Mutinous Rumblings of Pill Popping Public Prompts Drug Outfits' Focus on User-Friendly Dosing Schemes
IC50 be damned?
Flying back from Vancouver (coach) nearly 2 years ago to the day, Pulitzer prize winning journalist Laurie Garrett -- after an understandable rant over the questionable personal hygiene of her activist seat mate ("Is it chic to reek?") -- noted that the summer's advances in antiretroviral therapy could not be sustained without easier-to-take regimens. "They've done it with allergy medicine and antihypertensives," she observed, "surely they can do it with AIDS meds." Chelsea Westminster's irrepressible Brian Gazzard is fond of relaying the fact that a full 50% of transplant patients, "whose own sister or brother has had a kidney surgically removed in order to save his sibling's life," will fail to take the medication they need (once-a-day azathioprine or twice-a-day cyclosporine) in order to avoid transplant rejection. In Europe at large, the overarching principle to prescription writing has always been, "If it needs to be taken more than twice a day, it's not given."
Two years hence, we have edged considerably closer to user-friendly treatment regimens, but we are not quite there yet. Glaxo Wellcome, ever first to jump on a new marketing angle, had twice daily Combivir (AZT and 3TC in one pill) on the shelves before you could say "under-investigated pharmacokinetics." ("It's not AZT; it's Combivir!") Not to worry that, up until Combivir's launch, AZT had been generally accepted as a TID (and, prior to that, as a q6h) dosed medicine. Glaxo answered our concerns with a quick-and-dirty 16-week viral load equivalency study. (Why fuss with messy pharmacokinetics? AZT'd been dosed BID in Europe since day one.) The FDA looked the other way.
More recently, Merck and Agouron, under pressure from the onslaught of the twice daily "convenience" of a SQV/RTV dual protease combo, are out to prove that their imminently more popular PIs can also conform to the demands of an increasingly mutinous (and un- "undetectable") patient population. But how are patients and care givers to evaluate the legitimacy of the new BID -- and QD -- claims? Are short-term viral suppression results sufficient? This month Mike Barr and Spencer Cox take a look a the dizzying array of dosing modifications in the works and attempt to sort the science from the sleaze.
While no one from Roxane or Glaxo has yet gone knocking door to door hyping the use of once-daily nevirapine and lamivudine, clinicians in Europe and Canada -- arguably ahead of the learning curve -- are already openly discussing the possibilities of the brave, new and vastly simplified antiretroviral regimens. In a recent presentation to a group of HIV care providers in Scottsdale, (AZ), British Columbia's Julio Montaner had this to say:
"Restrictions regarding what can and cannot be eaten, what medicines may or may not be used, and oral intake of fluids may sound trivial at first glance; but they often become insurmountable obstacles in the long term. It is for this reason that attempts have been initiated towards the development of simplified and user friendlier treatment regimens. Recent data (all requests to Dr. Montaner for specific citations went unanswered) demonstrate that several drugs of proven antiviral efficacy can be used on simplified once daily regimens. Among them, 3TC in doses of 300 mg once daily, ddI in doses of 400 mg once daily and nevirapine in doses of 200 mg once daily for the first two weeks increasing to 400 mg once daily thereafter. When nevirapine is used once daily, it is generally recommended that it be given at bedtime as it may have a slight sedative effect."
Along those same lines, several new drugs such as adefovir -- possibly PMPA -- and efavirenz are currently being developed for once daily therapy. It is also possible that Abbott's second generation protease inhibitor ABT-378, used with 15 mg daily of ritonavir, may be given once daily.
Similarly, physicians in Frankfurt have released interim results from their all QD study of once daily ddI+3TC+nevirapine (N=70). At 20 weeks, according to Goethe University's Schlomo Staszewski, 90% of the study participants' plasma HIV RNA levels have fallen below the limit of quantification (400 copies/mL). In another study, dubbed "Atlantic," at Amsterdam University's Academic Medical Center, Joep Lange and colleagues have been comparing three different ddI+d4T-based regimens (the two nukes plus 3TC, the two nukes plus nevirapine, and the two nukes plus Crixivan). And to their surprise, the group which has fared the worst (judged by the percent of patients with "undetectable" plasma viral loads at week 24) turns out to be the Crixivan-containing group. "It's all about compliance," sighs Lange.
On the protease inhibitor front, Merck and Agouron both recently presented data from studies of their inhibitors in twice-a-day regimens. The current recommended dosing of both Crixivan and Viracept is three times daily. Neither of the companies, though, locked in a life-or-death struggle for market share, is willing to let its rival gain any sort of competitive edge.
Viracept, with a plasma half-life of 4.5 hours, enjoys a pharmacokinetic profile slightly more amenable to BID dosing than does that of Crixivan, with a plasma half-life somewhere around 3.2 hours. When Viracept was dosed at 1,250 mg BID, drug levels stayed about the minimum concentration thought necessary for therapeutic effect (the so-called IC50) and were comparable to the drug plasma levels achieved using the standard dosing schedule of 750 mg TID. In a small 6-month pilot study of BID dosed nelfinavir in combination with d4T and 3TC, viral load responses were good, with 14 out of 15 patients achieving plasma HIV RNA levels, 500 copies/mL by week 24.
For Merck, the situation is a little dicey. Knowing that Crixivan's pharmacokinetics were likely to look bad on a BID dosing schedule, the company initiated pilot studies that focused on plasma HIV RNA responses rather than on drug levels in the blood. Three groups of patients who were naïve to protease inhibitors and to 3TC were assigned to receive Crixivan 800 mg TID, 1,000 mg BID or 1,200 mg BID. All patients were given AZT+3TC.
About 30 patients were enrolled in each of the three groups, with an average CD4 count of 275 and a baseline viral load of 4.7 log copies/mL. After 32 weeks, 50% of patients treated with the standard 800 mg TID dose had viral load counts <500 copies/mL. Forty percent went below 50. For those treated with the BID regimen, 70% in both the 1,000 BID and 1,200 BID groups had viral loads <500 copies/mL. Sixty percent went below 50. So the BID dosing actually appeared superior to the TID schedule. (Echoes of Lange's Atlantic experience.)
All this was well and good until sneaky, envious Abbott Laboratories arrived on the scene. Still smarting from Norvir's less-than-stellar showing in the protease pageant, Abbott scientists are determined to figure out a way to make the viciously unpalatable ritonavir significantly less so. The latest brainstorm is to use tiny bits of the drug to potentiate the effects of their up-and-coming PI ABT-378 or, in the meantime, Crixivan itself. So in a PK study of Crixivan (1,200 mg BID) compared to Crixivan alone (also 1,200 mg BID) in combination with very low doses of ritonavir, Abbott carefully examined the pharmacokinetic profiles of the two regimens.
In combination with Norvir, levels of Crixivan stay well above the minimal acceptable concentrations throughout the dosing -- and the effects of food on Crixivan are eliminated. (So conceivably Crixivan and Norvir could be taken together on a full stomach.) The troubling news came from the PK data of BID Crixivan alone: at the 1,200 mg BID dose, blood levels of indinavir drop well below the IC50 for several hours between each dose. Certainly, more than one devil's advocate has pointed out that 1) The IC50s for these drugs are somewhat arbitrarily determined; and 2) The exact relationship between protease inhibitor plasma concentration and the quantity of active drug available for virus inhibition has not been well characterized, but the pharmacokinetic data on twice daily Crixivan is nevertheless far from reassuring.
Merck responds to these concerns by noting -- accurately -- that blood levels of Crixivan have not been correlated to antiviral response. (Although they were very quick to note that that low blood levels of Invirase, hard gel saquinavir, led to poor antiviral efficacy.) Merck believes that the demonstrated 32-week antiviral potency of Crixivan BID speaks for itself -- and that blood levels of drug are of little consequence. If the drug works, who cares if the pharmacokinetics are less than ideal? Furthermore, ever eyeing an opportunity to snipe at its chief competitor's product, Merck sales reps note that 90% of Viracept is bound to plasma proteins in the bloodstream (and is therefore unavailable for any protease inhibiting) whereas only 60% of Crixivan is so plasma protein bound. As a result, they say, simple blood levels of drug may not accurately reflect levels of active drug.
While TAG's Antiviral Project director, Spencer Cox, argues that it's probably too early to convert these TID meds into BID ones, physicians around the country have already begun doing so. Little did Newsday's intrepid science reporter know how effortlessly the money-minting pharmaceutical houses would be able to grant her wish. But then, maybe PK sleight-of-hand and dose-modification-by-fiat are not exactly what she had in mind. For TAG, the gold standard would be equivalent efficacy outcomes shown to endure out to one year -- blood levels of drug notwithstanding. But that sort of long-term information is simply not available yet. In the meantime, care givers and patients alike seem willing to wager that the trade-off between improved adherence and less-than-perfect pharmacokinetics will tip the balance in favor of more durable viral suppression -- rather than against it. Perhaps it is "all about compliance."
|ddI||12 hrs*||400 mg QD|
|nevirapine||25-30 hrs||400 mg QD|
|3TC||12 hrs*||300 mg QD|
|efavirenz||40-55 hrs||600 mg QD|
|delavirdine||5.8 hrs||600 mg BID|
|adefovir||16-18 hrs*||60-120 mg QD|
|indinavir||1.5-2 hrs||1,000-1,200 mg BID|
|nelfinavir||3.5-5 hrs||1,250 mg BID|