Quantification of the spatial distribution of rectally applied surrogates for microbicide and semen in colon with SPECT and magnetic resonance imaging

Ying J. Cao, Brian S. Caffo, Edward J. Fuchs, Linda A. Lee, Yong Du, Liye Li, Rahul P. Bakshi, Katarzyna Macura, Wasif A. Khan, Richard L. Wahl, Lisa A. Grohskopf, Craig W. Hendrix

Research output: Contribution to journalArticlepeer-review

Abstract

AIMS We sought to describe quantitatively the distribution of rectally administered gels and seminal fluid surrogates using novel concentration-distance parameters that could be repeated over time. These methods are needed to develop rationally rectal microbicides to target and prevent HIV infection. METHODS Eight subjects were dosed rectally with radiolabelled and gadolinium-labelled gels to simulate microbicide gel and seminal fluid. Rectal doses were given with and without simulated receptive anal intercourse. Twenty-four hour distribution was assessed with indirect single photon emission computed tomography (SPECT)/computed tomography (CT) and magnetic resonance imaging (MRI), and direct assessment via sigmoidoscopic brushes. Concentration-distance curves were generated using an algorithm for fitting SPECT data in three dimensions. Three novel concentration-distance parameters were defined to describe quantitatively the distribution of radiolabels: maximal distance (Dmax), distance at maximal concentration (DCmax) and mean residence distance (Dave). RESULTS The SPECT/CT distribution of microbicide and semen surrogates was similar. Between 1h and 24h post dose, the surrogates migrated retrograde in all three parameters (relative to coccygeal level; geometric mean [95% confidence interval]): maximal distance (Dmax), 10cm (8.6-12) to 18cm (13-26), distance at maximal concentration (DCmax), 3.8cm (2.7-5.3) to 4.2cm (2.8-6.3) and mean residence distance (Dave), 4.3cm (3.5-5.1) to 7.6cm (5.3-11). Sigmoidoscopy and MRI correlated only roughly with SPECT/CT. CONCLUSIONS Rectal microbicide surrogates migrated retrograde during the 24h following dosing. Spatial kinetic parameters estimated using three dimensional curve fitting of distribution data should prove useful for evaluating rectal formulations of drugs for HIV prevention and other indications.

Original languageEnglish (US)
Pages (from-to)1013-1022
Number of pages10
JournalBritish Journal of Clinical Pharmacology
Volume74
Issue number6
DOIs
StatePublished - Dec 2012

Keywords

  • Gastrointestinal distribution
  • HIV microbicide
  • HIV prevention
  • Pharmacokinetics
  • Rectal dosing

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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