Characterizing the non-linear pharmacokinetics of miltefosine in paediatric visceral leishmaniasis patients from Eastern Africa
| Autor: | Alexandra Solomos, Ahmed Eleojo Musa, Monique Wasunna, Semra Palić, Jos H. Beijnen, Joseph Olobo, Thomas P. C. Dorlo, Anke E. Kip, Fabiana Alves, Jane Mbui |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Microbiology (medical) Adult medicine.medical_specialty Phosphorylcholine 030106 microbiology Antiprotozoal Agents Gastroenterology 03 medical and health sciences 0302 clinical medicine Pharmacokinetics Internal medicine medicine AcademicSubjects/MED00740 Humans Pharmacology (medical) 030212 general & internal medicine Dosing Child Original Research Pharmacology Miltefosine Cumulative dose business.industry Leishmaniasis Africa Eastern medicine.disease Bioavailability Regimen Infectious Diseases Visceral leishmaniasis AcademicSubjects/MED00290 Leishmaniasis Visceral business AcademicSubjects/MED00230 medicine.drug |
| Zdroj: | Journal of Antimicrobial Chemotherapy |
| ISSN: | 1460-2091 0305-7453 |
| Popis: | Background Conventional miltefosine dosing (2.5 mg/kg/day) for treatment of visceral leishmaniasis (VL) is less effective in children than in adults. A higher allometric dose (median 3.2 mg/kg/day) was therefore investigated in paediatric VL patients in Eastern Africa. Results of this trial showed an unforeseen, lower than dose-proportional increase in exposure. Therefore, we performed a pooled model-based analysis of the paediatric data available from both dosing regimens to characterize observed non-linearities in miltefosine pharmacokinetics (PK). Methods Fifty-one children with VL were included in this analysis, treated with either a conventional (n = 21) or allometric (n = 30) miltefosine dosing regimen. PK data were analysed using non-linear mixed-effects modelling. Results A two-compartment model following first-order absorption and linear elimination, with two separate effects on relative oral bioavailability, was found to fit these data best. A 69% lower bioavailability at treatment start was estimated, presumably due to initial malnourishment and malabsorption. Stagnation in miltefosine accumulation in plasma, hampering increased drug exposure, was related to the increase in cumulative dose (mg/kg/day). However, the allometric regimen increased exposure 1.7-fold in the first treatment week and reduced the time to reach the PK target by 17.4%. Conclusions Miltefosine PK in children suffering from VL are characterized by dose-dependent non-linearities that obstruct the initially expected exposure levels. Bioavailability appeared to be affected by the cumulative dose, possibly as a consequence of impaired absorption. Despite this, allometric dosing led to a faster target achievement and increased exposure compared with conventional dosing. |
| Databáze: | OpenAIRE |
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