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) that is currently being evaluated in combination regimens with various nucleoside analogs, including didanosine. Due to the pH-dependent solubility of delavirdine, the buffering agents in didanosine formulations may reduce delavirdine absorption. To evaluate the potential interaction between these agents, 12 HIV-infected patients (mean [± standard deviation] CD4⁺ cell count, 304 ± 213/mm³) were enrolled in a three-way crossover single-dose study. Didanosine (125 to 200 mg given as buffered tablets) and delavirdine mesylate (400 mg) pharmacokinetics were evaluated when each drug was given alone (treatments A and B, respectively), when the two drugs were given concurrently (treatment C), and when didanosine was given 1 h after delavirdine (treatment D). Delavirdine exposure was reduced by concurrent administration of didanosine. The maximum drug concentration in serum (C(max)) was reduced from 7.22 ± 4.0 to 3.51 ± 1.9 μM, and the area under the concentration-time curve from 0 h to infinity (AUC(0→∞)) was reduced from 22.5 ± 14 to 14 ± 5.7 μM γ h. The extent of N-dealkylation, as indicated by the ratio of the N-dealkylated delavirdine AUC(0→∞) to the delavirdine AUC(0→∞), was unchanged across study treatments (P = 0.708). Reductions in didanosine exposure were observed during concurrent administration with delavirdine with a C(max) reduction from 4.65 ± 2.0 to 3.22 ± 0.59 μM and an AUC(0→∞) reduction from 7.93 ± 3.9 to 6.54 ± 2.3 μM · h. Thus, concurrent administration of delavirdine and didanosine may reduce the AUC(0→∞) of both drugs, although the clinical significance of this reduction is unknown. Administration of delavirdine 1 h before didanosine avoided the interaction. Due to the single-dose nature of this study, these findings require further evaluation at steady state.