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Translational pharm...
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Dorlo, Thomas P C
(författare)
Translational pharmacokinetic modelling and simulation for the assessment of duration of contraceptive use after treatment with miltefosine.
- Artikel/kapitelEngelska2012
Förlag, utgivningsår, omfång ...
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2012-05-10
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Oxford University Press (OUP),2012
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printrdacarrier
Nummerbeteckningar
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LIBRIS-ID:oai:DiVA.org:uu-494611
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-494611URI
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https://doi.org/10.1093/jac/dks164DOI
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Språk:engelska
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Sammanfattning på:engelska
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Ämneskategori:art swepub-publicationtype
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OBJECTIVES: Use of miltefosine in the treatment of visceral leishmaniasis (VL) is hampered by its potential teratogenicity. The duration of adequate contraceptive cover in females of child-bearing potential after cessation of a potentially teratogenic drug therapy remains debated. The objective of this study was to provide a rational approach to suggest durations of contraceptive cover for various miltefosine regimens.METHODS: A human reproductive safety threshold exposure limit was derived using animal-to-human dose conversion. Pharmacokinetic (PK) data for miltefosine in females are lacking; a previously developed population PK model and a comprehensive anthropometric dataset were used to simulate PK data for Indian female VL patients receiving miltefosine for 5, 7, 10 or 28 days. Probability of supra-threshold miltefosine exposure was used to evaluate adequate durations of post-treatment contraceptive cover for the various regimens.RESULTS: PK data were simulated for 465 treated Indian female VL patients of child-bearing potential with a median age of 25 years (IQR 16-31 years) and median weight of 38 kg (IQR 34-42 kg). From animal reproductive toxicity studies, a human reproductive safety threshold exposure limit was derived of 24.5 μg · day/mL. Probability of 'unprotected' supra-threshold miltefosine exposure was very low (<0.2%) for a post-treatment contraceptive cover period of 4 months for the standard 28 day regimen, and of 2 months for the shorter regimens.CONCLUSIONS: To our knowledge, this is the first study providing rational suggestions for contraceptive cover for a teratogenic drug based on animal-to-human dose conversion. For the 28 day miltefosine regimen, post-treatment contraceptive cover may be extended to 4 months, whereas for all shorter regimens 2 months may be adequate.
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Biuppslag (personer, institutioner, konferenser, titlar ...)
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Balasegaram, Manica
(författare)
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Lima, María Angeles
(författare)
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de Vries, Peter J
(författare)
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Beijnen, Jos H
(författare)
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Huitema, Alwin D R
(författare)
Sammanhörande titlar
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Ingår i:Journal of Antimicrobial Chemotherapy: Oxford University Press (OUP)67:8, s. 1996-20040305-74531460-2091
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