title: Single-dose pharmacokinetics of delavirdine mesylate and didanosine in patients with human immunodeficiency virus infection.
abstract: 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 (Cmax) was reduced from 7.22 +/- 4.0 to 3.51 +/- 1.9 microM, and the area under the concentration-time curve from 0 h to infinity (AUC0-->infinity) was reduced from 22.5 +/- 14 to 14 +/- 5.7 microM.h. The extent of N-dealkylation, as indicated by the ratio of the N-dealkylated delavirdine AUC0-->infinity to the delavirdine AUC0-->infinity, was unchanged across study treatments (P = 0.708). Reductions in didanosine exposure were observed during concurrent administration with delavirdine with a Cmax reduction from 4.65 +/- 2.0 to 3.22 +/- 0.59 microM and an AUC0-->infinity reduction from 7.93 +/- 3.9 to 6.54 +/- 2.3 microM.h. Thus, concurrent administration of delavirdine and didanosine may reduce the AUC0-->infinity 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.
authors.affiliation: Department of Pharmacy Practice, State University of New York at Buffalo, USA.
authors.forename: G D
authors.initials: GD
authors.lastname: Morse
authors.forename: M A
authors.initials: MA
authors.lastname: Fischl
authors.forename: M J
authors.initials: MJ
authors.lastname: Shelton
authors.forename: S R
authors.initials: SR
authors.lastname: Cox
authors.forename: M
authors.initials: M
authors.lastname: Driver
authors.forename: M
authors.initials: M
authors.lastname: DeRemer
authors.forename: W W
authors.initials: WW
authors.lastname: Freimuth
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000097:blood / Q000188:drug therapy*; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D020008:Delavirdine; D016049:Didanosine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D015497:HIV-1; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D010879:Piperazines / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D019380:Anti-HIV Agents; D007211:Indoles; D010879:Piperazines; D020008:Delavirdine; D016049:Didanosine