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Visceral leishmania...
Visceral leishmaniasis relapse hazard is linked to reduced miltefosine exposure in patients from Eastern Africa : a population pharmacokinetic/pharmacodynamic study
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- Dorlo, Thomas P. C. (author)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Netherlands Canc Inst, Antoni Van Leeuwenhoek Hosp, Dept Pharm & Pharmacol, Louwesweg 6, NL-1066 EC Amsterdam, Netherlands.
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- Kip, Anke E. (author)
- Netherlands Canc Inst, Antoni Van Leeuwenhoek Hosp, Dept Pharm & Pharmacol, Louwesweg 6, NL-1066 EC Amsterdam, Netherlands.
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- Younis, Brima M. (author)
- Univ Khartoum, Inst Endem Dis, Khartoum, Sudan.
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- Ellis, Sally J. (author)
- Drugs Neglected Dis initiat, Geneva, Switzerland.
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- Alves, Fabiana (author)
- Drugs Neglected Dis initiat, Geneva, Switzerland.
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- Beijnen, Jos. H. (author)
- Netherlands Canc Inst, Antoni Van Leeuwenhoek Hosp, Dept Pharm & Pharmacol, Louwesweg 6, NL-1066 EC Amsterdam, Netherlands.
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- Njenga, Simon (author)
- Kenya Govt Med Res Ctr, Nairobi, Kenya.
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- Kirigi, George (author)
- Kenya Govt Med Res Ctr, Nairobi, Kenya.
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- Hailu, Asrat (author)
- Addis Ababa Univ, Addis Ababa, Ethiopia.
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- Olobo, Joseph (author)
- Makerere Univ, Kampala, Uganda.
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- Musa, Ahmed M. (author)
- Univ Khartoum, Inst Endem Dis, Khartoum, Sudan.
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- Balasegaram, Manica (author)
- Drugs Neglected Dis initiat, Geneva, Switzerland.
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- Wasunna, Monique (author)
- Drugs Neglected Dis initiat, Nairobi, Kenya.
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- Karlsson, Mats O (author)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
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- Khalil, Eltahir A. G. (author)
- Univ Khartoum, Inst Endem Dis, Khartoum, Sudan.
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(creator_code:org_t)
- 2017-09-06
- 2017
- English.
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In: Journal of Antimicrobial Chemotherapy. - : OXFORD UNIV PRESS. - 0305-7453 .- 1460-2091. ; 72:11, s. 3131-3140
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Abstract
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- Background: Low efficacy of miltefosine in the treatment of visceral leishmaniasis was recently observed in Eastern Africa. Objectives: To describe the pharmacokinetics and establish a pharmacokinetic/pharmacodynamic relationship for miltefosine in Eastern African patients with visceral leishmaniasis, using a time-to-event approach to model relapse of disease. Methods: Miltefosine plasma concentrations from 95 patients (48 monotherapy versus 47 combination therapy) were included in the population pharmacokinetic model using non-linear mixed effects modelling. Subsequently a time-to-event model was developed to model the time of clinical relapse. Various summary pharmacokinetic parameters (various AUCs, Time > EC50, Time > EC90), normalized within each treatment arm to allow simultaneous analysis, were evaluated as relapse hazard-changing covariates. Results: A two-compartment population model with first-order absorption fitted the miltefosine pharmacokinetic data adequately. Relative bioavailability was reduced (- 74%, relative standard error 4.7%) during the first week of treatment of the monotherapy arm but only the first day of the shorter combination regimen. Time to the relapse of infection could be described using a constant baseline hazard (baseline 1.8 relapses/year, relative standard error 72.7%). Miltefosine Time > EC90 improved the model significantly when added in a maximum effect function on the baseline hazard (half maximal effect with Time. > EC90 6.97 days for monotherapy). Conclusions: Miltefosine drug exposure was found to be decreased in Eastern African patients with visceral leishmaniasis, due to a (transient) initial lower bioavailability. Relapse hazard was inversely linked to miltefosine exposure. Significantly lower miltefosine exposure was observed in children compared with adults, further urging the need for implementation of dose adaptations for children.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
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- art (subject category)
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- By the author/editor
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Dorlo, Thomas P. ...
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Kip, Anke E.
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Younis, Brima M.
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Ellis, Sally J.
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Alves, Fabiana
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Beijnen, Jos. H.
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show more...
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Njenga, Simon
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Kirigi, George
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Hailu, Asrat
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Olobo, Joseph
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Musa, Ahmed M.
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Balasegaram, Man ...
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Wasunna, Monique
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Karlsson, Mats O
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Khalil, Eltahir ...
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Pharmaceutical S ...
- Articles in the publication
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Journal of Antim ...
- By the university
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Uppsala University