We examined combination chemotherapy with two potent agents of differing classes, abacavir, a nucleoside analogue, and amprenavir, an HIV type 1 protease inhibitor. Both drugs have been tested as single agents and have been shown to be effective and well tolerated (M. Saag, D. Lancaster, A. Sonnerborg, J. Mulder, R. Torres, R. Schooley, R. Harrigan, D. Kelleher, and W. Symonds, Abstr. 3rd Conf. Retroviruses Opportunistic Infect., abstr. 195, 1996; R. T. Schooley and the 141W94 Int. Study Group, Abstr. 36th Intersci. Conf. Antimicrob. Agents Chemother., abstr. LB7a, 1996). We demonstrated here that the dosing interval of the protease inhibitor portion of the combination has a major influence on the average in vitro anti-HIV effect of the regimen at steady state.
Prior in vitro evaluation (2
) demonstrated that abacavir and amprenavir were significantly synergistic, whether they were evaluated relative to a Loewe additivity or Bliss independence model of drug interaction.
While it is helpful to know that two drugs interact synergistically, it begs the question of how this knowledge may be put to practical use in an evaluation of combination chemotherapy regimens. It was our intention to develop here, for the first time, a system which would allow the evaluation of different regimens in combination.
Variability in the pharmacokinetics of the agents exerts a major influence on the antiviral effect seen. All of the variability seen in this evauation is attributable to between-patient variability in the pharmacokinetic profiles of the two drugs and the differences in administration schedules. This is so because the evaluation was performed against a single strain of virus, so there was no variability in sensitivities to the drugs being evaluated.
The value of the Monte Carlo (stochastic) approach, when compared to a simpler method using only mean parameter values (deterministic), can be illustrated as follows. Using, for instance, the median value for clearance misses the fact that 50% of the population will have larger clearances, lower concentrations, and therefore lesser effects. Depending on the spread of clearance values in the population, a portion of the population may have suboptimal effects, even while evaluation of the mean values of parameters indicated that the typical results might be acceptable. Consequently, we felt that it was imperative to perform a stochastic simulation.
Our evaluation had clear-cut results. The more fractionated schedule was superior. A regimen of 300 mg of abacavir orally q12h plus 800 mg of amprenavir orally q8h was significantly better than the regimen in which the amprenavir was administered q12h, whether one examined the mean effect for the population or proportions of the population whose mean effect was greater than two arbitrary values we chose (≥70 and ≥90% of the maximal effect). It is important to note that the effect results are generated from in vitro data.
Such results need to be placed into proper perspective. First, it should be pointed out that even when administered on a 12-h basis, the combination of abacavir and amprenavir is very potent, with the overall mean effect for a steady-state dosing interval exceeding 80% of maximum for this regimen. Further, almost half (46%) of the simulated subjects had a mean effect which was ≥90% of the maximal effect. Also, the addition of a third drug into the regimen (e.g., lamivudine or efavirenz), as is the current standard, might well further reduce the differences between the two modes of administration.
Another issue which needs to be addressed is the believability of the results. There are other data which support our findings. The conclusion which can be drawn from our investigation is that amprenavir, the protease inhibitor, is a drug for which time is greater than the EC95
is the pharmacodynamically linked variable. More fractionated schedules of the same total daily dose tend in most instances (but not always) to extend the times that concentrations exceed the EC95
. This result was also found in a single-agent evaluation of amprenavir by our hollow-fiber system, consistent with the findings here (Drusano et al., 38th ICAAC). In addition, while performed with different drugs, a trial in which nucleoside analogues (zidovudine and lamivudine) were administered on a 12-h schedule and another inhibitor of the HIV protease (indinavir) was administered at either 800 mg q8h or 1,200 mg q12h was recently reported (6
). The outcome in that study was as clear-cut as our results. When this combination was administered q8h, 91% of patients had their viral loads decline to below 400 copies/ml, while 64% of patients in the group receiving 1,200 mg q12h had their viral loads decline to below this level. Consequently, it should not be surprising that our simulation demonstrated that the combination of abacavir and amprenavir was also more effective when the protease inhibitor was administered on a more fractionated schedule. Given its different pharmacokinetic profile, it is also not surprising that amprenavir works somewhat better on a 12-h schedule than does indinavir. The point of this evaluation is that the already potent activity of the abacavir-amprenavir combination might be positively affected by a change in the schedule of administration for the protease inhibitor.
Such findings pose a dilemma for the clinician. The advent of effective antiretroviral chemotherapy also clarified issues regarding the emergence of viral resistance. There are two major pathways to emergence of resistance: one is suboptimal chemotherapy which does not suppress the viral copy number to below the detectability of the assay (and allows ongoing viral replication) and the other is poor compliance with the therapeutic regimen. Clearly, maximal antiviral effect would be desirable, would result in the largest proportion of patients with undetectable viral loads, and would lead to the recommendation of q8h dosing. However, frequent dosing results in poorer compliance from patients with their therapeutic regimen and poor compliance leads to resistance (3
). It seems that clinicians must choose between maximal antiviral effect, possibly leading to emergence of resistance from poor compliance, and suboptimal therapeutic effect, possibly leading to emergence of resistance from inadequate suppression of viral replication.
While all solutions to such conundrums are, in essence, patient specific (i.e., clinicians will suspect that some patients are more likely than others to be compliant, even with an 8-h regimen), it may be that the 12-h regimen may be preferred, even if it is less virologically active.
In summary, the ability to understand the way in which drugs interact for antiviral effect is key to designing appropriate regimens for testing in clinical trials. Issues of dose and schedule can be robustly addressed, and the full variability of pharmacokinetics for each of the agents can be examined for effect upon virological activity. It should be realized that the investigation described above was for a single HIV isolate. Use of such an approach for clinical trial design purposes would benefit from having multiple HIV isolates examined for virologic interaction and from having the simulation performed for each of these isolates. In such a way, the effect of full or partial resistance of a viral isolate to one or more of the agents in a combination regimen can be examined. Hopefully, the result will be the choice of the best doses and schedules of agents for examination in the clinical trial arena.