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PHARMACOKINETICS

Drug-Drug and Drug-Food Interactions Between Tenofovir Disoproxil Fumarate and Didanosine

Brian P. Kearney, PharmD, John R. Sayre, RN, John F. Flaherty, PharmD, Shan-Shan Chen, MPH, Sanjeev Kaul, PhD and Andrew K. Cheng, MD, PhD

From Gilead Sciences, Inc, Foster City, California (Dr Kearney, Mr Sayre, Dr Flaherty, Mr Chen, Dr Cheng); and Bristol-Myers Squibb Co, Princeton, New Jersey (Dr Kaul).

Address for reprints: Brian P. Kearney, PharmD, Gilead Sciences, Inc, 333 Lakeside Drive, Foster City, CA 94404.


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
The drug-drug and drug-food interactions between tenofovir DF and didanosine EC were evaluated in 2 pharmacokinetic studies in healthy adult subjects. When 400 mg was dosed with tenofovir DF, mean didanosine AUC was increased by 44% to 60% following fasted or fed administration. Staggered coadministration (2 hour, fasted) of a reduced didanosine dose of 250 mg resulted in equivalent didanosine exposure, while simultaneous administration with tenofovir DF in the fasted and fed state resulted in didanosine AUCs similar to that of the reference treatment of 400 mg alone in the fasted state. These data indicate that a dose reduction of didanosine is warranted when it is used with tenofovir DF. The drug-drug-food interaction of didanosine may offer more flexible dosing of didanosine EC when it is used with tenofovir DF. Patients receiving tenofovir DF and didanosine together should be carefully monitored for safety and efficacy.

Key Words: Tenofovir DF • didanosine EC • pharmacokinetics • drug interaction • HIV

Management of HIV infection involves the use of multiple antiretroviral drug agents. A significant obstacle to long-term success of treatment regimens is less-than-perfect adherence due to high pill burdens and often incompatible dosing requirements of the individual components.

Currently, there are a number of antiretrovirals that allow for once-daily therapy of HIV. Tenofovir disoproxil fumarate (tenofovir DF), is an orally bioavailable prodrug of tenofovir, the acyclic nucleotide analogue HIV reverse transcriptase inhibitor. The long half-life of tenofovir diphosphate, the active intracellular anabolite, allows for tenofovir DF to be dosed once daily and is often taken with food.1-8 Didanosine, a purine nucleoside analogue reverse transcriptase inhibitor, is also approved for once-daily dosing either as an older, buffered tablet or most often as an encapsulated, enteric-coated (EC) beadlet formulation (didanosine EC).9-12 For both formulations of didanosine, fasted administration is recommended as meals of varying caloric content and food types have been shown to reduce didanosine systemic exposure (AUC) by 18% to 55%.10-15

An earlier study demonstrated that coadministration of tenofovir DF with the buffered tablet formulation of didanosine resulted in a substantial increase in didanosine exposure while tenofovir pharmacokinetics was unaffected.8,16,17 While both tenofovir and didanosine are renally eliminated, this study demonstrated no alteration in didanosine renal clearance, suggesting that increased didanosine exposure may be due to increased systemic drug availability, similar to that observed during its coadministration with either ganciclovir or the antigout agent allopurinol.18-20 Ray and colleagues have since demonstrated in vitro that tenofovir- and ganciclovir- monophosphate can directly inhibit, while allopurinol indirectly inhibits, didanosine catabolism mediated by the enzyme purine nucleoside phosphorylase.21,22

Didanosine-associated adverse events are known to occur more frequently with higher didanosine doses and plasma exposures. During its development phase, the reported incidence of pancreatitis in patients receiving didanosine doses of <500 mg/d versus 500 to 750 mg/d were 6.3% and 13.3%, respectively23; therefore, higher didanosine exposure associated with tenofovir DF coadministration may lead to higher rates of didanosine-associated adverse events. Because concurrent use of these antiretroviral agents is frequent, most often in treatment-experienced patients, it was important to find a practical way to use these agents together.

Thus, two phase I, open-label, drug interaction studies were conducted in healthy subjects. Study 1 evaluated the drug-drug interaction between tenofovir DF (300 mg) and a 400-mg dose of didanosine EC dosage dosed with or without food. The objectives of this study were to confirm the results observed with the didanosine-buffered tablet formulation and to test if the increase in drug exposure due to tenofovir DF could be mitigated by the lowering of didanosine bioavailability with food. Study 2 assessed didanosine pharmacokinetics with a 38% lower dose to 250 mg and its administration with or without food to assess simplified didanosine EC dosing with tenofovir DF within a drug-drug-food interaction.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Pharmacokinetic Study Designs and Procedures
Both open-label, drug interaction studies were conducted in healthy male and female volunteers in a phase I study unit (MDS Pharma Services, Inc, Lincoln, Neb) in compliance with good clinical practice, under the review of the MDS Pharma Services Institutional Review Board and in accordance with the Declaration of Helsinki. Written informed consent was obtained from all subjects. Subjects aged 18 to 59 years were eligible if they met all inclusion and exclusion criteria and agreed to follow all study procedures. All subjects passed routine physical examination and clinical laboratory screening. On site, subjects were monitored by clinic staff for all protocol-defined study procedures such as study drug administration and adverse events. Adherence to study medication dosing while outside the study facility was reinforced through use of dosing diaries, telephone interviews, and pill counts.

In both studies, all subjects received the treatments in a fixed sequence as depicted in Figure 1. Briefly, the reference treatment of didanosine EC (Bristol-Myers Squibb Co, Princeton, NJ) 400 mg dosed alone on an empty stomach was administered on day 1 followed by multiple-dose administration of tenofovir DF (Gilead Sciences, Inc, Foster City, Calif) with food (standard breakfast) over the next 7 days to reach steady state. On day 8, didanosine EC was dosed in the fasted state, 2 hours before tenofovir DF administration with food. On day 9 in both studies, drugs were administered simultaneously with a standardized breakfast. In study 2, an additional assessment of simultaneous coadministration for both study drugs in the fasted state was performed on day 10. Also, and only in study 1, following completion of didanosine EC dosing, subjects continued receiving tenofovir DF with food until day 15, when tenofovir steady-state pharmacokinetics alone was assessed. The standardized breakfast (~373 kcal, ~20% fat) used for fed administration in both studies was composed of 2 pieces of toast with butter and jelly, 8 oz orange juice, and 8 oz low-fat milk, and study drug administration occurred within 5 minutes of completion of the meal.



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  		Figure 1. Pharmacokinetic study designs.

 
Pharmacokinetic evaluations of didanosine were performed following single-dose administration as it exhibits linear pharmacokinetics with negligible accumulation upon repeat administration and to minimize unnecessary drug exposures to study subjects.9-11 Didanosine EC administration was staggered from tenofovir DF and meals by 2 hours in accordance with its approved dosing recommendation to minimize the impact of food. Simultaneous coadministration with a meal was studied to investigate the 3-way interaction of these agents and food as the increase in didanosine exposures associated with tenofovir were of a similar magnitude to the decreases in drug level when didanosine EC is taken with food.

On each day of pharmacokinetic assessment, blood samples were collected over 24 hours (hour 0 [predose], 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 10, 12, 16, and 24) after study drug administration to estimate tenofovir or didanosine pharmacokinetic parameters. Following collection, serum (tenofovir) and plasma (didanosine) were obtained and aliquots were stored frozen (-20°C) until analysis.

Sample Analyses
Analysis of tenofovir concentrations in serum was performed using a validated liquid chromatography-tandem mass spectrometry (LC/MS/MS) assay by MDS Pharma Services, Inc (Montreal, Quebec, Canada) as described previously.24 The standard curve spanned a concentration range of 3.00 to 600 ng/mL, with between-batch precision (coefficient of variation [%CV]) and accuracy (% nominal) metrics for the lower limit of quantification (LLOQ; 3.01 ng/mL) of 9.2% and 98.0%, respectively.

Concentrations of didanosine in plasma were determined by validated LC/MS/MS methods by Bristol-Myers Squibb Co (Saint-Nazaire, France) in study 1 and by MDS Pharma Services, Inc (Montreal, Canada) in study 2. The standard curves of the 2 assays spanned concentration ranges of 0.500 to 500 ng/mL and 100 to 10 001 ng/mL for studies 1 and 2, respectively. Mass (m/z) transitions for didanosine were 237 -> 137 in both studies. The internal standards for study 1 and 2 were 13C-dianosine (m/z 242 -> 142) and d-thymidine (m/z 243 -> 127), respectively. Between-batch precision (%CV) and accuracy (% bias) measures for the LLOQ were ≤9.7% and ≤6.6%, respectively, for both assays.

Pharmacokinetic Analyses
Steady-state tenofovir and single-dose didanosine pharmacokinetic parameters were determined by noncompartmental methods using the linear/log trapezoidal rule (WinNonlin, Version 3, Standard Edition; Pharsight Corporation, Mountain View, Calif). Key pharmacokinetic parameters determined included the area under the serum or plasma concentration-time curve (AUC), maximum observed concentration in serum or plasma (Cmax), time of maximum observed concentration (Tmax), and elimination half-life (T1/2).

Statistical Design and Analyses
Both studies were powered (>90%) to detect a ±20% change in Cmax or AUC based on the intrasubject variance for didanosine and tenofovir AUC and Cmax on a natural log scale (basee). Pharmacokinetic parameters were summarized by treatment using descriptive statistics. Tests for significant differences between coadministration of tenofovir DF and didanosine and each drugs' administration alone were evaluated using apairwise t test within analysis of variance appropriate for a crossover design in SAS (SAS Institute, Cary, NC). A P value of <.05 was considered statistically significant. In addition, to allow for direct assessment of the magnitude of differences in drug exposures, 90% confidence intervals (CIs) were calculated for the (geometric) mean ratio for Cmax and AUC for each drug when dosed concomitantly versus administration alone.25

Safety Evaluations
Adverse events, laboratory tests, vital signs, and physical examination findings were evaluated at regular intervals. Laboratory safety assessment samples (serum chemistries, hematology, and urinalysis) were collected at screening, baseline, and at each treatment period. In addition, clinic staff members contacted subjects by telephone when dosing outside the clinic and again several days following the final clinic visit to inquire about adverse events. Adverse events were coded using the fifth edition of the COSTART dictionary. All subjects who received at least 1 dose of study medication were included in safety analyses.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Pharmacokinetic Results
For both studies, 28 subjects were enrolled, with approximately even numbers of male and female healthy volunteers (Table I). In study 1, 25 of 28 subjects completed all treatments. All 28 subjects enrolled in study 2 completed all periods of study. Review of dosing diaries and pill counts did not identify dosing discrepancies or notable adherence violations.


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  		Table I Demographic Characteristics and Disposition of Healthy Subjects Participating in Pharmacokinetics Studies

 

Study 1
The pharmacokinetics of tenofovir was unaffected (P = ns for all comparisons) when tenofovir DF 300 mg was administered with and without didanosine EC 400 mg (Table II).


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  		Table II Tenofovir Steady-State Pharmacokinetics Following Coadministration of Tenofovir DF and Didanosine in Healthy Volunteers

 

Didanosine Cmax and AUC0-{infty} were elevated when didanosine EC 400 mg was coadministered with tenofovir DF regardless of the conditions of coadministration (Table III). Figure 2 presents didanosine plasma concentration-time profiles following administration alone and with staggered or simultaneous administration of didanosine EC 400 mg with tenofovir DF. Mean didanosine Cmax (P < .001) and AUC0-{infty} (P < .001) were each 48% higher with 90% CIs of +25% to +76% and +31% to + 67%, respectively, following staggered coadministration of didanosine EC 400 mg with tenofovir DF. Following simultaneous administration of didanosine EC 400 mg and tenofovir DF with a meal, didanosine Cmax and AUC0-{infty} mean ratios (90% CI) were increased by 64% (P < .001; 90% CI, +41% to +89%) and 60% (P < .001; 90% CI, +44% to + 79%), respectively, relative to didanosine EC 400 mg dosed alone in the fasted state. When dosed with tenofovir DF, Didanosine exposures were equivalent with and without food (data not shown). Consistent with the effect of drug administration with a meal, didanosine Tmax (4.00 vs 1.96 hours, median values) was delayed, while T1/2 was unaffected (1.93 vs 2.28 hours, median values; Table III, Figure 2).


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  		Table III Didanosine Pharmacokinetic Parameters Following Coadministration With and Without Tenofovir DF in Healthy Volunteers

 


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  		Figure 2. Mean (95% confidence interval) didanosine plasma concentration-time profiles following administration of didanosine EC 400 mg alone and with tenofovir DF in study 1.

 

Study 2
Didanosine dose reduction to 250 mg when coadministered with tenofovir DF resulted in similar systemic exposures to administration of didanosine EC 400 mg alone in the fasted state as assessed by AUC0-{infty}. Figure 3 presents didanosine plasma concentration-time profiles following administration alone, staggered, and also simultaneous administration of didanosine EC with tenofovir DF. When didanosine EC 250 mg was administered in the fasted state 2 hours before tenofovir DF with a meal, the mean didanosine AUC was identical to that of the reference treatment of didanosine EC 400 mg dosed alone in the fasted state (<1% difference, P = ns; Table III). Administration of didanosine EC 250 mg simultaneously with tenofovir DF, with or without a meal, also resulted in mean didanosine AUCs similar (P = ns) to that of reference treatment (Table III). For all methods of administration, didanosine Cmax for the 250-mg dose of didanosine EC was lower than the 400-mg dose given alone in the fasted state; however, only simultaneous coadministration with a meal resulted in a statistically significant difference in peak didanosine concentrations (P < .05).



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  		Figure 3. Mean (95% confidence interval) didanosine plasma concentration-time profiles following administration of didanosine EC 400 mg alone and upon dose reduction to 250 mg in study 2. Staggered administration is presented in the left panel; simultaneous administration, either with or without food, is presented in the right panel.

 
Safety Results
All treatments in both studies were well tolerated, with most adverse events mild or moderate in severity. Headache was the most common adverse event reported in both studies (39% and 29% of patients in studies 1 and 2, respectively), most often reported during the periods of multiple-dose administration of tenofovir DF. Other frequent adverse events included nausea, abdominal pain, diarrhea, flatulence, and mild dizziness, reported in 11% to 25% of subjects in either study. No subject discontinued either study due to adverse events; 3 subjects in study 1 withdrew consent for personal reasons. No deaths, serious adverse events, or clinically relevant changes in laboratory values attributable to study medication were observed in either study. In addition, no adverse clinical or laboratory events occurred more often or with increased severity when tenofovir DF and didanosine were given in combination versus their administration alone.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGEMENTS
 REFERENCES
 
Tenofovir DF is a preferred agent in the US Department of Health and Human Services Guidelines for the Treatment of HIV Infection26 and is indicated for use as part of antiretroviral therapy for treatment-naïve and -experienced HIV-infected adults. Due to their resistance profiles, tenofovir DF and didanosine are most often used together in treatment-experienced patients.7

In these pharmacokinetic studies, coadministration of tenofovir DF and didanosine EC at doses of 400 mg or 250 mg with and without food were well tolerated. Headache and gastrointestinal adverse events of mild to moderate severity were most frequently reported. This is not unexpected given the safety profile of these agents and the short-term dosing.

Chronically higher didanosine exposures resulting from dosing 400 mg with tenofovir DF may lead to a higher incidence in didanosine-associated adverse events, including pancreatitis.23 Thus, drug-drug and drug-food interaction studies of didanosine EC at full-dose (400 mg) and reduced dose (250 mg) were conducted to derive appropriate dosing recommendations for these agents on concurrent use. The investigation of didanosine EC 400 mg with tenofovir DF yielded similar results to those previously seen with the 400-mg dose of the buffered tablet formulation; furthermore, tenofovir pharmacokinetics was not affected by either didanosine buffered tablet or didanosine EC formulations. Importantly, this study identified that the magnitude of the increase in didanosine exposures was similar whether the dosing of didanosine EC was separated from tenofovir DF by 2 hours in these studies or by 1 hour in a previous study with buffered tablets.16,17

Study 2 demonstrated that a didanosine EC dose reduction to 250 mg administered 2 hours before tenofovir DF results in a similar didanosine AUC to that of didanosine EC 400 mg administered alone in the fasted state. In addition to evaluating this drug-drug interaction, these 2 studies also evaluated the impact of food on didanosine pharmacokinetics, as administration with a meal is known to lower its oral bioavailability. Both studies identified similar didanosine exposures dosed with or without food, indicating that food restrictions may not apply when didanosine EC is used with tenofovir DF. Also of note, the 3-way interaction of tenofovir DF, food, and the buffered tablet formulation of didanosine has not been evaluated, and thus no recommendations can be made regarding use of this dosage form with food. Similarly, while the mechanism for this interaction appears to be both postabsorption and evident 23 hours post-tenofovir DF dosing, the pharmacokinetics of didanosine upon its coadministration with tenofovir DF and meals of varying caloric and/or fat content is unknown. Kaul and colleagues have also reported that didanosine EC doses of 250 mg or 325 mg with tenofovir DF and a meal results in equivalent didanosine AUC versus administration of didanosine 400 mg alone.27 Together, these data indicate that a dose reduction of didanosine EC should be strongly considered when it is used with tenofovir DF. Didanosine dose reduction, while yielding similar systemic exposures (AUC), resulted in modestly lower didanosine Cmax levels. While these agents are prodrugs and achieve sustained intracellular concentrations of their activated forms at their site of action, patients using these agents in combination should be closely monitored for antiviral efficacy and safety when receiving this combination.7,8


   ACKNOWLEDGEMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
REFERENCES
 
Financial support for this work was provided by Gilead Sciences and Bristol-Myers Squibb. The authors wish to acknowledge the efforts of Bharat Damle, PhD, and Kirk Ryan, PharmD, in this work.

DOI: 10.1177/0091270005281351


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 

1. Naesens L, Balzarini J, Bischofberger N, De Clercq E. Antiretroviral activity and pharmacokinetics in mice of oral bis(pivaloyloxymethyl)-9-(2-phosphonylmethoxyethyl)adenine, the bis(pivaloyloxymethyl) ester prodrug of 9-(2-phosphonylmethoxyethyl)adenine. Antimicrob Agents Chemother. 1996;40: 22-28.[Abstract]

2. Srinivas RV, Robbins BL, Connelly MC, Gong YF, Bischofberger N, Fridland A. Metabolism and in vitro antiretroviral activities of bis(pivaloyloxymethyl) prodrugs of acyclic nucleoside phosphonates. Antimicrob Agents Chemother. 1993;37: 2247-2250.[Abstract/Free Full Text]

3. Robbins BL, Srinivas RV, Kim C, Bischofberger N, Fridland A. Anti-human immunodeficiency virus activity and cellular metabolism of a potential prodrug of the acyclic nucleoside phosphonate 9-R-(2-phosphonomethoxypropyl)adenine (PMPA), Bis(isopropyloxymethylcarbonyl)PMPA. Antimicrob Agents Chemother. 1998;42: 612-617.[Abstract/Free Full Text]

4. Barditch-Crovo P, Deeks SG, Collier A, et al. Phase I/II trial of the pharmacokinetics, safety, and antiretroviral activity of tenofovir disoproxil fumarate in human immunodeficiency virus-infected adults. Antimicrob Agents Chemother. 2001;45: 2733-2739.[Abstract/Free Full Text]

5. Deeks SG, Barditch-Crovo P, Lietman PS, et al. Safety, pharmacokinetics, and antiretroviral activity of intravenous 9-{2-(R)-(Phosphonomethoxy)propyl}adenine, a novel anti-human immunodeficiency virus (HIV) therapy, in HIV-infected adults. Antimicrob Agents Chemother. 1998;42: 2380-2384.[Abstract/Free Full Text]

6. Kearney BP, Gill SC, Flaherty JF, et al. Effect of demographic variables on the pharmacokinetics of tenofovir DF in HIV-infected patients and healthy subjects. Paper presented at: 41st Interscience Conference on Antimicrobial Agents and Chemotherapy; December 2001; Chicago, Ill. Abstract 504.

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8. Kearney BP, Flaherty JF, Shah J. Tenofovir disoproxil fumarate: clinical pharmacology and pharmacokinetics. Clin Pharmacokinet. 2004;43: 595-612.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

9. Knupp CA, Shyu WC, Dolin R, et al. Pharmacokinetics of didanosine in patients with acquired immunodeficiency syndrome-related complex. Clin Pharmacol Ther. 1991;49: 523-535.[Web of Science][Medline] [Order article via Infotrieve]

10. Perry CM, Balfour JA. Didanosine: an update on its antiviral activity, pharmacokinetic properties and therapeutic efficacy in the management of HIV disease. Drugs. 1996;52: 928-962.[Web of Science][Medline] [Order article via Infotrieve]

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12. Videx EC [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Co; January 2004.

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14. Damle BD, Yan JH, Behr D, et al. Effect of food on the oral bioavailability of didanosine from encapsulated enteric-coated beads. J Clin Pharmacol. 2002;42: 419-427.[Abstract]

15. Damle BD, Mummaneni V, Kaul S, Knupp C. Lack of effect of simultaneously administered didanosine encapsulated bead formulation (Videx EC) on oral absorption of indinavir, ketoconazole, or ciprofloxicin. Antimicrob Agents Chemother. 2002;46: 385-391.[Abstract/Free Full Text]

16. Kearney BP, Flaherty JF, Sayre JR, Wolf JJ, Coakley DF. A multiple-dose, randomized, crossover drug interaction study between tenofovir DF and lamivudine or didanosine. Paper presented at: First International AIDS Society Conference on HIV Pathogenesis and Treatment; July 2001; Buenos Aires, Argentina. Abstract 337.

17. Flaherty J, Kearney B, Wolf J, et al. Co-administration of tenofovir DF and didanosine: a pharmacokinetic and safety evaluation. Paper presented at: 41st Interscience Conference on Antimicrobial Agents and Chemotherapy; December 2001; Chicago, Ill. Abstract 1729.

18. Jung D, Griffy K, Dorr A. Effect of high-dose oral ganciclovir on didanosine disposition in human immunodeficiency virus (HIV)-positive patients. J Clin Pharmacol. 1998;38: 1057-1062.[Abstract/Free Full Text]

19. Cimoch PJ, Lavelle J, Pollard R, et al. Pharmacokinetics of oral ganciclovir alone and in combination with zidovudine, didanosine, and probenecid in HIV-infected subjects. J Acquir Immune Defic Syndr Hum Retrovirol. 1998;17: 227-234.[Web of Science][Medline] [Order article via Infotrieve]

20. Boelaert JR, Dom GM, Huitema AD, Beijnen JH, Lange JM. The boosting of didanosine by allopurinol permits a halving of the didanosine dosage. AIDS. 2002;16: 2221-2223.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

21. Kaul S, Shyu WC, Shukla UA, Dandekar KA, Barbhaiya RH. Absorption, disposition, and metabolism of {14C}didanosine in the beagle dog. Drug Metab Dispos. 1993;21: 447-453.[Abstract]

22. Ray AS, Olson L, Fridland A. Role of purine nucleoside phosphorylase in interactions between 2',3'-dideoxyinosine and allopurinol, ganciclovir, or tenofovir. Antimicrob Agents Chemother. 2004;48: 1089-1095.[Abstract/Free Full Text]

23. Grasela TH, Walawander CA, Beltangady M, et al. Analysis of potential risk factors associated with the development of pancreatitis in Phase I patients with AIDS or AIDS-related complex receiving didanosine. J Infect Dis. 1994;168: 1250-1255.

24. Kearney BP, Ramanathan S, Cheng AC, Ebrahimi R, Shah J. Systemic and renal pharmacokinetics of adefovir and tenofovir upon coadministration. J Clin Pharmacol. 2005;45: 935-940.[Abstract/Free Full Text]

25. Chow S-C, Liu J-P. Design and Analysis of Bioavailability and Bioequivalence Studies. New York: Marcel Dekker; 1992.

26. US Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Updated October 28, 2004. Washington, DC: US Department of Health and Human Services.

27. Kaul S, Damle B, Bassi K, et al. Pharmacokinetic evaluation of reduced doses of didanosine enteric coated capsules (ddI-EC) in combination with tenofovir disoproxil fumarate (TDF) and food for a once-daily antiretroviral regimen. Paper presented at: The Fourth International Workshop on Clinical Pharmacology of HIV Infection; 2003; Cannes, France. Abstract 8.1.
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