maraviroc
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Východisko. Přestože antiretrovirová terapie změnila klinický průběh HIV infekce, zůstává onemocnění AIDS nevyléčitelnou chorobou. Vznikají skupiny antiretrovirotik s novými mechanismy účinku. Mezi nimi inhibitory vstupu, jejichž jediným registrovaným zástupcem je maraviroc. Primárním cílem práce je vyhodnotit klinickou účinnost maravirocu pomocí parametru virové nálože změřené do 4. týdne od zahájení léčby, sekundárním cílem je vyhodnotit účinnost léčiva do 125. týdne sledováním změn hodnot virové nálože a změn počtu CD4+ lymfocytů. Rovněž je hodnocena bezpečnost léčiva. Metody a výsledky. Do skupiny pacientů jsme zařadili celkem 23 subjektů, dva pacienty z České republiky a 21 pacientů z Francie. Virová nálož poklesla ve 4., 24. i 48. týdnu více než o dva řády (-2,136; -2,448; -2,452 log10 kopií/ml). V počtu CD4+ lymfocytů docházelo k nárůstu hodnot (71,71; 142,00; 196,43 buněk/mm3). Bezpečnost léčiva byla hodnocena sledováním četnosti výskytu nežádoucích účinků. Získaná data jsme porovnali s registračními klinickými studiemi III. fáze. Během léčby se objevilo jedenáct podezření na nežádoucí účinky, žádné z těchto podezření nebylo dáno do příčinné souvislosti s terapií maravirocem. Nejčastější z nich patří do skupiny neurologických nežádoucích účinků. Závěry. Naše zkušenosti s maravirocem byly pozitivní, léčivo se osvědčilo jako účinné antiretrovirotikum pro kombinační léčbu HIV infekce.
Background. Although antiretroviral therapy has changed the clinical course of HIV infection, AIDS remains an incurable disease. Virus entry inhibitors, including maraviroc as the only registered representative of the class, represent a newly emerged group of anti-retrovirals with novel mechanism of action. The primary endpoint is to evaluate the clinical efficacy parameter of maraviroc by measuring viral load at the end of the 4 week treatment period. The secondary endpoint is to evaluate the effectiveness of the drug by monitoring the changes of the viral load values and CD4+ cell counts during the period of 125 weeks. Drug safety was also assessed. Methods and results. Data of 23 subjects were collected, 21 patients were from the Czech Republic and 2 patients from France. Decrease in viral load in the 4th, 24th and 48th week was more than two orders of magnitude (-2.136; -2.448; -2.452 log10 copies/ml). The CD4+ cell count increased (71.71, 143.00, 196.43 cells/mm3). Drug safety was assessed by monitoring the frequency of adverse effects. The data obtained were compared with the III. phase of clinical trials.
- Klíčová slova
- CCR5 inhibitory,
- MeSH
- AIDS MeSH
- cyklohexany terapeutické užití MeSH
- HIV infekce virologie MeSH
- inhibitory HIV fúze farmakologie imunologie terapeutické užití MeSH
- lidé středního věku MeSH
- lidé MeSH
- počet CD4 lymfocytů MeSH
- triazoly terapeutické užití MeSH
- virová nálož MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- klinické zkoušky MeSH
Special attention is required when pharmacological treatment is indicated for a pregnant woman. P-glycoprotein (MDR1) is a well-known transporter localized in the maternal blood-facing apical membrane of placental syncytiotrophoblast and is considered to play an important role in protecting the developing fetus. Maraviroc, a MDR1 substrate that is registered for treatment of HIV infection, shows a low toxicity profile, suggesting favorable tolerability also if administered to pregnant women. Nevertheless, there is only poor understanding to date regarding the extent to which it permeates across the placental barrier and what are the transport mechanisms involved. Endeavoring to clarify the passage of maraviroc across placenta, we used in this study the method of closed-circuit perfusion of maraviroc across human placental cotyledon. The data obtained confirmed slight involvement of MDR1, but they also suggest possible interaction with other transport system(s) working in the opposite direction from that of MDR1. Complementary in vitro studies, including cellular experiments on choriocarcinoma BeWo cells as well as transporter-overexpressing MDCKII and A431 cell lines and accumulation in placental fresh villous fragments, revealed maraviroc transport by MRP1, OATP1A2, and OATP1B3 transporters. Based on mRNA expression data in the placental tissue, isolated trophoblasts, and fetal endothelial cells, especially MRP1 and OATP1A2 seem to play a crucial role in cooperatively driving maraviroc into placental tissue. By the example of maraviroc, we show here the important interplay of transporters in placental drug handling and its possibility to overcome the MDR1-mediated efflux.
- MeSH
- akridiny farmakologie MeSH
- buňky MDCK MeSH
- látky proti HIV krev metabolismus farmakologie MeSH
- lékové interakce MeSH
- lidé MeSH
- maravirok krev metabolismus MeSH
- nádorové buněčné linie MeSH
- P-glykoproteiny antagonisté a inhibitory genetika metabolismus MeSH
- perfuze MeSH
- placenta účinky léků metabolismus MeSH
- placentární oběh MeSH
- přenašeče organických aniontů antagonisté a inhibitory genetika metabolismus MeSH
- protein OATP1B3 antagonisté a inhibitory genetika metabolismus MeSH
- proteiny spojené s mnohočetnou rezistencí k lékům genetika metabolismus MeSH
- psi MeSH
- regulace genové exprese MeSH
- ritonavir farmakologie MeSH
- těhotenství MeSH
- tetrahydroisochinoliny farmakologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- psi MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Maraviroc is a chemokine receptor 5 (CCR5) inhibitor used in the treatment of human immunodeficiency virus (HIV) that also shows therapeutic potential for several autoimmune, cancer, and inflammatory diseases that can afflict pregnant women. However, only limited information exists on the mechanisms underlying the transplacental transfer of the drug. We aimed to expand the current knowledge base on how maraviroc interacts with several placental ATP-binding cassette (ABC) efflux transporters that have a recognized role in the protection of a developing fetus: P-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2), and multidrug resistance protein 2 (ABCC2). We found that maraviroc does not inhibit any of the three studied ABC transporters and that its permeability is not affected by ABCG2 or ABCC2. However, our in vitro results revealed that maraviroc shows affinity for human ABCB1 and the endogenous canine P-glycoprotein (Abcb1) expressed in Madin-Darby canine kidney II (MDCKII) cells. Perfusion of rat term placenta showed accelerated transport of maraviroc in the fetal-to-maternal direction, which suggests that ABCB1/Abcb1 facilitates in situ maraviroc transport. This transplacental transport was saturable and significantly diminished after the addition of the ABCB1/Abcb1 inhibitors elacridar, zosuquidar, and ritonavir. Our results indicate that neither ABCG2 nor ABCC2 influence maraviroc pharmacokinetic but that ABCB1/Abcb1 may be partly responsible for the decreased transplacental permeability of maraviroc to the fetus. The strong affinity of maraviroc to Abcb1 found in our animal models necessitates studies in human tissue so that maraviroc pharmacokinetics in pregnant women can be fully understood. SIGNIFICANCE STATEMENT: Antiretroviral drug maraviroc shows low toxicity and is thus a good candidate for prevention of mother-to-child transmission of human immunodeficiency virus when failure of recommended therapy occurs. Using in vitro cell-based experiments and in situ dually perfused rat term placenta, we examined maraviroc interaction with the placental ABC drug transporters ABCB1, ABCG2, and ABCC2. We demonstrate for the first time that placental ABCB1 significantly reduces mother-to-fetus transport of maraviroc, which suggests that ABCB1 may be responsible for the low cord-blood/maternal-blood ratio observed in humans.
- MeSH
- ABC transportér z rodiny G, člen 2 metabolismus MeSH
- antagonisté receptoru CCR5 farmakokinetika terapeutické užití MeSH
- buňky MDCK MeSH
- HIV infekce farmakoterapie MeSH
- infekční komplikace v těhotenství farmakoterapie MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- maravirok farmakokinetika terapeutické užití MeSH
- maternofetální výměna látek * MeSH
- modely u zvířat MeSH
- P-glykoprotein metabolismus MeSH
- permeabilita MeSH
- placenta metabolismus MeSH
- placentární oběh MeSH
- plod metabolismus MeSH
- proteiny spojené s mnohočetnou rezistencí k lékům metabolismus MeSH
- psi MeSH
- těhotenství MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- psi MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
P-glycoprotein (ABCB1), an ATP-binding-cassette efflux transporter, limits intestinal absorption of its substrates and is a common site of drug-drug interactions (DDIs). ABCB1 has been suggested to interact with many antivirals used to treat HIV and/or chronic hepatitis C virus (HCV) infections. Using bidirectional transport experiments in Caco-2 cells and a recently established ex vivo model of accumulation in precision-cut intestinal slices (PCIS) prepared from rat ileum or human jejunum, we evaluated the potential of anti-HIV and anti-HCV antivirals to inhibit intestinal ABCB1. Lopinavir, ritonavir, saquinavir, atazanavir, maraviroc, ledipasvir, and daclatasvir inhibited the efflux of a model ABCB1 substrate, rhodamine 123 (RHD123), in Caco-2 cells and rat-derived PCIS. Lopinavir, ritonavir, saquinavir, and atazanavir also significantly inhibited RHD123 efflux in human-derived PCIS, while possible interindividual variability was observed in the inhibition of intestinal ABCB1 by maraviroc, ledipasvir, and daclatasvir. Abacavir, zidovudine, tenofovir disoproxil fumarate, etravirine, and rilpivirine did not inhibit intestinal ABCB1. In conclusion, using recently established ex vivo methods for measuring drug accumulation in rat- and human-derived PCIS, we have demonstrated that some antivirals have a high potential for DDIs on intestinal ABCB1. Our data help clarify the molecular mechanisms responsible for reported increases in the bioavailability of ABCB1 substrates, including antivirals and drugs prescribed to treat comorbidity. These results could help guide the selection of combination pharmacotherapies and/or suitable dosing schemes for patients infected with HIV and/or HCV.
- MeSH
- antivirové látky farmakologie MeSH
- atazanavir sulfát farmakologie MeSH
- benzimidazoly farmakologie MeSH
- Caco-2 buňky účinky léků metabolismus MeSH
- fluoreny farmakologie MeSH
- hepatitida C komplikace farmakoterapie virologie MeSH
- HIV infekce komplikace farmakoterapie virologie MeSH
- imidazoly farmakologie MeSH
- krysa rodu rattus MeSH
- látky proti HIV farmakologie MeSH
- lékové interakce MeSH
- lidé středního věku MeSH
- lidé MeSH
- Lopinavir farmakologie MeSH
- maravirok farmakologie MeSH
- P-glykoprotein antagonisté a inhibitory metabolismus MeSH
- potkani Wistar MeSH
- ritonavir farmakologie MeSH
- saquinavir farmakologie MeSH
- senioři MeSH
- střeva účinky léků MeSH
- zidovudin farmakologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
