SINGLE-DOSE PHARMACOKINETICS OF DELAVIRDINE MESYLATE AND DIDANOSINE IN PATIENTS WITH HUMAN-IMMUNODEFICIENCY-VIRUS INFECTION

Delavirdine is a nonnucleoside reverse transcriptase inhibitor with in vitro activity against human immunodeficiency virus type 1 (HIV-1) th at is currently being evaluated in combination regimens with various n ucleoside analogs, including didanosine. Due to the pH-dependent solub ility of delavirdine, the buffering agents in didanosine formulations may reduce delavirdine absorption. To evaluate the potential interacti on between these agents, 12 HIV-infected patients (mean [+/- standard deviation] CD4(+) cell count, 304+/-213/mm(3)) were enrolled in a thre e-way crossover single-dose study. Didanosine (125 to 200 mg given as buffered tablets) and delavirdine mesylate (400 mg) pharmacokinetics w ere evaluated when each drug was given alone (treatments A and B, resp ectively), when the two drugs were given concurrently (treatment C), a nd when didanosine was given 1 h after delavirdine (treatment D). Dela virdine exposure was reduced by concurrent administration of didanosin e. The maximum drug concentration in serum (C-max) was reduced from 7. 22+/-4.0 to 3.51+/-1.9 mu M, and the area under the concentration-time curve from 0 h to infinity (AUC(0-->infinity)) was reduced from 22.5/-14 to 14+/-5.7 mu M . h. The extent of N-dealkylation, as indicated by the ratio of the N-dealkylated delavirdine AUC(0-->infinity) to the delavirdine AUC(0-->infinity), was unchanged across study treatments (P=0.708). Reductions in didanosine exposure were observed during conc urrent administration with delavirdine with a C-max reduction from 4.6 5+/-2.0 to 3.22+/-0.59 mu M and an AUC(0-->infinity) reduction from 7. 93+/-3.9 to 6.54+/-2.3 mu M . h. Thus, concurrent administration of de lavirdine and didanosine may reduce the AUC(0-->infinity) of both drug s, although the clinical significance of this reduction is unknown, Ad ministration of delavirdine 1 h before didanosine avoided the interact ion. Due to the single-dose nature of this study, these findings requi re further evaluation at steady state.