Pharmacokinetics and Disposition of Rilpivirine (TMC278) Nanosuspension as a Long-Acting Injectable Antiretroviral Formulation
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Published:2010-05
Issue:5
Volume:54
Page:2042-2050
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ISSN:0066-4804
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Container-title:Antimicrobial Agents and Chemotherapy
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language:en
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Short-container-title:Antimicrob Agents Chemother
Author:
van ′t Klooster Gerben1, Hoeben Eva2, Borghys Herman2, Looszova Adriana2, Bouche Marie-Paule2, van Velsen Frans1, Baert Lieven1
Affiliation:
1. Tibotec BVBA, Gen. De Wittelaan L 11B 3, B-2800 Mechelen, Belgium 2. Johnson & Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, 2340 Beerse, Belgium
Abstract
ABSTRACT
The next-generation human immunodeficiency virus type 1 (HIV-1) nonnucleoside reverse transcriptase inhibitor rilpivirine (TMC278) was administered in rats and dogs as single intramuscular (IM) or subcutaneous (SC) injections, formulated as a 200-nm nanosuspension. The plasma pharmacokinetics, injection site concentrations, disposition to lymphoid tissues, and tolerability were evaluated in support of its potential use as a once-monthly antiretroviral agent in humans. Rilpivirine plasma concentration-time profiles showed sustained and dose-proportional release over 2 months in rats and over 6 months in dogs. The absolute bioavailability approached 100%, indicating a complete release from the depot, in spite of rilpivirine concentrations still being high at the injection site(s) 3 months after administration in dogs. For both species, IM administration was associated with higher initial peak plasma concentrations and a more rapid washout than SC administration, which resulted in a stable plasma-concentration profile over at least 6 weeks in dogs. The rilpivirine concentrations in the lymph nodes draining the IM injection site exceeded the plasma concentrations by over 100-fold 1 month after administration, while the concentrations in the lymphoid tissues decreased to 3- to 6-fold the plasma concentrations beyond 3 months. These observations suggest uptake of nanoparticles by macrophages, which generates secondary depots in these lymph nodes. Both SC and IM injections were generally well tolerated and safe, with observations of a transient inflammatory response at the injection site. The findings support clinical investigations of rilpivirine nanosuspension as a long-acting formulation to improve adherence during antiretroviral therapy and for preexposure prophylaxis.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Reference32 articles.
1. Arasteh, K., A. Rieger, P. Yeni, A. Pozniak, G. Boogaerts, R. van Heeswijk, M. P. de Béthune, M. Peeters, and B. Woodfall. 2009. Short-term randomized proof-of-principle trial of TMC278 in patients with HIV type-1 who have previously failed antiretroviral therapy. Antivir. Ther.14:713-722. 2. Baert, L., W. Dries, M. François, A. Wouters, E. Bastanie, K. Iterbeke, F. Stappers, P. Stevens, L. Schueller, G. van ′t Klooster, P. Van Remoortere, J. Rosier, G. Kraus, and P. Wigerinck. 2009. Development of a long-acting injectable formulation using nanoparticles of rilpivirine (TMC278) for HIV treatment. Eur. J. Pharm. Biopharm.72:502-508. 3. Bønnelykke Sørensen, V., H. Wroblewski, S. Galatius, S. Haunsø, and J. Kastrup. 2000. Assessment of continuous skeletal muscle blood flow during exercise in humans. Microvasc. Res.59(2):301-309. 4. Burger, D. M., A. S. Bergshoeff, R. de Groot, D. Gibb, S. Walker, J.-M. Tréluye, and R. M. W. Hoetelmans, on behalf of the PENTA 5 Study Group. 2004. Maintaining the nelfinavir trough concentration above 0.8 mg/L improves virologic response in HIV-1-infected children. J. Pediatr.145:403-405. 5. Connor, E. M., R. S. Sperling, R. Gelber, P. Kiselev, G. Scott, M. J. O'Sullivan, R. VanDyke, M. Bey, W. Shearer, R. L. Jacobson, E. Jimenez, E. O'Neill, B. Bazin, J.-F. Delfraissy, M. Culnane, R. Coombs, M. Elkins, J. Moye, P. Stratton, and J. Balsley. 1994. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N. Engl. J. Med.331:1173-1180.
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