Use of drug effect interaction modeling with Monte Carlo simulation to examine the impact of dosing interval on the projected antiviral activity of the combination of abacavir and amprenavir

The delineation of optimal regimens for combinations of agents is a difficu lt problem, in part because, to address it, one needs to (i) have effect re lationships between the pathogen in question and the drugs in the combinati on, (ii) have knowledge of how the drugs interact (synergy, antagonism, and additivity), and (iii) address the issue of true between-patient variabili ty in pharmacokinetics for the drugs in the population. We have developed a n approach which employs a fully parametric assessment of drug interaction using the equation of W, R. Greco, G, Brave, and J, C. Parsons (Pharmacol, Rev. 47:331-385, 1995) to generate an estimate of effects for the two drugs and have linked this approach to a population simulator, using Monte Carlo methods, which produce concentration-time profiles for the drugs in combin ation. This software automatically integrates the effect over a steady-stat e dosing interval and produces an estimate of the mean effect over a steady -state interval for each simulated subject. In this way, doses and schedule s can be easily evaluated, This software allows for a rational choice of do se and schedule for evaluation in clinical trials. We evaluated different s chedules of administration for the combination of the nucleoside analogue a bacavir plus the human immunodeficiency virus type 1 protease inhibitor amp renavir. Amprenavir was simulated as either 800 mg every 8 h (q8h) or 1,200 mg q12h, each along with 300 mg q12h of abacavir. Both regimens produced e xcellent effects over the simulated population of 500 subjects, with averag e percentages of maximal effect (as determined from the in vitro assays) of 90.9% +/- 11.4% and 80.9% +/- 18.6%, respectively. This difference is stat istically significant (P << 0.001), In addition, 68.8 and 46.0% of the popu lation had an average percentage of maximal effect which was greater than o r equal to 90% for the two regimens. We can conclude that the combination o f abacavir plus amprenavir is a potent combination when it is given on eith er schedule. However, the more fractionated schedule for the protease inhib itor produced significantly better effects in combination. Clinicians need to explicitly balance the improvement in antiviral effect seen with the mor e fractionated regimen against the loss of compliance attendant to the use of such a regimen. This approach may be helpful in the preclinical evaluati on of multidrug anti-infective regimens.