Sometimes Less is More
At this year's Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) a recurring theme was the difficulty patients have in adhering to complicated drug regimens and how noncompliance frequently leads to drug failure. Although this problem is multifaceted, involving emotional and psychological issues, one obvious way to make things easier for patients would be to require them to take less pills, fewer times each day. Pharmaceutical companies have realized that this may be a valuable marketing tool for their products; and many are scrambling to come up with less complicated dosing schedules, sometimes without much hard data to go on. In some cases (as with Abbott's protease inhibitor, ritonavir), a drug's ability to improve the absorption of other drugs, and therefore reduce the total number of pills required, has become a major selling point.
AZT/3TC Combo Pill
Last year Glaxo Wellcome introduced a 300 mg twice a day version of AZT. Up until that point AZT was only available in 100 mg capsules. To take the standard 600 mg per day dose, two capsules, three times a day (TID) were required. By introducing the 300 mg tablet, Glaxo Wellcome was able to scale down to one pill, twice a day (BID). Aside from simplifying dosing for the patient, Glaxo was interested in putting AZT on the same schedule as its other highly successful nucleoside analog, 3TC, and its number one competitor, d4T (manufactured by Bristol-Myers Squibb), both of which are taken twice a day. Glaxo received FDA clearance for marketing the 300 mg version of AZT in October 1996.
Taking things one step further, Glaxo has now combined 300 mg of AZT and 150 mg of 3TC into a single tablet, called, logically enough, Combivir. Patients using AZT and 3TC can now take one tablet twice a day for that portion of the regimen. The FDA cleared Combivir for marketing while ICAAC was in progress, and the product is now available in pharmacies. Patients who are taking only one of the agents can still obtain AZT or 3TC separately.
Once a Day ddI
In a similar vein, Bristol-Myers Squibb, the manufacturer of ddI and d4T, is seeking FDA clearance for marketing a once-daily (QD) version of ddI. Laboratory studies indicate that the active component of ddI has an intracellular half-life of at least 25 hours (G. Ahluwalia et al., Drug Metabolism and Disposition. 1993; 21(2):369-76), making once a day dosing feasible. During Phase 1 studies for the original ddI approval process, once-, twice- and thrice-daily regimens were examined. Twice-daily dosing resulted in antiviral activity superior to that observed with once-daily administration. However, the majority of patients treated with the once-daily dose experienced clinical improvement and increases in CD4 cell count. The single dose was considered a reasonable alternative, particularly in combination regimens (H. Liebman and T. Cooley. Clinical Infectious Diseases. 1996; 16(Suppl 1):S52-8). Colin McLaren, Ph.D., Director of Antiviral Clinical Research at Bristol-Myers, explained that since monotherapy was the order of the day, the once a day regimen was considered too risky because if the dose were missed, the patient would be without treatment for over 24 hours.
Times have changed and anything that simplifies dosing and improves compliance is advantageous. Bristol-Myers is now conducting regulatory trials for approval of once a day ddI. Protocol AI 454-143 (143) is a 12-week equivalency study, comparing the combination of d4T, at the standard twice-daily dose, with either once-daily or twice-daily ddI. Protocol 148, a 48-week trial, is still being developed to look at protease inhibitor-containing regimens. It will most likely look at ddI, once daily, plus d4T, twice daily, plus a protease inhibitor versus AZT plus 3TC plus a protease inhibitor. Bristol-Myers will present data from the two studies to the FDA late next year to support the claim for once a day dosing. Anyone interested in participating in the 143 study may call 800/TRIALS-A. (As the 148 protocol is not finalized, information on enrollment is not yet available.)
In the regulatory trials Bristol-Myers is using a 200 mg version of ddI that is not commercially available (this will require two 200 mg tablets, once a day as opposed to two 100 mg tablets, twice a day). The new, larger tablet still contains the antacid buffer that prevents ddI from being degraded by stomach acids and, like the current formulation, must be chewed or dissolved in water. Aside from the inconvenience of the buffered tablets, Bristol-Myers feels that the antacid itself may cause some adverse effects. Capsules are being developed that contain tiny enteric-coated beads of ddI (similar to Contac capsules). The enteric coating would allow ddI to pass through the stomach unaffected by acid, to be absorbed in the intestines. This formulation would require only one capsule per day. It has gone through preliminary studies and will go into stability and clinical trials early next year.
Several community trials were presented at ICAAC and the annual meeting of the Infectious Disease Society of America (IDSA). While these small cohort trials looked at once a day dosing of ddI, they did not include a comparison arm of the standard twice a day dose, so it was not possible to collect equivalency information. However, the studies did support the efficacy and feasibility of the once-daily 400 mg dose and did not demonstrate additional side effects (see IDSA posters 210 and 211). A group of French hospitals presented a poster at ICAAC (I-128) on the STADI Pilot Study results. Once a day ddI (this study used 300 mg) was combined with twice a day d4T in 52 antiretroviral naïve patients with CD4 cell counts between 100 and 500 (mean 330). Participants experienced a mean viral load decrease from 4.51 log copies/ml (Chiron Assay) at baseline to 3.03 log copies/ml at 24 weeks, a 1.48 log (96.7%) reduction. Sixty-two percent of participants had undetectable viral load (below 500 copies/ml) at week 24.
As treatment trends move away from double nucleoside analog combinations to protease inhibitor-containing regimens, reducing ddI from twice to once a day would be most helpful for patients who are combining it with Merck's indinavir. Between the food restrictions for both drugs and the fact that they need to be taken at least two hours apart to prevent ddI from interfering with indinavir absorption, the dosing schedule of this combination is particularly complicated. A community study presented at IDSA (poster 215) evaluated an indinavir, ddI, and d4T combination in an open label 12-month study. Fifty patients, who had previously used nucleoside analogs but not protease inhibitors, received once-daily ddI, twice-daily d4T and thrice-daily indinavir. An interim analysis was performed after 27 subjects were enrolled for six months. These participants' median baseline viral load was 25,090. At six months, 94% experienced undetectable viral loads (500 copies/ml), representing a 1.70 log decrease. (These figures exclude 5 of the 27 participants who were judged to be noncompliant with this apparently easier dosing regimen.) The combination proved to be potent, but again there was no comparison arm with twice-daily ddI.
Ritonavir Combinations Reduce Pill Burden
Abbott Laboratories' protease inhibitor ritonavir enhances plasma levels of the three other commercially available protease inhibitors by blocking their metabolism in the liver. This effect has been especially beneficial for the original hard gel formulation of Hoffmann-La Roche's saquinavir (brand name Invirase), which has very poor bioavailability. The usual dose of Invirase is 600 mg, three times a day. By combining 400 mg of ritonavir with just 400 mg of Invirase twice a day, saquinavir concentrations are increased twenty times and maintained over a longer period of time. The benefit of this combination is twofold for Invirase users: twice a day dosing and better bioavailability.
But how does this combination work to suppress viral load? At ICAAC, Charles Farthing, M.D., presented data from a study looking at four different dose combinations of ritonavir and Invirase in protease inhibitor-naïve patients (LB-3). The 400 mg-400 mg twice a day dose was the best tolerated of the regimens and maintained viral load below detection (200 copies/ml) in approximately 90% of patients at 48 weeks.
Concern has been expressed as to whether protease inhibitors can cross the blood brain barrier. For this reason, Dr. Farthing and colleagues conducted a substudy using 13 participants who had not received any other antiviral therapy except the ritonavir-Invirase combination. Twelve of the 13 had undetectable cerebrospinal fluid (CSF) viral loads (400 copies/ml), leading researchers to conclude that this protease-inhibitor-only regimen is effective in suppressing HIV in CSF (although questions remain about how accurately CSF levels reflect actual drug levels in the brain).
Hoffmann-La Roche has developed Fortovase, a more bioavailable soft gel formulation of saquinavir that received FDA approval on November 7. Fortovase will quickly replace Invirase on pharmacy shelves. The required dose of Fortovase is 1,200 mg (six 200 mg capsules), three times a day, which is double the dose of Invirase. As mentioned above, some people are currently taking Invirase and ritonavir together for increased bioavailability and easier dosing. Ironically, the same amount of Fortovase as Invirase (400 mg BID) is used when combined with ritonavir. This is because ritonavir already increases the bioavailability of saquinavir to close to 100%, regardless of the formulation. Without ritonavir, Fortovase users will face 18 large, oil-filled capsules (3,600 mg), divided into three doses per day, and may prefer to achieve the same blood levels of saquinavir by taking four capsules (800 mg) of Fortovase in combination with eight capsules (800 mg) of ritonavir, apportioned into two doses per day. Hoffmann-La Roche is to be commended for developing a better version of its drug, and for those who do not want to take two protease inhibitors, or cannot tolerate ritonavir, even at reduced doses, the more bioavailable Fortovase is an important development. However, for those who combine Fortovase with ritonavir, the new formulation is basically interchangeable with the old.
Indinavir is another protease inhibitor whose dosing regimen could possibly be improved with the addition of ritonavir. The standard dose of indinavir is 2,400 mg per day, two 400 mg capsules three times a day, on an empty stomach or with a low-fat snack. Ann Hsu, M.D., from Abbott, presented data at ICAAC on the pharmacokinetics of a ritonavir-indinavir combination in HIV-negative subjects (oral presentation A-57). Abbott set out to demonstrate that with the addition of 400 mg of ritonavir twice a day, the indinavir dose could be reduced to 400 mg twice a day.
Due to rapid metabolism, the peak and trough concentrations of indinavir vary 50-fold with the standard regimen. Because the trough levels are close to the minimum amount of drug needed to inhibit HIV, indinavir must be taken on a strict 8-hour schedule to prevent drug levels from ever falling too low. Dr. Hsu stated that co-administration of indinavir with ritonavir caused indinavir levels to be more constant, with lower peaks and higher troughs. Another benefit of adding ritonavir might be an easing of the food restrictions for indinavir users. It may be possible to take the combination with a light meal as opposed to on an empty stomach. Obviously, research on safety and efficacy is still needed in HIV-positive individuals.
One reason why Abbott is so interested in pursuing these and other ritonavir-protease inhibitor combinations is to enable a reduction in the dose of ritonavir. Many people have been forced to discontinue ritonavir at the standard 600 mg BID dose because of side effects and drug interactions. At the lower dose, ritonavir has been better tolerated.
There is the question, though, as to how effective ritonavir is at 400 mg BID and exactly what role it plays, aside from preventing the metabolism of other protease inhibitors. Ritonavir does have a different resistance profile than saquinavir but not indinavir. Plus there are indications of an independent antiviral effect at the lower dose, although 400 mg twice a day on its own would be suboptimal, according to the early, dose-ranging ritonavir trials from several years ago. To insure there is sufficient viral suppression, it is a good idea to include other antivirals in any double protease inhibitor regimen.
Twice a Day Indinavir
If possible, Merck would reduce the number of doses of indinavir without relying on the addition of ritonavir. In an ICAAC presentation, Bach-Yen Nguyen, M.D., of Merck reported on a pilot, open-label study comparing the standard indinavir 800 mg, TID dose with 1,000 mg or 1,200 mg of indinavir BID, each in combination with AZT and 3TC (oral presentation I-91). Preliminary data on the first 46 patients (out of 88) after 20 weeks of therapy showed that the changes in viral load and CD4 counts were comparable in all three groups. Many in the ICAAC audience voiced concerns about administering a higher dose twice a day. Low trough levels (as mentioned above) might promote the eventual emergence of indinavir-resistant HIV, even if the initial viral load response to BID and TID dosing is similar. Higher peak levels might eventually lead to more side effects, such as kidney stones. Dr. Nguyen stated that there were slightly more adverse events at the 1,200 mg BID dose, but not significantly so. Merck claims that there is no tight correlation between any pharmacokinetic parameters (such as peak and trough levels) and indinavir's antiviral effect based on its experience in previous TID trials. For this reason it did not test blood levels in the BID trial. This lack of information caused further consternation in the ICAAC audience. At the end of ICAAC, Jon Condra, a Senior Investigator at Merck, stated that the company was about to conduct a larger equivalency study of twice versus thrice a day indinavir (in combination with AZT and 3TC) that would finally check drug levels in some participants. This trial is currently enrolling 600 participants worldwide to examine safety and efficacy and will include a pharmacokinetics substudy (Merck protocol 069).
Despite Merck's claims that trough levels do not correlate with antiviral activity, there were two posters presented at ICAAC on small studies indicating that there is a connection. Poster I-173, by Mary-Ann Harris, M.D., and colleagues, of the Canadian HIV Trials Network, looked at indinavir peak and trough levels in 17 patients with advanced HIV (less than 50 CD4 cells) using a combination of indinavir, nevirapine and 3TC. Dr. Harris found peak levels were 56% of the figures published in the indinavir package insert. Trough levels were even less, measuring only 31% of those reported by Merck published data. (This may be attributed to the fact that nevirapine reduces indinavir levels, and the indinavir dose in this study was not increased.) Despite these lower drug levels, virologic responses were good with a median decrease in viral load of 3.03 log from baseline. Over 24 weeks treatment effects could be correlated with trough indinavir levels but not with peak indinavir levels or with peak or trough nevirapine levels. The investigators concluded that trough indinavir concentrations might be a critical factor in maintaining the antiviral effect of indinavir-containing combinations.
ICAAC poster A-15 summarized a study from the University of Minnesota that compared indinavir concentration levels at the standard TID dose in participants with detectable and undetectable viral loads (limit of detection was 500 copies/ml). Edward Acosta and colleagues found a correlation between indinavir levels and antiviral effect that just achieved statistical significance. (This may have been because the study group included only 13 patients.) In those who achieved undetectable viral loads, the minimum indinavir concentrations (trough levels) were seven times higher than the trough levels in those with detectable viral loads. Similar to the Canadian study mentioned above, the investigators concluded that a minimum threshold of drug exposure might be required to provide optimal viral suppression.
Keith Henry, M.D., of Regions Hospital in Minnesota, was one of the investigators in the University of Minnesota study. While he thinks it is a good idea, in general, to go from TID to BID dosing from the point of view of adherence, he is also concerned about achieving levels with BID dosing that provide adequate 24 hour coverage. "The original dosing selected for each drug was based on some data. Now the market is saying you better do something different." For Dr. Henry, the unanswered question in a real world setting is: Do the new strategies of taking higher doses fewer times a day or combining drugs to achieve a more convenient schedule moderate the variability that exists between individuals' metabolism and absorption? He feels that some of the government and industry studies that have been done to date on this topic are too short to be used as reliable guides and oversimplify a complex situation. Measuring drug concentrations, as was done in the University of Minnesota study, is of critical importance because the standard recommended dose does not suit each individual. "We're using the same doses, basically, in everybody. It's ridiculous." What Dr. Henry advocates instead, is monitoring therapeutic drug levels and adjusting the dose to achieve optimal trough levels. "The longer that the trough level of a drug falls below the comfort zone for suppressing the virus, the more likely it is for resistance to develop." This individualized approach will insure that each component of a combination regimen is "pulling its weight."
Drugs with longer half-lives are essential for once- or twice-daily dosing and will allow for the vagaries of individual metabolism. Trough levels of 50 to 100 times the amount needed to inhibit viral activity would give larger safety margins for easier dosing. The current meager trough levels of the protease inhibitors are only 0 to 5 times the amount needed to suppress 90% of HIV replication, after adjusting for protein binding (J. Mellors, ICAAC 1997, oral session 166-I minilecture).
Also the pills themselves should contain higher drug doses and not require special handling. Pharmaceutical companies are clambering to respond to this need. A 200 mg ritonavir capsule has been developed that lasts four to six weeks without refrigeration. Abbott will be filing an application for FDA approval at the end of the month and hopes the new formulation will be available by mid-1998. DuPont Merck is working on increasing the amount of drug contained in its new NNRTI, Sustiva (DMP 266), from 200 to 600 mg. One tablet, once a day would then provide the total amount necessary for Sustiva dosing. Unfortunately, the new formulation will probably not be on the market until 1999.
While it is preferable to develop drugs from the onset that have better bioavailability than trying to force existing treatments to fit current needs, the development of any new compound is a lengthy process. It is important to continue to find ways to improve and combine the 11 currently FDA-approved antivirals so they can be used together as easily and effectively as possible. Pharmaceutical companies should be more willing to work together on this process; for example, collaboration between Bristol-Myers and Glaxo to develop a combination pill of d4T and 3TC would be beneficial to a great many people. Efforts to provide simple dosing regimens using well-absorbed and well-tolerated, long acting drugs will promote adherence to lifelong treatment regimens.
This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues. Visit GMHC's website to find out more about their activities, publications and services.