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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.
Clin Infect Dis. 2019 04 24; 68(9):1530-1538.CI

Abstract

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.

Authors+Show Affiliations

Centre for Clinical Research, Kenya Medical Research Institute, Nairobi.Department of Medical Microbiology, Leishmaniasis Unit, College of Health Sciences, Makerere University, Kampala, Uganda.Drugs for Neglected Diseases Initiative, Nairobi, Kenya.Drugs for Neglected Diseases Initiative, Geneva, Switzerland.Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek Hospital/the Netherlands Cancer Institute, Amsterdam.Centre for Clinical Research, Kenya Medical Research Institute, Nairobi.Amudat Hospital, Uganda.Drugs for Neglected Diseases Initiative, Nairobi, Kenya.Drugs for Neglected Diseases Initiative, Nairobi, Kenya.Drugs for Neglected Diseases Initiative, Nairobi, Kenya.Drugs for Neglected Diseases Initiative, Nairobi, Kenya.Drugs for Neglected Diseases Initiative, Nairobi, Kenya.Drugs for Neglected Diseases Initiative, Geneva, Switzerland.Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek Hospital/the Netherlands Cancer Institute, Amsterdam.Drugs for Neglected Diseases Initiative, Geneva, Switzerland.

Pub Type(s)

Clinical Trial, Phase II
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30188978

Citation

Mbui, Jane, et al. "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." Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America, vol. 68, no. 9, 2019, pp. 1530-1538.
Mbui J, Olobo J, Omollo R, et al. 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. Clin Infect Dis. 2019;68(9):1530-1538.
Mbui, J., Olobo, J., Omollo, R., Solomos, A., Kip, A. E., Kirigi, G., Sagaki, P., Kimutai, R., Were, L., Omollo, T., Egondi, T. W., Wasunna, M., Alvar, J., Dorlo, T. P. C., & Alves, F. (2019). 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. Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America, 68(9), 1530-1538. https://doi.org/10.1093/cid/ciy747
Mbui J, et al. 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. Clin Infect Dis. 2019 04 24;68(9):1530-1538. PubMed PMID: 30188978.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Mbui,Jane, AU - Olobo,Joseph, AU - Omollo,Raymond, AU - Solomos,Alexandra, AU - Kip,Anke E, AU - Kirigi,George, AU - Sagaki,Patrick, AU - Kimutai,Robert, AU - Were,Lilian, AU - Omollo,Truphosa, AU - Egondi,Thaddaeus W, AU - Wasunna,Monique, AU - Alvar,Jorge, AU - Dorlo,Thomas P C, AU - Alves,Fabiana, PY - 2018/03/23/received PY - 2018/08/28/accepted PY - 2018/9/7/pubmed PY - 2020/7/3/medline PY - 2018/9/7/entrez KW - Eastern African children KW - allometric regimen KW - drug pharmacokinetics KW - miltefosine KW - visceral leishmaniasis SP - 1530 EP - 1538 JF - Clinical infectious diseases : an official publication of the Infectious Diseases Society of America JO - Clin Infect Dis VL - 68 IS - 9 N2 - 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. SN - 1537-6591 UR - https://www.unboundmedicine.com/medline/citation/30188978/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_ L2 - https://academic.oup.com/cid/article-lookup/doi/10.1093/cid/ciy747 DB - PRIME DP - Unbound Medicine ER -