Reyataz Dosing Options Discussed

Excerpts From the FDA Atazanavir Hearing

Atazanavir has been developed as a once-a-day (QD) protease inhibitor to treat HIV infection in combination with other antiretrovirals. Its approved dosage will be 400 mg QD, taken with food. The convenience of QD dosing is expected to enhance regimen adherence and contribute to treatment effectiveness.

Atazanavir (ATV) is distinguished among protease inhibitors by having little impact on blood lipid levels such as cholesterol and triglycerides. Patients who had developed high lipid levels after taking other protease inhibitors experienced normalization of lipids after switching to atazanavir. Atazanavir also had a unique and favorable resistance profile among protease inhibitor-naive patients in which resistance, when it occurred via the protease mutation I50L, produced a virus with increased susceptibility to other protease inhibitors. A dose limiting side effect is the development of jaundice or yellowing of the eyes due to otherwise benign bilirubin increases in a large proportion of patients.

In a head-to-head comparison for 48 weeks, atazanavir performed as well as efavirenz for lowering viral load below the limits of detection in a large phase III clinical trial in people beginning their first anti-HIV regimens. However, in 24 week data from a trial in people with prior protease inhibitor therapy, 400 mg of atazanavir QD did not perform as well as a standard dose of Kaletra. But when blood levels of a 300 mg dose of atazanavir were boosted by 100 mg of ritonavir (RTV), reductions of viral load after 24 weeks were equivalent to those produced by Kaletra in the treatment-experienced population.

On May 13, 2003, an FDA antiviral advisory committee, a panel of experts convened by the federal Food and Drug Administration, met to discuss data submitted by Bristol-Myers Squibb (BMS) to support the approval of atazanavir. The day-long meeting considered issues ranging from possible cardiac effects to the type and quantity of "food" that should accompany a dose of atazanavir. Although data on the efficacy of ritonavir-boosted atazanavir for treating protease inhibitor-experienced patients was shown at the meeting, it had not been received in time for evaluation by the FDA, and was not officially considered part of the sponsor's application. This created a quandary for the committee members who, while generally convinced of atazanavir's efficacy in a treatment-naive population, felt that unboosted atazanavir for patients with prior PI mutations would not be a wise choice. They felt they had no alternative but to consider data about boosted atazanavir that had not been officially presented to them.

The following are edited excerpts from the hearing that focus on the issues of atazanavir blood levels at the end of a dose cycle (Cmin; minimum concentration) and the question of whether to support the approval of unboosted atazanavir knowing that in practice, it will likely be boosted with ritonavir in treatment-experienced patients. Boosting with ritonavir improved Cmin considerably. There were also a few questions about the compromising effect that adding ritonavir to the regimen might have on the lipid benefits seen with unboosted atazanavir.

Despite the apparent effectiveness of 400 mg atazanavir in treatment-naive patients, several committee members were concerned by data from pharmacokinetic (PK) studies that revealed wide variability in the Cmin at 24 hours. They questioned if subtherapeutic doses at Cmin in some treatment-naive patients were responsible for treatment failures seen in the Phase III study.

The significance of Cmin is acknowledged in this sentence from the sponsor's briefing document: "The association of Cmin with antiretroviral activity is consistent both with HIV being a continuously replicating virus, and with drug needing to be present at all times in concentrations that equal or exceed those concentrations required to inhibit viral replication."

The lower range of Cmin in atazanavir PK studies at 400 mg QD was 12 ng/ml. The EC90 of atazanavir, the drug concentration observed to inhibit virion production by 90 percent in a cell-based assay, after adjustment for protein binding, was about 75 ng/ml against a laboratory strain of HIV. However, similar assays performed with actual HIV isolates from treatment-naive patients produced a median EC90 of 14 ng/ml, with values ranging from 2.4 to 40.6 ng/ml.

It should also be noted that only 24-hour Cmins were reported. Data on 48-hour Cmin, such as might result from a skipped daily dose, were not presented.

Cmax: the maximum concentration of a drug in the body after dosing. It defines the peak level after dosing. Cmax is often associated with side effects.

Cmin: the lowest concentration of a drug after dosing. It defines the trough level at the point when another dose is taken.

EC50: A point half-way between a concentration of drug that produces 100% suppression of HIV in a laboratory test and one that produces no suppression. EC90 reflects 90% suppression.

Pharmacokinetics (PK): the study of the absorption, distribution, metabolism and elimination of drugs in the body.

Therapeutic drug monitoring (TDM): measuring blood drug levels so that the most effective dosage can be attained with minimal toxicity.


Discussants: Antiviral Drugs Advisory Committee Chair: Roy Gulick, M.D., M.P.H.; Members: Eugene Sun, M.D., Rory Remmel, Ph.D., Courtney Fletcher, Pharm.D., Wm. Christopher Mathews, M.D., Janet Englund, M.D., Thomas Tephly, M.D., Princy Kumar, M.D. For FDA: Debra Birnkrant, M.D. For B.M.S.: Michael Giordano, M.D., Steven Schnittman, M.D.

A complete transcript of the FDA hearing can be found under "Antiviral Drugs" at:

On the Cmin in Naive Patients

Dr. Sun (Abbott Labs): In your analysis of the virologic failures from your various clinical trials, have you analyzed the pharmacokinetics in those patients, especially given the fact that there is a fairly large variability in PK, particularly around Cmin (see Table 1), and that that might account for a substantial part of the failures that you can't attribute just to phenotypic analysis?

Table 1: Mean (Range) Steady-State Pharmacokinetic Parameters of Atazanavir
 ATV 400 mg
ATV 300 mg/RTV 100 mg
Cmax (ng/ml)5,358
Cmin (ng/ml)218

Dr. Schnittman (BMS): We have not selectively analyzed the pharmacokinetic parameters in those subjects who have failed. In fact, when one goes back and looks at these patients, many of the reasons for failure have to do with adherence, compliance or other issues that really have no bearing on what the actual absorption of drug is.

Dr. Remmel: At the 400 mg dose, clearly, there was good effect with atazanavir, but I am concerned about the pharmacokinetic variability of the drug.

While the sponsor probably wouldn't want to encourage concentration monitoring (TDM), this is a major issue in terms of many of the protease inhibitors, especially because they are all CYP3A substrates, and I think that we could see some benefit if it was to be done. But I would like to see some sort of indication of how many patients who fell at the low end for the Cmins or area under the curve were actually failing, and what that component is in terms of the efficacy of this drug.

Dr. Gulick: Then, Dr. Remmel, you suggest maybe TDM would be an interesting thing to think about for this drug?

Dr. Remmel: It is not something sponsors like to hear, but I think that we can understand more about this drug (by doing TDM). (The drug) does have a very large variability in the PKs when it is not taken with a boosted ritonavir dose. Now, it may be overly burdensome for certain patients and certain types of practices, but I think from the company's standpoint, I would want to know where my trough levels are.

Dr. Gulick: Dr. Fletcher, anything to add?

Dr. Fletcher: I would agree. I think as a Phase IV study, (TDM) would really be a worthwhile study to consider. It actually goes to Dr. Sun's question about what was the incidence of pharmacokinetic reasons for failure in patients, and if you look at the well-controlled pharmacokinetic studies that the sponsor presented, the range of trough concentration goes down to 12 nanograms per ml, which is below the adjusted IC50, and I think that has to clearly put a patient at risk of failure.

The best response is always to the first regimen. If there is an opportunity to improve the rates of response in naive patients, I would think that would be good for patients and good for the sponsor to take a look at. So, I would encourage some serious look at whether therapeutic drug monitoring could improve response of patients to this drug.

What Can the Drug Label Say About Atazanavir in Treatment-Experienced Patients?

Dr. Fletcher: This would be a question to the FDA. Would the agency consider, in the dosing recommendations, the use of the boosted atazanavir/ritonavir dose (300/100 mg regimen), or does the dosing really have to be constrained to the 400 mg once-daily dose (supported by available data)?

Dr. Birnkrant (FDA): As of today, it would be restricted to the 400 mg dose. The date by which a regulatory decision has to be made by law, is the 20th of June, so between now and then, there isn't that much time to review that additional data that came in late.

Dr. Mathews: There is a real dilemma, I think, facing the committee and the agency because the agency has not reviewed the 16-week data on the PK-boosted regimen, and yet the (unboosted) data that was reviewed in experienced patients (leaves a physician) with the decision of using a regimen which may have inferior virologic outcomes, but has a lot of advantages in terms of simplicity, tolerability, and so on.

Based on the data that is reviewed and reviewable at this point ... you could say that it's superior to placebo based on the comparisons that were done in that trial, but inferior to a regimen containing Kaletra.

Dr. Gulick: It puts us, as a committee, in an awkward position because we are seeing evidence of activity (in treatment-experienced patients), but it is not as good as a comparator arm; at the same time, we saw preliminary activity which hasn't been reviewed by the agency, which seemed to suggest similar virologic effects to a Kaletra-based arm. In addition, (we also saw) pharmacokinetics data to support better drug levels and a better Cmin, when boosted with ritonavir, so I think that we are feeling a bit conflicted about this point.

Dr. Birnkrant (FDA): Well, it is a dilemma for us, as well, to see snippets of data that look potentially promising, but given that it was submitted so late, it is difficult to review all of that data within such a short period of time.

Dr. Fletcher: Well, in my mind, (the boosted regimen data) is the only data that would really make the case for using the drug in the treatment-experienced patient. If you have to look at just the 400 mg once-daily regimen versus Kaletra, it wasn't as good as other available agents.

Dr. Gulick: Other thoughts on that?

Dr. Englund: But I also can sense at least from the people I work with, and I know the FDA appreciates this, too, is the sense of urgency. We have patients that are running out of alternatives.

Dr. Gulick: Other opinions about this? Dr. Mathews.

Dr. Mathews: Let me say that I think we would not be well advised to take the extreme position of saying that because it's inferior to a Kaletra-containing regimen, it shouldn't be approved for treatment-experienced patients. I mean I have lots of patients who are having a lot of trouble taking Kaletra or other PI-based regimens that are very anxious to get to a simplified PI regimen. On the other hand, I am going to have to tell them, "You are barely controlled right now, and the small difference in efficacy between what you are on now and this more simplified regimen may cost you long-term virologic control. We don't know."

Dr. Gulick: Clearly, the biggest need in the clinic right now is not so much the early failure people where you may have several options to choose from, but in the later stages where you want some good options. (The drug's benefits) in a naive regimen -- low pill count, once a day, apply in the salvage setting, as well.

Dr. Remmel: There is, of course, another class of experienced patients to consider, and those would be patients who already have disturbed lipid profiles and who you want to switch to lower their cholesterol or lower their triglycerides especially. That clearly would be advantageous for many patients in addition to simplifying their regimen.

Dr. Tephly: Exactly. We can't forget the advantage of the lipid-lowering quality of this particular agent.

Dr. Gulick: Other comments on the experienced? Dr. Kumar.

Dr. Kumar: I want to echo some of the comments that Dr. Mathews had said. In the treatment-naive patient, I think it is an excellent drug, it's a drug that I feel very, very comfortable with, but in the treatment-experienced patient, using it by itself, with unboosted dose, my concern is that failure begets failure, and in that setting, despite its convenience, the dosing, that it may lead to the development of more and more resistant mutants, so that is really what I am concerned about, using it as a single dose of 400 mg without boosting.

Dr. Mathews: I have a question about the (lipid) effects of boosted atazanavir compared to unboosted: In one of the slides that Dr. Grunfeld showed, in experienced patients, the proportion taking lipid-lowering therapy on unboosted regimens was about 4 percent; boosted, it was 7 percent, which is nearly twice as much. So, I think it is relevant to know what the direct comparison is; how much of (atazanavir's lipid) benefit is lost if it's boosted?

Dr. Giordano (BMS): We don't have data which is a head-to-head comparison of atazanavir boosted versus unboosted, so I can't answer that specific question. Sorry.

Dr. Gulick: Let's shift gears and talk about what the resistance data implied about the use of atazanavir in experienced patients. We saw lots of evidence for cross-resistance in the highly PI-experienced patient. Maybe we could also think again about atazanavir by itself versus boosted atazanavir.

Dr. Fletcher, why would a ritonavir-boosted atazanavir regimen work better against a resistant virus?

Dr. Fletcher: Well, it's because of, to use the term from the sponsors, the PK cushion. You have an inhibitor that is going to raise the atazanavir levels, and in the case of viruses that have decreased susceptibility, it will provide the more typical type of relationship between the concentration of drug and the concentration that the virus needs to inhibit it.

Dr. Remmel: Again, I think this is where sometimes a pharmacokinetic evaluation could be helpful. If you had a 5-fold increase in resistance, and you have a patient with a longer half-life, you might feel more comfortable about raising the dose slightly to make sure that you have a good therapeutic window.

For patients with shorter half-lives, you feel like you can't reliably raise that window. Because of a 24-hour dosing interval, you could go to a more frequent dosing interval or perhaps go to a boosted regimen. We haven't really talked about giving the drug on a BID (twice-a-day) schedule, but many patients could adhere to that schedule, and that might solve some of those problems.

Dr. Mathews: As I said earlier this afternoon, if you are trying to trade off toxicity, simplicity and lipid (benefits) with virological efficacy or effectiveness, having a more precise estimate of what the pharmacodynamic response pattern is in experienced patients is very important.

What Post-Approval Studies Should Be Considered?

Dr. Mathews: I mentioned a study that I thought should be done: a direct comparison of boosted versus unboosted for the lipid effect, but perhaps that could be studied in the context of another naive trial of boosted versus unboosted atazanavir to improve on the long-term response rate, because, for whatever reason, 65 percent suppressed at 48 weeks is not optimal.


The outstanding rationale for developing atazanavir for the HIV market has been once-daily dosing. The clear consensus of the FDA advisory committee was that 400 mg QD will produce adequate drug exposure for most treatment-naive patients (resistance testing prior to starting a first regimen is recommended to assess susceptibility). For those with ARV resistance, that dosage was recognized as inferior to a ritonavir-boosted dose. Yet there were also concerns that the unboosted dose will not provide sufficient coverage in a minority of naive patients. Higher doses produced unacceptable bilirubin increases, and while boosting with ritonavir was effective at increasing Cmin without increasing toxicity, the important lipid-neutral benefits of atazanavir may be compromised -- an unexplored issue for experienced persons, as well.

There is a real concern among community activists that QD dosing will be oversold in advertising for Reyataz. Since no information about the efficacy of a boosted regimen will appear on the product label, there will be a critical need for education to clarify the limitations of 400 mg QD in treatment-experienced individuals. For naive patients, discovering which are susceptible to low Cmin and would benefit from boosting, higher doses or more frequent dosing, may be a problem. Several committee members recommended TDM (therapeutic drug monitoring) of drug concentrations in the blood, a complicated assay that is not widely available in the U.S. post-marketing studies of TDM to determine the frequency of low Cmin in the patient population should receive top priority.