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/mm 3 ) 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 M, and the area under the concentration-time curve from 0 h to infinity (AUC 03ؕ ) was reduced from 22.5 ؎ 14 to 14 ؎ 5.7 M ⅐ h. The extent of N-dealkylation, as indicated by the ratio of the N-dealkylated delavirdine AUC 03ؕ to the delavirdine AUC 03ؕ , 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 M and an AUC 03ؕ reduction from 7.93 ؎ 3.9 to 6.54 ؎ 2.3 M ⅐ h. Thus, concurrent administration of delavirdine and didanosine may reduce the AUC 03ؕ 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.

The effect of a high-fat meal and the timing of this meal on the absorption of a 400-mg oral dose of cefpodoxime proxetil was evaluated in 20 healthy, adult, male volunteers in a four-way crossover study. The area under the plasma concentration-time curve, peak plasma concentration, and urinary recovery were significantly greater (P = .0001) after administration of cefpodoxime proxetil tablets with and 2 hours after a meal relative to dosing under fasted conditions or 1 hour before a meal. The time to peak concentration did not differ significantly among treatments, which suggests that food did not affect the rate of drug absorption. These results indicate that absorption of cefpodoxime proxetil is enhanced when tablets are taken with food or shortly after a meal.

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.