Didanosine reduces atevirdine absorption in subjects with human immunodeficiency virus infections

Abstract

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.