Raltegravir and other integrase inhibitors in the pipeline at Merck could prove promising agents for pre-exposure and post-exposure prophylaxis, suggest findings presented earlier this month at the International Workshop on Clinical Pharmacology of HIV Therapy in Amsterdam.
Raltegravir (marketed as Isentress) is an integrase inhibitor, a drug which blocks the integration of HIV’s genetic material into the DNA of a human cell. Raltegravir is already approved for use in combination antiretroviral treatment in the United States and European Union.
Manufacturer Merck is now supporting preliminary research into its potential use as an agent for pre-exposure prophylaxis (PrEP) – blocking HIV infection in HIV-negative people by using antiretroviral drugs in advance of exposure to the virus. Trials of pre-exposure prophylaxis using tenofovir (Viread) or tenofovir and FTC (Truvada) are already underway, but there is also interest in the potential of other types of antiretroviral drugs, such as CCR5 inhibitors and integrase inhibitors, to block HIV infection.
At this month's workshop researchers from the University of North Carolina presented data on the first step in the research process, which is an evaluation of how well raltegravir concentrates in the female genital tract. The higher the concentration of a drug in the female genital tract, the more attractive it becomes for use in pre-exposure prophylaxis, because this is one of the primary sites where protection against infection needs to occur.
A high concentration in the female genital tract also indicates that a drug is likely to limit onward transmission of HIV in women who are taking the drug for their own health.
Amanda Jones and colleagues from the University of North Carolina at Chapel Hill investigated the pharmacokinetic profile of multiple and single doses of raltegravir in seven healthy adult HIV-negative women.
They measured drug concentrations in blood and cervicovaginal fluid at eight time points over 12 hours following a single dose, and repeated this process during days three to six of dosing, after a pharmacokinetic steady state had been achieved. After seven days of dosing the time it took for drug levels to reach half of the steady state level (the terminal half-life) was measured. This measurement shows how long the drug might be expected to exert a protective effect, and hence its potential for intermittent rather than daily dosing.
The measurements showed that:
- Raltegravir levels take longer to peak in cervicovaginal fluid than in blood (12 hours vs 6 hours) and there was greater variability between individuals in cervicovaginal than blood levels of raltegravir.
- There was wide variation in the ratio of cervicovaginal to blood concentrations, from as low as 0.23 to as high as 2.26, yielding a median ratio after a single dose of 0.64. After steady state was achieved the ratio improved to 0.93, (93%) but the range remained wide: from 0.06 to 10.5 (interquartile range 0.41-1.69).
- The median half-life in cervicovaginal fluid was 17 hours, and two days after the last dose cervicovaginal concentrations were still at levels equivalent to those found in blood 12 hours after the last dose (for HIV treatment, raltegravir is dosed twice daily).
In comparison, the ratio of tenofovir concentration between cervicovaginal fluid and blood is 110%, and for FTC around 375%. Tenofovir also has a longer half-life, with recent monkey experiments suggesting that dosing up to three days before exposure to HIV may protect against infection.
Although current studies are testing daily dosing of PrEP, many experts believe the long-term future of PrEP will require intermittent dosing, since this reflects the realities of people’s sex lives. Drugs that permit intermittent dosing are also likely to be more forgiving of poor adherence even if they are prescribed for daily use.
Intriguingly, other data presented at the workshop by Jay Grobler of Merck suggest that a second generation integrase inhibitor currently being explored by the company could have greater potential than raltegravir as an agent for intermittent PrEP, subject to human pharmacokinetic studies.
MK-2048, the second generation compound, blocks HIV integration for four times longer than raltegravir. Because of the way that integrase inhibitors developed by Merck block HIV infection, drug levels in blood and cervicovaginal fluid may not be the only relevant parameter for considering their effectiveness as pre-exposure prophylaxis drugs.
Jones A et al. First-dose and steady-state pharmacokinetics (PK) of raltegravir (RAL) in the genital tract (GT) of HIV uninfected women. 10th International Workshop on Clinical Pharmacology of HIV Therapy, April 15-17, 2009, Amsterdam, abstract O_06.
Grobler JA et al. Functionally irreversible inhibition of integration by slowly dissociating strand transfer inhibitors. 10th International Workshop on Clinical Pharmacology of HIV Therapy, April 15-17, 2009, Amsterdam, abstract O_10.