Atevirdine is a nonnucleoside
reverse transcriptase inhibitor with in vitro activity against human immunodeficiency virus type 1 and is currently in phase II clinical trials.
Atevirdine is most soluble at a pH of < 2, and therefore, normal gastric acidity is most likely necessary for optimal bioavailability. Because of the rapid development of resistance in vitro,
atevirdine is being evaluated in combination with
didanosine and/or
zidovudine in both two- and three-
drug combination regimens. To examine the influence of concurrent
didanosine (buffered
tablet formulation) on the disposition of
atevirdine, 12 human immunodeficiency virus type 1-infected subjects (mean CD4+ cell count, 199 cells per mm3; range, 13 to 447 cells/mm3) participated in a three-way, partially randomized, crossover, single-dose study to evaluate the pharmacokinetics of
didanosine and
atevirdine when each
drug was given alone (treatments A and B, respectively) versus concurrently (treatment C). Concurrent administration of
didanosine and
atevirdine significantly reduced the maximum concentration of
atevirdine in serum from 3.45 +/- 2.8 to 0.854 +/- 0.33 microM (P = 0.004). Likewise, the mean
atevirdine area under the concentration-time curve from 0 to 24 h after administration of the combination was reduced to 6.47 +/- 2.2 microM.h (P = 0.004) relative to a value of 11.3 +/- 4.8 microM.h for
atevirdine alone.
Atevirdine had no statistically significant effect on the pharmacokinetic parameters of
didanosine. Concurrent administration of single doses of
atevirdine and
didanosine resulted in a markedly lower maximum concentration of
atevirdine in serum and area under the concentration-time curve, with a minimal effect on the disposition of
didanosine. It is unknown whether an interaction of similar magnitude would occur under steady-state conditions; thus, combination regimens which include both
atevirdine and
didanosine should be designed so that their administration times are separated. Since the duration of the buffering effect of
didanosine formulations is unknown,
atevirdine should be given prior to
didanosine.