M de Kock (1), KI Barnes (1), MM Nyunt (2), I Adam (3), L Workman (1), P Denti (1)
(1) Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, South Africa. (2) Johns Hopkins Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America. (3) Department of Obstetrics and Gynaecology, University of Khartoum, Khartoum, Sudan.
Objectives: Sulfadoxine/pyrimethamine (SP) is recommended for intermittent preventative (IPT) treatment of malaria during pregnancy. In this work, we present a secondary analysis of data previously interpreted without population modelling [1] that was characterised by large between-site variability. This was explained in part by differences in sampling schedule, with some pharmacokinetic profiles only sparsely sampled. The aim of this study was to characterise the pharmacokinetics (PK) of SP in pregnancy and after delivery using nonlinear mixed-effects modelling, and explore the effect of predefined covariates to possibly explain some of the variability between sites.
Methods: 98 women, in four African countries, each received a single fixed dose combination of 75 mg of pyrimethamine and 1500 mg of sulfadoxine orally, as IPT during pregnancy and again several weeks after delivery. In Mali and Zambia, samples were collected before dosing and 3, 6, 12 hours and 1, 3, 7, 14, 21, and 28 days following dosing, during pregnancy and after delivery. In Mozambique and Sudan, samples were collected before dosing and on day 1, 2, 3, 7, 14, 21, 28, and 42 following dosing during pregnancy and after delivery only before dosing and 7 days following dosing. NONMEM 7.3 [2] was used to analyse the PK data. The effect of body size was taken into account using allometric scaling with total body weight at dosing [3]. Study site, age, anaemia, mg/kg dose, pregnancy status, gestation trimester, and time after delivery were tested as predefined covariates, using the objective function value, goodness of fit plots, and visual predictive checks to guide the model development.
Results: Clearance during pregnancy was 75.8% higher for sulfadoxine and 11.5% lower for pyrimethamine than after delivery. Clearance after delivery was found to change gradually, with the “pregnancy effect” becoming negligible after around 3 months. Haematocrit-based scaling of plasma to whole blood concentrations and allometric scaling explained some of the variability between study sites, but substantial site specific differences in the PK profiles of the individuals remained.
Conclusions: The dose of sulfadoxine during pregnancy should possibly be increased while pregnancy-related changes in pyrimethamine are not expected to be clinically relevant. Further research is necessary to elucidate whether dose optimisation, to address the underexposure to sulfadoxine in pregnant women, is necessary, viable and safe with the current fixed dose combination of SP.
References:
[1] Nyunt, M.M. et al. Pharmacokinetics of sulfadoxine and pyrimethamine in intermittent preventive treatment of malaria in pregnancy. Clin Pharmacol Ther. 87(2), 226-234 (2010).
[2] Beal, S. et al. NONMEM users guides (1989–2009). Ellicott City, MD, USA: ICON Development Solutions; 2009.
[3] Anderson, B. J. et al. Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol. 48, 303–32 (2008).
Reference: PAGE 25 (2016) Abstr 5857 [www.page-meeting.org/?abstract=5857]
Poster: Drug/Disease modeling - Absorption & PBPK