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Antimicrobial Agents and Chemotherapy, February 2002, p. 385-391, Vol. 46, No. 2
0066-4804/01/$04.00+0     DOI: 10.1128/AAC.46.2.385-391.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Lack of Effect of Simultaneously Administered Didanosine Encapsulated Enteric Bead Formulation (Videx EC) on Oral Absorption of Indinavir, Ketoconazole, or Ciprofloxacin

Bharat D. Damle,^1* Vanaja Mummaneni,¹ Sanjeev Kaul,¹ and Catherine Knupp²

Clinical Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Bristol-Myers Squibb Company, Princeton, New Jersey 08543,¹ Pfizer Inc., Ann Arbor, Michigan 48105²

Received 30 April 2001/ Returned for modification 27 September 2001/ Accepted 4 November 2001

Top Abstract Introduction Materials and Methods Results Discussion References

 
Didanosine formulation that contains a buffer to prevent it from acid-mediated degradation can result in a significant decrease in the oral absorption of certain drugs because of interactions with antacids. An enteric formulation of didanosine is unlikely to cause such drug interactions because it lacks antacids. This study was undertaken to determine whether the enteric bead formulation of didanosine (Videx EC) influences the bioavailability of indinavir, ketoconazole, and ciprofloxacin, three drugs that are representative of a broader class of drugs affected by interaction with antacids. Healthy subjects of either gender were enrolled in three separate open-label, single-dose, two-way crossover studies. Subjects were randomized to treatment A (800 mg of indinavir, 200 mg of ketoconazole, or 750 mg of ciprofloxacin) or treatment B (same dose of indinavir, ketoconazole, or ciprofloxacin, but with 400 mg of didanosine as an encapsulated enteric bead formulation). A lack of interaction was concluded if the 90% confidence interval (CI) of the ratio of the geometric means of log-transformed C_max and AUC_0- values (i.e., values for the area under the concentration-time curve from time zero to infinity) of indinavir, ketoconazole, and ciprofloxacin were contained entirely between 0.75 and 1.33. For indinavir (n = 23), the point estimate (90% CI; minimum, maximum) of the ratios of C_max and AUC_0- values were 0.99 (0.91, 1.06) and 0.96 (0.91, 1.02), respectively. In the ketoconazole study, 3 of 24 subjects showed anomalous absorption of ketoconazole (i.e., an 8-fold-lower AUC compared to historical data), which was the reference treatment. A post hoc analysis performed after these three subjects were excluded indicated that the point estimates (90% CI) of the ratios of C_max and AUC_0- values were 0.99 (0.86, 1.14) and 0.97 (0.85, 1.10), respectively. For ciprofloxacin (n = 16), the point estimate (90% CI) of the ratios of C_max and AUC_0- values were 0.92 (0.79, 1.07) and 0.91 (0.76, 1.08), respectively. All three studies clearly indicated a lack of interaction. The T_max and t_1/2 for indinavir, ketoconazole, and ciprofloxacin were similar between treatments. Our results showed that the lack of interaction of didanosine encapsulated enteric bead formulation with indinavir, ketoconazole, and ciprofloxacin indicates that this enteric formulation of didanosine can be concomitantly administered with drugs whose bioavailability is known to be reduced by interaction with antacids.

Top Abstract Introduction Materials and Methods Results Discussion References

 
The objective of this study was to determine whether the enteric bead formulation of didanosine (Videx EC) influences the bioavailability of indinavir, ketoconazole, and ciprofloxacin, agents that are representative of a broader class of drugs affected by interaction with antacids. Didanosine (Videx) is a nucleoside reverse transcriptase inhibitor that is widely used as a component of antiretroviral combination therapies to treat human immunodeficiency virus (HIV) type 1 infection. Didanosine is administered orally with antacids to protect it against acid-induced hydrolysis in the stomach (1). The influence of buffers in didanosine formulations on the absorption of coadministered drugs, such as antibiotics and antifungals, that are routinely used to treat opportunistic infections in AIDS patients is an important consideration. In general, drugs that interact with buffers in the didanosine formulations fall under two main categories: those that require an acidic pH for absorption, such as indinavir and ketoconazole, and those that can be chelated by cations of the buffer, such as ciprofloxacin.

Indinavir sulfate (Crixivan) is an HIV protease inhibitor that is often used with didanosine for antiretroviral therapy. Indinavir exhibits a pH-dependent, aqueous solubility that decreases from 60 mg/ml at pH 3.5 to <0.03 mg/ml at pH 5.0 (14). Simultaneous administration of didanosine, as a chewable or dispersible buffered tablet, and indinavir resulted in a significantly lower exposure of the subjects to indinavir (Videx package insert; Bristol-Myers Squibb, Princeton, N.J.). This was attributed to the reduced solubility of indinavir because of an increase in gastric pH by the buffering agents in the didanosine formulation. However, no clinically significant pharmacokinetic interaction was observed when a didanosine-buffered formulation was administered 1 h after indinavir (Videx package insert).

Ketoconazole (Nizoral) is recommended for the treatment of superficial fungal infections. It is practically insoluble at pH >3 and precipitates at pH 5.5 (4). Its bioavailability is significantly reduced by coadministration of drugs that increase gastric pH such as H₂-receptor antagonists and antacids (3, 6). Similarly, when didanosine formulations containing antacids are coadministered with ketoconazole, they will impair the absorption of the antifungal agent. However, ketoconazole can be given at least 2 h after the buffered didanosine formulation without changes in its absorption characteristics (11).

Ciprofloxacin (Cipro) is a fluoroquinolone antibiotic. The drug is well absorbed; however, its bioavailability is significantly reduced when administered with divalent and trivalent metallic cations (magnesium and aluminum), resulting in therapeutic failure (19). The mechanism of the interaction is believed to involve chelation of cations with the carboxylic acid and the adjacent ketone group on the fluoroquinolone molecule (16). There is also indirect evidence that chelation occurs with ciprofloxacin and calcium (9). Coadministering placebo tablets of didanosine formulation containing magnesium and aluminum cations with ciprofloxacin resulted in a 98% decrease in the bioavailability of ciprofloxacin (20). Administration of ciprofloxacin at least 2 h before or 6 h after a didanosine formulation that contains a buffer does not affect its absorption (18).

To eliminate the need for the use of buffers in the didanosine formulations, an enteric bead formulation of didanosine (Videx EC) was developed and approved in the United States and Europe. Clinically significant interactions with drugs that are affected by changes in gastric pH, such as indinavir and ketoconazole, and those that are chelated by antacids, such as ciprofloxacin, are considered unlikely with this new formulation. Hence, this study was undertaken to confirm that didanosine administered as an encapsulated enteric bead formulation does not have any effect on the pharmacokinetics of coadministered indinavir, ketoconazole, and ciprofloxacin.

Top Abstract Introduction Materials and Methods Results Discussion References

 
Study design. Three separate, open-label, single-dose, randomized, balanced, two-way crossover studies were conducted to determine the effect of concomitant administration of didanosine, as an encapsulated enteric bead formulation, on the pharmacokinetics of indinavir, ketoconazole, and ciprofloxacin in normal healthy subjects of either gender.

Studies 1 to 3. In study 1, a total of 24 subjects were randomized, 23 of whom completed the study, to receive treatment A, consisting of 800 mg of indinavir (two 400-mg Crixivan capsules) or treatment B, consisting of 800 mg of indinavir (two 400-mg Crixivan capsules) plus 400 mg of didanosine (one 400-mg capsule) as an enteric bead formulation in each treatment period. In study 2, 25 subjects were randomized, 24 of whom completed the study, to receive treatment A, consisting of 200 mg of ketoconazole (one 200-mg Nizoral tablet), or treatment B, consisting of 200 mg of ketoconazole (one 200-mg Nizoral tablet) plus 400 mg of didanosine (one 400-mg capsule) as an enteric bead formulation in each treatment period. In study 3, 17 subjects were randomized, 16 of whom completed the study, to receive treatment A, consisting of 750 mg of ciprofloxacin (one 750-mg Cipro tablet), or treatment B, consisting of 750 mg of ciprofloxacin (one 750-mg Cipro tablet) plus 400 mg of didanosine (one 400-mg capsule) as an enteric bead formulation in each treatment period. All three studies were conducted at the Bristol-Myers Squibb Clinical Research Center, Hamilton, Hamilton, N.J. The protocol and informed consent was reviewed and approved by the Institutional Review Board at Robert Wood Johnson University at Hamilton, Hamilton, N.J.

Male or female subjects, 18 to 50 years of age and with a minimum body weight of 60 kg, were enrolled in both studies. Female subjects of childbearing potential had a confirmed negative pregnancy test 72 h prior to the study and had to be using an effective, nonhormonal method of birth control during the course of the study. Subjects were in good health as determined by medical and laboratory tests conducted 3 weeks prior to the study start and by physical examination conducted on the morning of the first dose of the study. For all studies, the washout period between treatments was at least 72 h. Each treatment was given after an overnight fast for at least 10 h, which was maintained for 4 h after treatment. Water intake was allowed during the fasting period, except for 1 h before and 2 h after dosing. Each treatment was given with 240 ml of room temperature tap water. Serial blood samples were collected after each treatment over a period of 12 h for study 1 and 24 h for studies 2 and 3. Clinical evaluations, including laboratory tests, were performed during screening and prior to discharge to assess safety and tolerance. Safety assessment was done by monitoring the occurrence of adverse events (AEs), physical examinations, vital signs, clinical laboratory results, and electrocardiograms from prestudy screen through discharge. Written informed consent was obtained from all subjects before the study start.

Sample analyses. Quantitation of indinavir was based on a previously published high-pressure liquid chromatography (HPLC)-UV assay which was cross-validated for human plasma (5). Plasma concentrations of ketoconazole and ciprofloxacin were determined by using validated HPLC assays with fluorescence detection; these assays were also based on previously published methods (22, 23). Didanosine concentrations were measured by using a validated radioimmunoassay method (C. Knupp, B. Damle, P. Nichola, and S. Kaul, Abstr. 40th Intersci. Conf. Antimicrob. Agents Chemother., abstr. 1664, 2000).

For indinavir, ketoconazole, and ciprofloxacin, the standard curves were linear over the concentration ranges of 5 to 500, 40 to 8,000, and 100 to 3,000 ng/ml, respectively. The coefficient of determination (R ²) values were 0.992. Mean predicted concentrations of the quality control samples (QCs) were within 10% of their nominal values; between- and within-day variabilities were within 6% relative standard deviation (SD). For didanosine, the standard curves were described by a four-parameter logistic regression model in the range of 3 to 200 ng/ml. The R ² values were 0.995. Mean predicted concentrations of the QCs were within 5% of their nominal values; between- and within-day variabilities were within 10% relative SD. These standard curves and QC data indicated that the assays were precise and accurate.

Pharmacokinetic analyses. The plasma concentration-time data were analyzed by a noncompartmental method. The peak concentration in plasma (C_max) and the time to peak concentration in plasma (T_max) were obtained from experimental observations. Using no weighting factor, the terminal log-linear phase of the plasma concentration-time curve was identified by least-square linear regression of at least three datum points, which yielded a minimum mean square error. The half-life of the terminal log-linear phase (T_1/2) was calculated as 0.693/K, where K is the absolute value of the slope of the terminal log-linear phase. The area under the plasma concentration-time curve from zero to infinity (AUC_0-) was determined by summing the areas from time zero to the time of the last measured concentration, which was calculated by using conventional trapezoidal and log-trapezoidal methods and the extrapolated area. The extrapolated area was determined by dividing the final concentration by the slope of the terminal log-linear phase.

Statistical analyses. To demonstrate the effect of coadministration of didanosine on the pharmacokinetics of indinavir, ketoconazole, and ciprofloxacin, an analysis of variance model appropriate for a two-period, two-treatment, crossover design was used for analysis of the C_max and AUC_0- values. Both parameters were log transformed prior to analysis. The factors in the analysis were treatment sequences, subject within sequence, period, and treatment. The F statistic for sequence effects used the type I sum-of-squares for sequence in the numerator and the type I sum-of-squares for subjects within sequence as the denominator. For each parameter, the confidence interval (CI) for the difference between the least-squares means on the natural log scale was converted to the CI for the ratio of means on the original scale. A lack of interaction was concluded if the 90% CI of the ratio of means for C_max and AUC_0- values of indinavir, ketoconazole, and ciprofloxacin was contained entirely between 0.75 and 1.33. For indinavir, this CI was chosen, since a change in AUC by 29% upon coadministration of clarithromycin does not appear to warrant dose modification (Crixivan package insert; Merck & Co., Inc.,West Point, Pa.). For ketoconazole, this CI was chosen because a change in exposure of ketoconazole by as much as 59% when taken with food does not appear to be of clinical relevance since the package insert does not provide guidance for administration with regard to meal (7). For ciprofloxacin, this CI was chosen because no adjustment of ciprofloxacin dose is required for elderly subjects despite an increase in exposure by 48% in the elderly compared to young adults (2). Only descriptive statistics were determined for the T_max and T_1/2 values of indinavir, ketoconazole, and ciprofloxacin and for all pharmacokinetic parameters for didanosine.

Top Abstract Introduction Materials and Methods Results Discussion References

 
Pharmacokinetics. The mean plasma concentration-time profiles for indinavir, ketoconazole, and ciprofloxacin given as single agent and when given concomitantly with didanosine are depicted in Fig. 1,2,and 3,respectively. The geometric means, ratio of geometric means, and their 90% CIs for C_max and AUC_0- are summarized in Table 1.

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FIG. 1. Mean (n = 23) plasma concentration-time profile for indinavir administered alone and concomitantly with the encapsulated enteric bead formulation of didanosine. Error bars represent one SD.

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TABLE 1. Point estimates and 90% CI for log-transformed Cmax and AUC0- values for indinavir, ketoconazole, and ciprofloxacin administered alone (treatment A) and concomitantly with the didanosine encapsulated enteric bead formulation (treatment b)

Based on the point estimates of the log-transformed data (n = 23), the geometric mean C_max and AUC_0- values of indinavir were 1.4 and 0.96% lower, respectively, when indinavir was administered simultaneously with didanosine compared to the administration of indinavir alone (Table 1). The 90% CI of the ratios of the geometric means for both C_max and AUC_0- fell within the prespecified range of 0.75 to 1.33, indicating a lack of interaction (Table 1). There were no statistically significant sequence or period effects for C_max and AUC_0- values of indinavir. The median (minimum, maximum) values of T_max for indinavir as a single agent and indinavir coadministered with didanosine were 0.75 (0.75, 1.50) and 0.75 (0.05, 1.50), respectively; the arithmetic mean (SD) T_1/2 values were 1.80 (0.42) and 1.83 (0.39) h, respectively.

Based on the point estimates of the log-transformed data (n = 24), the geometric mean C_max and AUC_0- values of ketoconazole were ca. 33.7 and 30.0% higher, respectively, when administrated with didanosine compared to ketoconazole given alone (Table 1). The point estimates of the ratio for C_max and AUC_0- values were nearly equal or slightly greater than the upper limit of the prespecified equivalence interval (133%). The lower 90% CI for both parameters was contained within the prespecified range of 75 to 133%, but the upper 90% CI fell above this range, thereby failing to satisfy the requirement for concluding a lack of interaction (Table 1). This was intriguing because the plasma concentration-time profiles for ketoconazole administered alone or in combination with didanosine were superimposable. Critical examination of the data revealed that three subjects had markedly lower C_max and AUC_0- values for ketoconazole (ranges of 140 to 420 ng/ml and 990 to 1,500 h · ng/ml, respectively) when administered alone compared to the other subjects in this study (ranges of 1,480 to 7,060 ng/ml and 3,430 to 26,530 h · ng/ml, respectively) and also in comparison with values reported in the literature given at an equivalent dose (ranges of 3,000 to 4,400 ng/ml and 12,700 to 14,400 h · ng/ml, respectively) (Fig. 4).When administered in combination with didanosine, these three subjects had C_max and AUC_0- values for ketoconazole comparable to the values for other subjects in the study and to values reported in the literature (Fig. 4). Because the reference treatment (ketoconazole alone) in these three subjects was questionable for evaluation of drug interaction, a post hoc analysis of the data was performed after exclusion of these subjects. In this post hoc analysis (n = 21), the geometric mean C_max and AUC_0- values of ketoconazole (based on log-transformed data) were lower by 1.4 and 3.1%, respectively, when ketoconazole was coadministered with didanosine, compared with administration of ketoconazole alone (Table 1). The 90% CI for the ratio of the treatment means for log-transformed C_max and AUC_0- was entirely contained within the equivalence interval of 0.75 to 1.33, thus satisfying the criteria for lack of interaction (Table 1). There were no statistically significant sequence or period effects for C_max and AUC_0- of ketoconazole. The median (minimum, maximum) values of T_max (n = 21) for ketoconazole administered alone and administered simultaneously with didanosine were 1.50 (0.75, 2.50) and 1.00 (0.75, 4.50), respectively; the arithmetic mean (SD) values of T_1/2 (n = 21) were 2.02 (0.67) and 2.25 (0.46) h, respectively.

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FIG. 4. AUC0- values of ketoconazole of all subjects when ketoconazole is given alone and when administered with the encapsulated enteric bead formulation of didanosine. The median AUC value reported in the literature for the 200- and 400-mg dose of ketoconazole is indicated by dotted lines. Subjects 7, 8, and 17 are highlighted as subjects that showed anomalous absorption of ketoconazole.

The geometric mean C_max and AUC_0- values of ciprofloxacin (n = 16) given simultaneously with didanosine were 8.1 and 9.1% lower, respectively, compared to the administration of ciprofloxacin alone (Table 1). The 90% CI of the ratios of the geometric means for both C_max and AUC_0- of ciprofloxacin fell within the prespecified range of 0.75 to 1.33, indicating a lack of interaction. There were no statistically significant sequence or period effects for the C_max and AUC_0- values of ciprofloxacin. The median (minimum, maximum) values of T_max for ciprofloxacin administered alone and simultaneously with didanosine were 1.50 (1.00, 3.50) and 1.50 (0.50, 3.50), respectively; the arithmetic mean (SD) values of T_1/2 were 6.33 (1.24) and 5.79 (1.44) h, respectively.

The mean concentration-time profiles of didanosine in the three studies are shown in Fig. 5.The arithmetic mean pharmacokinetic parameters for didanosine were similar when didanosine was coadministered with indinavir, ketoconazole, and ciprofloxacin; the C_max values were 979, 794, and 1,080 ng/ml, respectively, and the AUC_0- values were 2,827, 2,562, and 2,940 h·ng/ml, respectively (Table 2).

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FIG. 5. Mean plasma concentration-time profiles of didanosine administered as an encapsulated enteric bead formulation concomitantly with indinavir (n = 24), ketoconazole (n = 25), and ciprofloxacin (n = 17). Error bars represent one SD.

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TABLE 2. Arithmetic mean (SD) [range] pharmacokinetic parameters of didanosine (400 mg) after administration of the encapsulated enteric-coated bead formulation simultaneously with indinavir, ketoconazole, or ciprofloxacin

Safety and tolerability. No serious AEs occurred during these three studies. In the indinavir study, a total of 11 AEs, characterized as being mild or moderate in intensity, were experienced by four (16.7%) and five (20.8%) subjects after the administration of indinavir alone and indinavir plus didanosine, respectively; the most frequently reported AE was taste perversion. In subjects receiving ketoconazole, AEs were reported in one (4.2%) and two (8.3%) subjects after the administration of ketoconazole alone and simultaneously with didanosine, respectively. All observed AEs (headache, eccymosis, rhinitis, erythema, and disorder lacrimation) were rated by the investigator as mild or moderate in intensity. One subject was discontinued from the ketoconazole study after receiving the first treatment because of elevated lipase levels observed during the baseline evaluations (544 U/liter; normal lipase levels are 30 to 190 U/liter). Follow-up serum chemistry performed 1 week later indicated that the lipase levels (50 U/liter) were within the normal range. No other clinically meaningful changes were apparent in the vital signs and laboratory tests. In the ciprofloxacin study, mild to moderate AEs, including headache, nausea, and dizziness, were reported in four (23.5%) subjects receiving ciprofloxacin simultaneously with didanosine; no AEs were reported for those using ciprofloxacin alone. Across all three studies, all AEs were considered to be possibly or unlikely related to study drug(s) and were resolved without any treatment or medication prior to discharge of the subjects from the studies.

Top Abstract Introduction Materials and Methods Results Discussion References

 
All formulations of didanosine that contain buffering agents have the potential for interacting with agents whose oral bioavailability is impacted by changes in gastric pH or chelation with cations of the antacids. To name a few, such interaction has been observed for indinavir, ketoconazole, and ciprofloxacin. These interactions can be managed by adjusting the relative times of dosing, but this complicates therapy and may compromise patient adherence, thus increasing the possibility of therapeutic failures. Moreover, the inclusion of antacids in didanosine formulations makes them unpalatable dosage forms because of the inherent taste of the antacids. To overcome these difficulties, an encapsulated enteric bead formulation of didanosine was developed and is approved in the United States and Europe. Since the new enteric formulation of didanosine does not contain any buffer, interactions due to the presence of antacids are not expected, a hypothesis confirmed by the results of these three interaction studies.

In this study, statistical analysis of the systemic exposure of indinavir clearly indicated a lack of effect of the didanosine enteric bead formulation on the oral pharmacokinetics of indinavir. Since there are no buffering agents in the enteric formulation of didanosine, its administration does not perturb gastric pH and does not influence the absorption of indinavir. The absence of drug interaction between didanosine and indinavir provides a favorable pharmacological basis for inclusion of these two agents in a combination regimen for HIV infection.

Based on the planned statistical analyses for ketoconazole, a lack of interaction could not be concluded. The exposures of ketoconazole were increased by ca. 30 to 34% based on the point estimates. This increase is unlikely to be clinically meaningful, because changes of similar magnitude due to a food effect have not warranted recommendations for dosing ketoconazole with regard to meals (7). Based on the upper bound of the 90% CI for the C_max and AUC values for ketoconazole, it can be statistically argued that ketoconazole exposures may be increased in some subjects by as much as 84%. The C_max and AUC_0- values for the combination treatment in the current study with a 200-mg dose of ketoconazole were ca. 3.6- and 4.6-fold lower than those observed after administration of a 400-mg dose of ketoconazole, a result which is consistent with the more than dose proportional increase in ketoconazole exposure (10). The 400-mg dose of ketoconazole is recommended in cases of serious infections or if the clinical response is insufficient and is known to be safe. Hence, an apparent increase in the systemic exposure of 84% in some subjects is unlikely to pose safety concerns. It could be argued that the increase in the exposure to ketoconazole upon coadministration with didanosine may be due to an increase in the absorption or decrease in the clearance of ketoconazole. Since the half-life of ketoconazole remained essentially unchanged, the coadministration of didanosine with ketoconazole did not decrease the clearance of ketoconazole. This is not surprising because didanosine is partly metabolized by noncytochrome P450-mediated nucleoside salvage pathways and is partly eliminated in the urine as unchanged drug, whereas the metabolism of ketoconazole is cytochrome P450 mediated (6, 12). Furthermore, since these two agents belong to different classes of compounds with markedly different physicochemical properties, there appears to be no pharmacokinetic rationale that the coadministration of ketoconazole with didanosine increases the exposure to ketoconazole due to an increase in the fraction absorbed. As evidenced by the data presented in Fig. 4, this apparent increase is a manifestation of the anomalous nature of absorption of ketoconazole when given alone in 3 of the 24 subjects. It should be noted that the three subjects in this study that showed poor ketoconazole absorption upon administration of ketoconazole alone did not similarly show any problem with absorption of ketoconazole in the combination treatment. Furthermore, review of the pharmacokinetic literature for ketoconazole did not reveal any subgroup of subjects which may have consistently poor absorption of ketoconazole. Review of the analytical data, subject dosing records, and demographic and other factors did not reveal any inconsistency, and thus the exact reason for the anomalous ketoconazole absorption in these three subjects is unclear. Nonetheless, the post hoc statistical analysis performed after we excluded these three subjects confirmed the lack of an interaction between the enteric formulation of didanosine and ketoconazole.

Like ketoconazole, the bioavailability of itraconazole is significantly reduced by concomitant administration of compounds that increase gastric pH (13). Furthermore, May et al. have reported that the oral absorption of itraconazole is significantly impaired by coadministration of a didanosine formulation that contains antacids (17). The lack of clinically relevant interaction between ketoconazole and didanosine in the present study suggests that the enteric bead formulation of didanosine is not likely to alter the oral absorption of related azole compounds, such as itraconazole. Unlike itraconazole, the bioavailability of fluconazole is not significantly affected when gastric acidity is decreased by simultaneous administration of cimetidine or antacids because fluconazole has better water solubility and bioavailability compared to itraconazole (3). Hence, a drug interaction with fluconazole due to pH-dependent absorption is not of any clinical significance.

Simultaneous administration of didanosine as an encapsulated enteric bead formulation with ciprofloxacin had no significant influence on the oral pharmacokinetics of ciprofloxacin. Moreover, both agents were found to be safe and well tolerated in healthy subjects, indicating that they may be incorporated into combination regimens that require both antiviral therapy and antibiotic prophylaxis. Like ciprofloxacin, the bioavailability of other fluoroquinolone antimicrobial agents, such as levofloxacin (8), gatifloxacin (15), and moxifloxacin (21) is also markedly reduced by coadministration of magnesium- or aluminum-containing antacids. Given the similarity in chemical structure and chelation-based interaction with metallic cations among quinolones, the lack of interaction between ciprofloxacin and didanosine in the present study suggests that the enteric bead formulation of didanosine is not likely to alter the oral absorption of other coadministered quinolones. Like quinolones, tetracyclines are susceptible to chelation-based interaction with antacids. These data also suggest that absorption of tetracyclines will not be influenced by concomitant administration of this enteric formulation of didanosine.

It is important to note that the 90% CI for the C_max and AUC of indinavir and ketoconazole also satisfy the commonly used equivalence interval of 0.8 to 1.25. The lower limits of the 90% CI for ciprofloxacin C_max (0.79 to 1.07) and AUC (0.76 to 1.08) are only slightly below the lower bound for the 0.8 to 1.25 interval and hence do not warrant modification of ciprofloxacin dose.

In conclusion, the lack of an interaction of a didanosine encapsulated enteric formulation with the three drugs evaluated in this study, each representative of a broader class, suggests that this formulation can be concomitantly administered with drugs whose bioavailability may be otherwise decreased due to antacid coadministration. Elimination of buffers from didanosine formulations, and hence the source of several drug interactions, makes Videx EC a better dosage form for the administration of didanosine.

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FIG. 2. Mean (n = 24) plasma concentration-time profile for ketoconazole administered alone and concomitantly with the encapsulated enteric bead formulation of didanosine. Error bars represent one SD.

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FIG. 3. Mean (n = 16) plasma concentration-time profile for ciprofloxacin administered alone and concomitantly with the encapsulated enteric bead formulation of didanosine. Error bars represent one SD.

 
We thank the personnel of MDS Pharma Services, Inc., Sunnyvale, Calif., for plasma sample analyses, and Peter Nichola, Bristol-Myers Squibb, Hopewell, N.J., for statistical analyses.

 
* Corresponding author. Mailing address: Clinical Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543. Phone: (609) 252-5383. Fax: (609) 252-7035. E-mail: bharat.damle{at}bms.com.

Top Abstract Introduction Materials and Methods Results Discussion References

 

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Antimicrobial Agents and Chemotherapy, February 2002, p. 385-391, Vol. 46, No. 2
0066-4804/01/$04.00+0     DOI: 10.1128/AAC.46.2.385-391.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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