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/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.

Delavirdine Malabsorption in HIV‐Infected Subjects with Spontaneous Gastric Hypoacidity

“…The present study confirms that pharmacokinetic exposure to delavirdine, another drug with pH‐dependent solubility, is significantly lower in subjects with gastric hypoacidity. The lower exposure to delavirdine in the present study is comparable in magnitude to the reduction seen in drug interaction studies between delavirdine and single doses of either antacids 4 or buffered formulations of didanosine 5 . However, administration of buffered didanosine with delavirdine for 14 days to HIV patients was not associated with a statistically significant reduction in delavirdine exposure 6 .…”

“…Delavirdine is a weakly basic compound (pk a ∼ 4.45), which is 200‐fold less soluble at a pH of 7.4 versus a pH of 2 3 . Single‐dose studies of delavirdine pharmacokinetics during conditions of pharmacologically induced gastric hypoacidity (concomitant administration with antacids or buffered formulations of didanosine) found reduced exposure to delavirdine by approximately 30% and 48% to 57%, respectively 4 , 5 . However, chronic administration of buffered didanosine with delavirdine was not associated with a statistically significant reduction in delavirdine exposure in HIV patients 6 .…”

Drug interactions with antiretrovirals

“…As mentioned previously, didanosine may lower the plasma AUC of delavirdine, and delavirdine decreases the plasma AUC of didanosine by approximately 20% [22]. Therefore, the combined use of didanosine and delavirdine may provide lower drug exposure for each of these antivirals, especially if taken concurrently.…”

“…The current formulation of didanosine (ddI), which is buffered to minimize gastric degradation of didanosine, has been reported to reduce the plasma AUC of certain antimicrobials such as itraconazole, ketoconazole, dapsone, ciprofloxacin, tetracycline, and ganciclovir [21]. More recently, didanosine has been shown to decrease the plasma AUC of delavirdine (an NNRTI) and of indinavir (a PI) during single-dose studies [22][23][24]. The mechanism for these interactions is likely to be through gastric pH elevation and subsequent reduction in solubility of the second drug.…”

Buprenorphine assay and plasma concentration monitoring in HIV-infected substance users

“…While the development of potent antiretroviral therapy (ART) has led to extended survival in patients with both HIV infection and opioid addiction, the use of methadone has been associated with numerous drug-drug interactions [13]. For example, withdrawal symptoms have been well described with the introduction of NNRTIs such as nevirapineor efavirenz-containing ART regimens [14,15].…”