Pharmacokinetics of a CCR5 inhibitor in rhesus macaques following vaginal, rectal and oral application

Objectives: This study measured and compared the pharmacokinetics of CMPD167, a small molecule antiretro- viral CCR5 inhibitor with potential as an HIV microbicide, following vaginal, rectal and oral administration in rhe- sus macaques.
Methods: A vaginal hydroxyethylcellulose (HEC) gel, a rectal HEC gel, a silicone elastomer matrix-type vaginal ring and an oral solution, each containing CMPD167, were prepared and administered to rhesus macaques pretreated with Depo-Provera. CMPD167 concentrations in vaginal fluid, vaginal tissue (ring only), rectal fluid and blood plasma were quantified by HPLC–mass spectrometry.
Results: CMPD167 concentrations measured in rectal fluid, vaginal fluid and blood plasma were highly depend- ent on both the route of administration and the formulation type. Although rectal and vaginal fluid concentra- tions were highest when CMPD167 was administered locally (via either gel or ring), lower concentrations of the drug were also measured in these compartments following administration at the remote mucosal site or orally. CMPD167 levels in the vaginal and rectal fluid following oral administration were relatively low compared with local administration.
Conclusions: The study provides clear evidence for vaginal – rectal and rectal – vaginal drug transfer pathways and suggests that oral pre-exposure prophylaxis with CMPD167 may be less efficacious at preventing sexual trans- mission of HIV-1 than topically applied products.

Microbicide Vaginal Rings: Technological Challenges and Clinical Development

Vaginal rings (VRs) are flexible, torus-shaped, polymeric devices designed to sustain delivery of pharmaceutical drugs to the vagina for clinical benefit. Following first report in a 1970 patent application, several steroid-releasing VR products have since been marketed for use in hormone replacement therapy and contraception. Since 2002, there has been growing interest in the use of VR technology for delivery of drugs that can reduce the risk of sexual acquisition of human immunodeficiency virus type 1 (HIV-1), the causative agent of acquired immunodeficiency syndrome (AIDS). Although no vaginally-administered product has yet been approved for HIV reduction/prevention, extensive research efforts are continuing and a number of VR devices offering sustained release of so-called ‘HIV microbicide’ compounds are currently being evaluated in late-stage clinical studies. This review article provides an overview of the published scientific literature within this important field of research, focusing primarily on articles published within peer-reviewed journal publications. Many important aspects of microbicide-releasing VR technology are discussed, with a particular emphasis on the technological, manufacturing and clinical challenges that have emerged in recent years.