Pharmacokinetics and efficacy of a vaginally administered maraviroc gel in rhesus macaques

Objectives: To investigate the pharmacokinetics (PK) of maraviroc, a CCR5-targeted HIV-1 entry inhibitor, in rhesus macaques following vaginal administration of various maraviroc-loaded aqueous hydroxyethylcellulose (HEC) gels, and to correlate the PK data with efficacy in a single high-dose vaginal SHIV-162P3 challenge model.

Methods: Maraviroc concentrations in vaginal fluid (Weck-Cel® sponge), vaginal tissue (punch biopsy) and plasma were assessed over 72 h following single dose vaginal application of various maraviroc-loaded HEC gels. The range of maraviroc gel concentrations was sufficiently broad (0.003 – 3.3% w/w) such that test gels included both fully solubilised and predominantly dispersed formulations. The efficacy of the HEC gels against a single high dose vaginal SHIV-162P3 challenge was also measured, and correlated with the PK concentrations.

Results: Maraviroc concentrations in vaginal fluid (range 104 – 107 ng/mL), vaginal tissue (100-1200 ng/g) and plasma (< 102 ng/mL) were highly dependent on maraviroc gel loading, irrespective of the form of the maraviroc component within the gel (solubilised vs. dispersed). Fluid and plasma concentrations were generally highest 0.5 or 2 h after gel application, before declining steadily out to 72 h. Maraviroc concentrations in the various biological compartments correlated strongly with the extent of protection against vaginal SHIV-162P3 challenge. Complete protection was achieved with a 3.3% w/w maraviroc gel.

Conclusions: A high degree of correlation between PK and efficacy was observed. Based on the data obtained with the 3.3% w/w maraviroc gel, maintenance of vaginal fluid and tissue levels in the order of 107 ng/mL and 103 ng/g, respectively, are required for complete protection with this compound.

The Birth of Shakespeare's Birthplace

"There is, indeed, little doubt,” the formidable scholar James Orchard Halliwell-Phillipps confidently explained to the Victorian readers of his Outlines of the Life of Shakespeare, “that the Birth-place did not become one of the incentives for pilgrimage until public attention had been specially directed to it at the time of the Jubilee.” That's broadly true. The earliest reference to the three-gabled, half-timbered house (two houses, originally) on Henley Street in Stratford-upon-Avon as the birthplace of William Shakespeare dates only from the late 1750s, when it was so named in Samuel Winter's town map. During the Stratford Jubilee, which David Garrick organized in 1769, the “small old house,” as the actor's first biographer called it, was fully recognized and promoted as the place where Shakespeare was born. Even so, Halliwell-Phillipps's observation conceals more than it reveals, because there is also little doubt that the dwelling that tradition calls Shakespeare's birthplace did not suddenly acquire that status during the first week of September 1769. The process by which the unremarkable piece of real estate that John Shakespeare purchased sometime in the late sixteenth century was transformed into what Barbara Hodgdon has rightly called the “controlling ideological center” of Shakespeare biography was long, slow, and far from inevitable. That process is the subject of this essay.