René Verloes

Tibotec BVBA

Generaal De Wittelaan L11 B3

B-2800 Mechelen

Belgium

rverloes@tibbe.JNJ.com

TMC278 long acting – a parenteral nanosuspension formulation that provides sustained clinically relevant plasma concentrations in HIV-negative volunteersR Verloes,1 G van‘t Klooster,1 L Baert,1 F van Velsen,1 M-P Bouche,2 K Spittaels,1 J Leempoels,3 P Williams,1 G Kraus,1 P Wigerinck1 1Tibotec BVBA, Mechelen, Belgium; 2Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium; 3Johnson & Johnson Pharmaceutical Research and Development, Merksem, Belgium

TUPE0042

Abstract

Conclusions

Acknowledgments

Background: TMC278, a next-generation NNRTI, has shown potent sustained activity against HIV-1 after qd oral doses in a Phase IIb trial of treatment-naïve patients. Potential future uses of parenteral depot formulations of TMC278 could include maintenance therapy or pre-exposure prophylaxis. We investigated the pharmacokinetics and tolerability after intramuscular (IM) and subcutaneous (SC) injections of a TMC278 long-acting (LA) formulation.

Methods: TMC278 was formulated as a sterile nanosuspension using Elan’s NanoCrystal® technology. Pharmacokinetic (PK) and injection-site reactions (ISRs) were evaluated after a single abdominal SC or gluteal IM (IMg) injection in 51 HIV-negative volunteers at doses of 200mg, 400mg and 600mg, or vehicle (placebo). A further group of nine volunteers received a single 400mg injection into the deltoid (IMd) rather than the gluteal muscle.

Results: TMC278 was slowly released from the injection site. Plasma concentrations of TMC278 reached a maximum around 3 days and then fell biphasically to below 10ng/mL by 12–26 weeks. Mean PK parameters, after 400mg SC and IMg injections, were 70ng/mL and 99ng/mL for maximum plasma concentration (Cmax), and 57 600 and 61 400ng•h/mL for area under the plasma concentration-time curve from time of administration to Week 12 after dosing (AUC0–Week 12), respectively. Corresponding values after a 400mg IMd injection were 80ng/mL for Cmax, and 63 780ng•h/mL for AUC0–Week 12. Serious adverse events (AEs) or grade 3 or 4 AEs were not reported. ISRs consisting of redness, bruising, pain and sometimes indurations were more common after TMC278 than after placebo injections. The IMg route was better tolerated than the IMd route. At the 400mg dose, IMd injection induced more spontaneous pain and pain at touch (6/6 volunteers), albeit of moderate severity, than after IMg injection (2/6 volunteers). Based on a greater number of ISRs with the SC versus the IM route, IM injection was better tolerated than SC injection.

Conclusions: A TMC278 LA depot formulation administered in single doses provided prolonged exposure to TMC278 for several months and was well tolerated.

• InjectableLAformulationsmayprovideanewparadigm in ARV use and may facilitate long-term compliance.

•TMC278LAisapromisingdepotformulation;theconcept is viable– single 400mg and 600mg doses gave prolonged

TMC278 plasma exposure of approximately 20ng/mL after 8 weeks

– PK exposures were comparable after IM and SC injections

– favorable safety and tolerability: no serious AEs, grade 3 or 4 AEs or rash• injections were well tolerated, particularly

whenadministeredIMg;indurationsweremorefrequent after SC than after IM injections

• placebo injections were better tolerated thaninjectionswithTMC278LA;600mgIMginjections were better tolerated than 600mg SC and than 400mg IMd injections.

•Nextsteps:toperformamultiple-dosetrialinHIV-negativehealthyvolunteers;continuewithIMandSC(allowing self-administration) injections.

• Wewouldliketoacknowledge – the volunteers who participated in the clinical study

– the trial site personnel at J&J Pharmaceutical Research and Development (PRD), Merksem, Belgium

– Jan Rosier, Mark Martens, Sophie Lachau-Durand, Rolf van Heeswijk, and other colleagues from Tibotec BVBA, Mechelen, Belgium

– Eva Hoeben, Herman Borghys, Marc François, Willy Dries, Sandra De Jonghe, Marieke Voets, Katelijne Anciaux, Liesbeth Grooten and Adriana Looszova, and other colleagues from J&J PRD, Beerse, Belgium

– Richard Hooijmaijers, and other colleagues from Kinesis Pharma, Breda, The Netherlands.

in vitro

10-fold protein binding-corrected EC50

Supported by Tibotec This poster is available on-line at www.tibotec.com.Presented at the XVIIth International AIDS Conference, Mexico City, Mexico, August 3–8 2008.

JD125440 AIDS Verloes Poster.indd 1 25/7/08 15:17:41