Pharmacokinetics, Safety, and Efficacy of an Allometric Miltefosine Regimen for the Treatment of Visceral Leishmaniasis in Eastern African Children: An Open-label, Phase II Clinical Trial
| Autor: | Jorge Alvar, Thaddaeus Egondi, Alexandra Solomos, Joseph Olobo, Anke E. Kip, Lilian Were, Truphosa Omollo, Patrick Sagaki, G. Kirigi, Fabiana Alves, Thomas P. C. Dorlo, Robert Kimutai, Jane Mbui, Monique Wasunna, Raymond Omollo |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Microbiology (medical) Male medicine.medical_specialty drug pharmacokinetics Phosphorylcholine 030231 tropical medicine 030106 microbiology Antiprotozoal Agents Phases of clinical research Eastern African children Gastroenterology Drug Administration Schedule 03 medical and health sciences 0302 clinical medicine Pharmacokinetics Internal medicine medicine Humans visceral leishmaniasis Dosing Adverse effect Child Articles and Commentaries Miltefosine business.industry Africa Eastern medicine.disease 3. Good health Discontinuation allometric regimen Regimen Infectious Diseases Visceral leishmaniasis Treatment Outcome Area Under Curve Child Preschool Leishmaniasis Visceral Female Patient Safety business miltefosine medicine.drug Leishmania donovani |
| Zdroj: | Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America |
| ISSN: | 1537-6591 |
| Popis: | Background Convenient, safe, and effective treatments for visceral leishmaniasis in Eastern African children are lacking. Miltefosine, the only oral treatment, failed to achieve adequate efficacy, particularly in children, in whom linear dosing (2.5 mg/kg/day for 28 days) resulted in a 59% cure rate, with lower systemic exposure than in adults. Methods We conducted a Phase II trial in 30 children with visceral leishmaniasis, aged 4–12 years, to test whether 28 days of allometric miltefosine dosing safely achieves a higher systemic exposure than linear dosing. Results Miltefosine accumulated during treatment. Median areas under the concentration time curve from days 0–210 and plasma maximum concentration values were slightly higher than those reported previously for children on linear dosing, but not dose-proportionally. Miltefosine exposure at the start of treatment was increased, with higher median plasma concentrations on day 7 (5.88 versus 2.67 μg/mL). Concentration-time curves were less variable, avoiding the low levels of exposure observed with linear dosing. The 210-day cure rate was 90% (95% confidence interval, 73–98%), similar to that previously described in adults. There were 19 treatment-related adverse events (AEs), but none caused treatment discontinuation. There were 2 serious AEs: both were unrelated to treatment and both patients were fully recovered. Conclusions Allometric miltefosine dosing achieved increased and less-variable exposure than linear dosing, though not reaching the expected exposure levels. The new dosing regimen safely increased the efficacy of miltefosine for Eastern African children with visceral leishmaniasis. Further development of miltefosine should adopt allometric dosing in pediatric patients. Clinical Trials Registration NCT02431143. Allometric miltefosine dosing for 28 days in Eastern African children with visceral leishmaniasis demonstrated increased and less-variable exposure than linear miltefosine dosing, with improved efficacy and a satisfactory safety profile. |
| Databáze: | OpenAIRE |
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