PD model to describe the relationship between piperaquine exposure and QT-prolongation in order to evaluate the cardiovascular safety in patients with uncomplicated malaria.
Methods: PK samples and electrocardiogram (ECG) measurements were obtained from a total of 1,000 patients, enrolled in a multi-centre safety trial in Burkina Faso, Mozambique, Ghana, and Tanzania [1-3]. All patients had uncomplicated P. falciparum malaria and received a standard 3-day treatment of dihydroartemisinin-piperaquine. Nonlinear mixed-effects modelling (NONMEM v.7) was used to evaluate PK-PD properties of piperaquine. Both QTc-prolongation (?QTc) and absolute QTc-intervals (QTc) were evaluated with separate modelling approaches. Direct exposure-response models with linear and Emax relationships were investigated to describe effect of piperaquine on ?QTc/QTc intervals. A cosine function was implemented to account for the circadian rhythm of the cardiovascular system. A stepwise covariate search was used to evaluate the relationship between PK-PD parameters and patient characteristics.
Results: A three-compartment disposition model with three-transit absorption compartments described the piperaquine concentration-time profile well. Body weight was added using an allometric function on all clearance and volume parameters (?OFV = -381). No additional significant covariates were found during the stepwise covariate approach. The effect of piperaquine on ?QTc was described by a linear relationship, resulting in a 6.14 msec QTc-prolongation per 100 ng/mL increase in population piperaquine concentration. The absolute QTc-interval showed a clear circadian rhythm and the effect of piperaquine was best described by an Emax model. The QTc-interval oscillated with a peak amplitude of 5 msec due to the circadian rhythm, and the maximum population increase in QTc-interval, due to drug effect, was 44.8 msec.
Conclusions: The developed PK-PD model described the relationship between piperaquine concentrations and ?QTc/QTc intervals effectively. The model demonstrated that an increased piperaquine concentration was directly related to a prolongation of the QTc interval. However, the prolongation estimated from the model was considered to have an acceptable safety profile in the clinical setting of life-saving malaria treatment.
References:
[1] Baiden R, Oduro A, Halidou T, Gyapong M, Sie A, Macete E, et al. Prospective observational study to evaluate the clinical safety of the fixed-dose artemisinin-based combination Eurartesim(R) (dihydroartemisinin/piperaquine), in public health facilities in Burkina Faso, Mozambique, Ghana, and Tanzania. Malaria journal. 2015;14:160.
[2] Adjei A, Narh-Bana S, Amu A, Kukula V, Nagai RA, Owusu-Agyei S, et al. Treatment outcomes in a safety observational study of dihydroartemisinin/piperaquine (Eurartesim((R))) in the treatment of uncomplicated malaria at public health facilities in four African countries. Malaria journal. 2016;15:43.
[3] Kabanywanyi AM, Baiden R, Ali AM, Mahende MK, Ogutu BR, Oduro A, et al. Multi-Country Evaluation of Safety of Dihydroartemisinin/Piperaquine Post-Licensure in African Public Hospitals with Electrocardiograms. PloS one. 2016;11(10):e0164851.
