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

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Rectally applied drugs have been imaged using radioisotopes and magnetic resonance contrast agents. However, prior studies have not described the distribution and clearance of rectally-applied drugs in quantitative terms with respect to complex three dimensional paths through the gastrointestinal tract. Such tools would allow statistical comparisons of candidate products in development or comparison of drug product with the distribution of a drug target, for example, HIV infected seminal fluid. WHAT THIS STUDY ADDS• New quantitative spatial parameters, derived from three dimensional curve fitting, have been successfully applied in this study to quantify the distribution of rectally-applied gels. Indirect assessment using nuclear medicine techniques avoided the distortion and redistribution associated with sigmoidoscopic sampling. Thus, these measurements can be repeated over time to create concentration-distance-time surfaces to describe rectal product distribution and clearance within the gastrointestinal lumen to inform microbicide and other rectal product development. AIMSWe 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. METHODSEight 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 (DC max ) and mean residence distance (Dave). RESULTSThe SPECT/CT distribution of microbicide and semen surrogates was similar.Between 1 h and 24 h post dose, the surrogates migrated retrograde in all three parameters (relative to coccygeal level; geometric mean [95% confidence interval]): maximal distance (Dmax), 10 cm (8.6-12) to 18 cm (13-26), distance at maximal concentration (DC max ), 3.8 cm (2.7-5.3) to 4.2 cm (2.8-6.3) and mean residence distance (Dave), 4.3 cm (3.5-5.1) to 7.6 cm (5.3-11). Sigmoidoscopy and MRI correlated only roughly with SPECT/CT. CONCLUSIONSRectal microbicide surrogates migrated retrograde during the 24 h 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.

Isoosmolar Enemas Demonstrate Preferential Gastrointestinal Distribution, Safety, and Acceptability Compared with Hyperosmolar and Hypoosmolar Enemas as a Potential Delivery Vehicle for Rectal Microbicides

“…The origin of the centerline was normalized to the coccygeal plane defined as the transverse plane crossing the coccyx in the SPECT/CT as previously described. 28 The distance between the origin of the centerline and the coccygeal plane was recorded as D min (minimum distance associated with the closest point where a radiolabeled signal was detected within the luminal path of the colon). Previously defined imaging pharmacokinetic-distance parameters-D max (distance associated with the most proximal radiolabel signal within the colon), D Cmax (distance at concentration maximum), and D ave (mean residence distance)-were calculated for further analysis.…”

“…Previously defined imaging pharmacokinetic-distance parameters-D max (distance associated with the most proximal radiolabel signal within the colon), D Cmax (distance at concentration maximum), and D ave (mean residence distance)-were calculated for further analysis. 28 …”

In vivooptical imaging of human vaginal gel thickness distributions with a probe-based, dual-modality instrument

“…Remote sensing imaging techniques, such as magnetic resonance imaging (MRI) and single-photon emission computed tomography (SPEC-CT), can provide information about such vaginal gel distributions. [10][11][12][13][14][15] While these imaging modalities provide excellent information on the pelvic anatomy and general microbicide gel distribution, they typically lack the resolution to detect the thin coating layers, of the order of 100 μm, that may be sufficient for microbicide gel functioning. 7,8 Further, contrast agents typically must be added to the gels before imaging, and this may limit the time between gel insertion and imaging since the contrast agent can separate from the gel into the tissues and fluids of the body.…”

Simultaneous Evaluation of Safety, Acceptability, Pericoital Kinetics, and Ex Vivo Pharmacodynamics Comparing Four Rectal Microbicide Vehicle Candidates

“…Coital simulation and HIV surrogate preparations were performed as previously described. 19,20,[22][23][24][25] All research participants were also given a dose of each study product for dosing at home in the context of RAI with a partner. The study products were partially blinded because investigators preparing the radiolabeled study product could discern subtle differences in the products.…”

“…Previously defined pharmacokinetic-distance parameters D max (furthest point at which the radiosignal was detected), DC max (distance at concentration maximum), and D ave (mean resident distance) were calculated. 30 Overlapping study product and HIV surrogate analysis. Phase B SPECT/CT scans followed per rectum dosing of 111 In-DTPA-labeled study product (microbicide vehicle) and, 1 h later, 99m Tc-sulfur colloid (HIV surrogate) in autologous seminal plasma following simulated RAI (sRAI).…”